neurotransmitter receptor hypothesis of depression

Neurobiology of Depression

• First Online: 03 February 2022

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• Hernán Silva 7  

Part of the book series: Depression and Personality ((DP))

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Hypotheses about the pathophysiology of depression have evolved over time. This chapter covers the most important findings in this regard. First, the classical monoamine hypothesis posited that depression is caused by an alteration in levels of one or more of the monoamines: serotonin, norepinephrine, and dopamine. More recently, research on the glutamatergic system has aroused great interest by examining the mechanism of action of ketamine, an N-methyl-D-aspartic acid (NMDA) receptor antagonist. Likewise, stressful life events can precipitate depressive episodes in vulnerable individuals. Abnormalities in the HPA axis have been associated with a hyperactive response to stress in depressed patients (the diathesis-stress model). Increased levels of inflammatory markers have been found in patients with depression and anti-inflammatory agents are being studied as antidepressants. Reduced production of BDNF and neuroplasticity can lead to depression. These pathophysiological mechanisms are reciprocally connected with each other. Major Depression is a heterogeneous entity and a variety of biological mechanisms may be involved.

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Department of Psychiatry, North Campus, Faculty of Medicine, University of Chile, Santiago, Chile

Hernán Silva

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Department of Psychiatry and Mental Health East, Faculty of Medicine, University of Chile, Millennium Institute for Research in Depression and Personality (MIDAP), Santiago, RM, Chile

Juan Pablo Jiménez

Alberto Botto

Research Department of Clinical Educational and Health Psychology, University College London, London, UK

Peter Fonagy

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Silva, H. (2021). Neurobiology of Depression. In: Jiménez, J.P., Botto, A., Fonagy, P. (eds) Etiopathogenic Theories and Models in Depression. Depression and Personality. Springer, Cham. https://doi.org/10.1007/978-3-030-77329-8_8

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The receptor hypothesis and the pathogenesis of depression: Genetic bases and biological correlates

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• 1 Hunan University of Chinese Medicine & Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha 410208, Hunan, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
• 2 State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
• 3 Hunan University of Chinese Medicine & Hunan Engineering Technology Center of Standardization and Function of Chinese Herbal Decoction Pieces, Changsha 410208, Hunan, China; State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. Electronic address: [email protected].
• PMID: 33711432
• DOI: 10.1016/j.phrs.2021.105542

Depression has become one of the most prevalent neuropsychiatric disorders characterized by anhedonia, anxiety, pessimism, or even suicidal thoughts. Receptor theory has been pointed out to explain the pathogenesis of depression, while it is still subject to debate. Additionally, gene abnormality accounts for nearly 40-50% of depression risk, which is a significant factor contributing to the onset of depression. Accordingly, studying on receptors and their gene abnormality are critical parts of the research on internal causes of depression. This review summarizes the pathogenesis of depression from six of the most related receptors and their associated genes, including N-methyl-D-aspartate receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, glucocorticoid receptor, 5-hydroxytryptamine receptor, GABA A receptor α2, and dopamine receptor; and several "non-classic" receptors, such as metabotropic glutamate receptor, opioid receptor, and insulin receptor. These receptors have received considerable critical attention and are highly implicated in the onset of depression. We begin by providing the biological mechanisms of action of these receptors on the pathogenesis of depression. Then we review the historical and social context about these receptors. Finally, we discuss the limitations of the current state of knowledge and outline insights on future research directions, aiming to provide more novel targets and theoretical basis for the early prevention, accurate diagnosis and prompt treatment of depression.

Keywords: Depression; Gene abnormality; Pathogenesis; Receptors; Review.

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• Open access
• Published: 13 September 2024

Permethrin exposure primes neuroinflammatory stress response to drive depression-like behavior through microglial activation in a mouse model of Gulf War Illness

• Sean X. Naughton 1   na1 ,
• Eun-Jeong Yang 1   na1 ,
• Umar Iqbal 1 ,
• Kyle Trageser 1 ,
• Daniel Charytonowicz 2 ,
• Sibilla Masieri 1 ,
• Molly Estill 3 ,
• Henry Wu 1 ,
• Urdhva Raval 1 ,
• Weiting Lyu 4 ,
• Qing-li Wu 4 ,
• Li Shen 3 ,
• James Simon 4 ,
• Robert Sebra 2 &
• Giulio Maria Pasinetti 1 , 5  

Journal of Neuroinflammation volume  21 , Article number:  222 ( 2024 ) Cite this article

Metrics details

Gulf War Illness (GWI) is a chronic multisymptom disorder that affects approximately 25–32% of Gulf War veterans and is characterized by a number of symptoms such as cognitive impairment, psychiatric disturbances, chronic fatigue and gastrointestinal distress, among others. While the exact etiology of GWI is unknown, it is believed to have been caused by toxic exposures encountered during deployment in combination with other factors such as stress. In the present study we sought to evaluate the hypothesis that exposure to the toxin permethrin could prime neuroinflammatory stress response and elicit psychiatric symptoms associated with GWI. Specifically, we developed a mouse model of GWI, to evaluate the effects of chronic permethrin exposure followed by unpredictable stress. We found that subjecting mice to 14 days of chronic permethrin exposure followed by 7 days of unpredictable stress resulted in the development of depression-like behavior. This behavioral change coincided with distinct alterations in the microglia phenotype, indicating microglial activation in the hippocampus. We revealed that blocking microglial activation through Gi inhibitory DREADD receptors in microglia effectively prevented the behavioral change associated with permethrin and stress exposure. To elucidate the transcriptional networks impacted within distinct microglia populations linked to depression-like behavior in mice exposed to both permethrin and stress, we conducted a single-cell RNA sequencing analysis using 21,566 single nuclei collected from the hippocampus of mice. For bioinformatics, UniCell Deconvolve was a pre-trained, interpretable, deep learning model used to deconvolve cell type fractions and predict cell identity across spatial datasets. Our bioinformatics analysis identified significant alterations in permethrin exposure followed by stress-associated microglia population, notably pathways related to neuronal development, neuronal communication, and neuronal morphogenesis, all of which are associated with neural synaptic plasticity. Additionally, we observed permethrin exposure followed by stress-mediated changes in signal transduction, including modulation of chemical synaptic transmission, regulation of neurotransmitter receptors, and regulation of postsynaptic neurotransmitter receptor activity, a known contributor to the pathophysiology of depression in a subset of the hippocampal pyramidal neurons in CA3 subregions. Our findings tentatively suggest that permethrin may prime microglia towards a state of inflammatory activation that can be triggered by psychological stressors, resulting in depression-like behavior and alterations of neural plasticity. These findings underscore the significance of synergistic interactions between multi-causal factors associated with GWI.

Introduction

A significant proportion of veterans who have experienced deployment face the debilitating effects of depression upon their return to civilian life [ 1 ]. Several studies indicate that the prevalence of depression is notably higher among deployed veterans compared to the general population, underscoring the urgent need for targeted interventions and support services to address the mental health needs of this vulnerable group [ 2 ]. Following their return from deployment, veterans initially appeared healthy [ 3 ]. Still, over time, various health problems emerged, with research identifying traumatic brain injury, social isolation, and psychological stress as key factors contributing to the development and persistence of depressive symptoms [ 3 , 4 ]. Understanding the complex interplay between deployment-related stressors and depressive symptomatology is crucial for developing effective prevention and treatment strategies tailored to the unique needs of this demographic.

Gulf War Illness (GWI) is a term used to describe a range of chronic and often debilitating symptoms reported by veterans who served in the 1990–1991 Gulf War (GW). At least 25% of Gulf War veterans have reported symptoms such as significant mood disturbances and neurological issues, fatigue, musculoskeletal pain, cognitive problems, respiratory difficulties, gastrointestinal issues, and rashes [ 5 ]. Exposure to GW-related chemicals, such as pyridostigmine bromide (a drug used to protect against nerve agents like sarin gas), N, N-diethyl-m-toluamide, and pyrethroid insecticides, has been linked to the development of GWI [ 6 ]. Pyrethroids, including permethrin, were applied by soldiers to their skin and uniforms every 4–5 days using a 0.5% spray, with reported usage significantly exceeding the recommended guidelines [ 7 ]. Permethrin exposure is currently recognized as a potential factor contributing to the onset of GWI [ 8 , 9 ]. The primary mechanism of action for permethrin involves binding to voltage-gated sodium channels (VGSCs), leading to prolonged opening and alterations in neuronal firing [ 10 , 11 , 12 ]. Previous studies have shown that pyrethroids, which can cross the blood-brain barrier (BBB), can stimulate microglial activation by interacting with VGSCs in microglia [ 13 ]. This interaction can lead to an excessive accumulation of intracellular sodium ions and the release of major pro-inflammatory cytokines, such as tumor necrosis factor-alpha in microglia [ 13 ].

The delay between their deployment and the onset of persistent fatigue, problems, affective psychological disorders such as depression, and cognitive dysfunctions, among others, has made it difficult for the medical community to target a common underlying mechanism primarily related to the mental health of the disorder accurately [ 3 ]. Clinical research has recently reported that immune dysfunction and chronic inflammation play significant roles in the symptoms experienced by affected veterans [ 14 ]. Both the central nervous system and peripheral immune system are implicated in the pathogenesis of GWI, as observed in rodent models [ 15 ]. Microglia play a crucial role in neuroinflammation by initiating a range of inflammatory responses upon activation, including the release of pro-inflammatory cytokines and alterations to the neuronal environment [ 16 ]. In particular, microglia have been observed to adapt their morphology and function to support neurons through various mechanisms: releasing soluble factors that modulate neurotransmission, phagocytosing damaged dendritic elements, and facilitating synaptic plasticity [ 17 ]. This dynamic interaction between microglia and neurons has been increasingly recognized as a critical factor in the onset and progression of depression [ 18 ]. Hence, a comprehensive understanding of the molecular mechanisms behind these immune responses in the brain under GW-related conditions is vital for advancing the development of biomarkers and therapies that address symptoms and neuropathology of GWI, especially about depression.

The impact of prolonged exposure to permethrin, particularly when combined with GW-related chemicals, has been shown to affect neurological outcomes and other CNS-related symptoms in preclinical studies [ 19 ]. In order to better understand the nature of these neurological changes associated with exposure to GWI, it is essential to develop models that not only replicate the diverse chemicals and conditions of GW deployment but also account for potential interactions among physiological and psychological stressors. Thus, a comprehensive approach is crucial to identify causal factors and develop effective therapeutic strategies. In the present study, we sought to simulate GWI-like conditions in mice by administering permethrin followed by unpredictable stress to evaluate the combined effects on neuroinflammation caused by microglial activation, neural activity, and neurophysiological impairments and to uncover the underlying mechanistic factors in GWI.

Materials and methods

All of the experimental procedures were approved by the Animal Care Committee of Icahn School of Medicine at Mount Sinai (Approval number: IACUC-2019-0043). Mice, including C57BL/6 (WT), Cx3Cr1 CreEr (strain: 021160), and hM4Di (Designer Receptors Exclusively Activated by Designer Drugs (DREADD), R26-hM4Di/mCitrine, (strain: 026219)), were procured from the Jackson Laboratory. Crossbreeding was conducted between Cx3Cr1 CreEr mice and transgenic mice expressing cre recombinase-inducible hM4Di-DREADD, aiming to establish consistent expression of Gi inhibitory receptors on microglia [ 20 ]. Double transgenic mice were identified by PCR as recommended by Jackson Laboratory, while nontransgenic littermates were employed as age-matched controls. For genotyping, the primers were used (Cx3Cr1 CreEr ;mutant reverse; 5′-CGGTTATTCAACTTGCACCA-3′, WT reverse; 5′-GGATGTTGACTTCCGAGTTG − 3′, and common forward; 5′-AAGACTCACGTGGACCTGCT-3′, R26-hM4Di/mCitrine; mutant reverse; 5′-TCATAGCGATTGTGGGATGA-3′, mutant forward; 5′-CGAAGTTATTAGGTCCCTCGAC-3′, WT reverse; 5′-CCGAAAATCTGTGGGAAGTC-3′, and WT forward; 5′-AAGGGAGCTGCAGTGGAG TA-3. WT mice were used in all experiments except for Fig.  2 D, which specifically displays data from Cx3Cr1 CreEr /hM4Di-DREADD mice. Each cage ( N  = 4–5 mice) was housed under a 12-hour light/dark cycle, with lights on from 07:00 to 19:00 h, maintaining a steady temperature of 23 °C in a room with water and a standard rodent chow diet (LabDiet, MO, USA,5053). They had unrestricted access to food and water. The Institutional Animal Care and Use Committee (approval number: IACUC-2019-0043) at the Icahn School of Medicine at Mount Sinai approved all protocols that complied with NIH guidelines. Female mice were excluded from this study because stress-induced behavioral deficits vary by sex and require different behavioral paradigms to produce comparable stress-induced behavioral and immunological outcomes [ 21 ]. As a result, the conclusions of this study are limited to male mice.

Permethrin pharmacokinetic studies

C57BL/6J mice ( N  = 5 per each group) were administered an acute dose of 200 mg/kg permethrin and sacrificed at 0, 2, 4, 18, 24, 28, 30, or 48 h post-treatment. Additionally, an untreated control group was included to validate analytical detection. Blood was collected via cardiac puncture, and the animals were immediately perfused with ice-cold PBS. Brains were then collected and homogenized in 0.2% formic. All blood and homogenized tissue samples were promptly snap-frozen and stored at -80 °C until further processing.

Analytical method

Three internal standards (ISs), 13C6-trans-permethrin (50 µg/mL), 13C6-cis-permethrin (50 µg/mL), and 13C6-3-phenoxybenzoic acid (100 µg/mL), were dissolved in nonane and mixed, then diluted in acetone to make the final concentration of 13C6-trans-permethrin, 13C6-cis-permethrin, and 13C6-3-phenoxybenzoic acid was 33 ng/mL, 33 ng/mL, and 67 ng/mL, respectively. The combined organic phases were evaporated to dryness under nitrogen before reconstitution for LC-MS/MS analysis. The residue was reconstituted in 400 µL of acetonitrile and centrifuged at 16,500 xg for 10 min. For each sample extract, 1 µL was injected into an UPLC-QqQ/MS system for analysis under dynamic multiple reaction monitoring mode in duplicate.

LC-MS method

The instrument used for chemical analysis was an Agilent 1290 Infinity II UHPLC (Agilent Technology, CA, USA) hyphenated with 6470 triple quadrupole mass spectrometry with electrospray ionization source (ESI) (Santa Clara, CA, USA). Agilent MassHunter Optimizer (version B.07.00) was used for standard compound-related parameters optimization, and MassHunter Workstation software Data Acquisition (version B.08.00) and Quantitative Analysis (version B.07.01) were used for data processing. The columns used for compound separation were AcquityTM Premier HSS T3 C18 VanGuardTM FIT (2.1 × 100 mm, 1.8 μm). For the chromatographic part, mobile phase A was water, and mobile phase B was methanol; both mobile phases were modified with 10 mM ammonium acetate. The compounds were separated using a gradient program. The mass spectrometer operated in the positive ionization mode for permethrin and the negative ionization mode for 3-PBA. WinNonlin professional software version 8.0 (Pharsight, CA, USA) was used to calculate the pharmacokinetic parameters. The peak plasma or brain concentration (C max ) and the peak time (T max ) were expressed as the mean ± SEM.

Animal treatments

As previously established for permethrin exposure [ 19 , 22 ], mice aged 7–8 weeks of the C57/BL6J strain ( N  = 9–10 per group) were randomly allocated to treatment cohorts. They were administered either permethrin (200 mg/kg in 5% DMSO in corn oil, Sigma-Aldrich, MO, USA) or vehicle (5% DMSO in corn oil) via intraperitoneal injection for 14 days. Following this treatment period, mice were exposed to unpredictable or no stress for 7 days. Behavioral testing took place on the subsequent day (day 22), followed by euthanasia of the animals on the same day. To inhibit microglia activation, Cx3Cr1 CreEr /hM4Di-DREADD mice were treated with JHU37160 (Tocris Bioscience, Bristol, UK, 7198/50) for 14 consecutive days.

Unpredictable stress exposure

Consistent with our ongoing study and published experiment [ 23 ], mice were exposed to random, unpredictable stress for 7 days, which is insufficient to induce depression-like behavior. The unpredictable stress paradigm involved subjecting animals to two stressors daily, administered separately in the morning (10:00–11:00) and evening sessions (17:00–18:00) (Table  1 ). Briefly, stressors included wet bedding for 6 h, placing cages on an orbital shaker for 20 min, exposure to hot air (via a hair dryer) for 10 min, tilting cages at a 45° angle for overnight, forced restraint for 60 min, cold water exposure for 5 min, no bedding for 6 h, overnight water restriction, and exposure to light during the dark cycle.

Behavioral tests

Before initiating behavioral testing, all animals were introduced into the behavioral testing room and given one hour to acclimate in their respective home cages. We performed the Open Field Test (OFT) first, followed by the Forced Swim Test (FST) on the same day. A rest period of 2 h was provided between the two behavioral assessments. The behavioral session was recorded via a near-infrared camera and analyzed using ANY-maze™ tracking software (Stoelting Co., IL, USA). Each test employed established protocols, detailed below:

As previously established [ 24 ], mice( N  = 9–10 per group) were positioned within a plastic square enclosure measuring 40 cm × 40 cm × 38 cm for 15 min to measure anxiety-like behavior. The behavioral session was captured on the video camera and analyzed using ANY-maze™ software. Quantification of anxiety-like behavior involved measuring the total time spent along the edges and corners of the box, as well as the time spent in the center of the open field.

As previously established [ 25 ], mice ( N  = 9–10 per group) were introduced into a large 4 L beaker filled with clean water at approximately 21 °C for 6 min to assess depressive-like behavior. The total duration of immobility, defined as the absence of movement in all four limbs, was measured using ANY-maze software.

Tissue preparation

After completing the exposure paradigm and behavioral testing, mice were randomly assigned for use in immunohistochemistry or molecular studies. For Immunohistochemistry studies, mice were euthanized by administering 100 mg/kg ketamine and 10 mg/kg xylazine, followed by intracardiac perfusion with 1× phosphate-buffered saline (PBS), followed by perfusion with 4% paraformaldehyde (PFA). The brain tissue was fixed in 4% PFA for 24 h for subsequent immunohistochemistry. For mice used in molecular studies mice were euthanized by administering 100 mg/kg ketamine and 10 mg/kg xylazine, followed by thoracotomy. Brain tissues, were dissected into the hippocampus for single-nucleus sequencing or Olink assays. All samples were stored at − 80 °C–4 °C until further analysis.

Immunohistochemistry

Fixed brains ( N  = 4–6 per group) were immersed in 4% PFA and subsequently dehydrated in PBS. Brain Section (50 μm) underwent washing with PBS, permeabilization with PBS + 0.2% Triton X-100 (PBST), and blocking with 2% normal goat serum in PBST. Ionized calcium-binding adaptor molecule 1(IBA-1,1:1000, Ab178846, Abcam, MA, USA) was applied and incubated overnight at 4 °C in PBST with 2% normal goat serum. Following rinsing, brain sections were treated with Alexa Fluor 568-labeled (1:500 in 2% normal goat serum in PBST) for 1 h at room temperature. Brain sections were then washed, mounted, and coverslipped on microscope slides. Imaging was conducted using a Zeiss LSM 880 Confocal Microscope (Zeiss, DE, Germany). Microscopy and image analysis were performed at the Microscopy CoRE at the Icahn School of Medicine at Mount Sinai.

Sholl analysis

To assess the complexity of each cell, a Sholl analysis was conducted [ 26 ]. The determination of soma volume, branch length, number of terminal points, and number of intersection segments in brain sections from the hippocampus and prefrontal cortex (PFC) was conducted utilizing IMARIS 9.1.2 (Bit Plane Inc, MA, USA). The analysis encompassed the following steps: In 3D analysis, z-stack confocal images underwent processing using AutoQuant X3.1 (Media Cybernetics, MD, USA) to eliminate blurriness, followed by analysis with IMARIS. The surface tool was utilized to reconstruct the cell bodies (somas) of the microglia, whereas the filaments tool was employed to reconstruct the branches. One microglial cell was chosen per total process area, and its cell body and soma were traced along with the surface and filament for each process. The quantification involved determining the number of primary processes and branch tips. Each image selected one microglial cell per 0.045 µm 2 , with concentric circles drawn from the soma at 5 μm spacing to measure the intersections of each cell with each circle. Soma volume, branch length, number of terminal points, and number of intersection segments were quantified, and averages were determined among samples within the same group. The analysis encompassed 4 to 6 mice (2–4 tissue sections per mouse and 4–10 microglia per section) per group, conducted by a single investigator, while an independent evaluator performed the quantification analysis in a blinded manner, utilizing code to conceal knowledge of the experimental groups.

Single nuclei sequencing (scRNA-Seq)

Single nuclei suspensions were processed using the 10X Genomics Chromium NEXT Gem Single Cell 3’ v3.1 kit, targeting 6000 cells per sample ( N  = 1 per group). The resulting libraries were sequenced on a NovaSeq 6000, targeting 50,000 reads per single nucleus. Sequenced reads were processed and aligned to < Genome > using the 10X Genomics Cellrange r toolkit. The resulting raw counts matrices were further preprocessed using the scanpy 1.8.2 package. In brief, raw unique molecular identifier (UMI) count matrices for four experimental samples were passed through cellbender 0.2.0 , for the purposes of filtering out empty droplets and reducing background noise stemming from ambient RNA. The relevant parameter settings for each sample for cellebender as follow; Vehicle-no stress; expected cell:10,000;Total Droplets Included:20,000; False Positive Rate:0.1; Epochs:100, Vehicle-stress; expected cell:12,434;Total Droplets Included:15,000; False Positive Rate:0.01; Epochs:100, Permethrin-no stress; expected cell:4212;Total Droplets Included:10,000; False Positive Rate:0.01; Epochs:100, Permethrin-stress; expected cell:3368;Total Droplets Included:10,000; False Positive Rate:0.01; Epochs:100. Following successful droplet filtering and ambient RNA removal, scrublet 0.2.3 was used with default configuration parameters to detect and remove cellular doublets. Quality control metrics were calculated for each cell and gene across all samples, including the calculation of percentage of count deriving from mitochondrial (mt), hemoglobin (hb), and ribosomal (ribo) genes (Supplementary Fig.  1 ). On a per-sample basis, outlier cells were identified on the basis of any one of the following metrics falling outside 5-times the median absolute deviation: log1p_total_counts , log1p_n_genes_by_counts , pct_counts_in_top_20_genes , pct_counts_mt , pct_counts_hb , and pct_counts_ribo . Lastly, genes expressed in less than 20 cells were filtered out. In total, 21,566 cells and 21,545 genes remained after filtering. Total counts per cell were normalized to 1e 4 , with data scaled to log-plus-one. The scanpy function sc.pp.highly_variable_genes was used to calculate highly variable genes, with a minimum mean of 0.0125, a maximum mean of 3, and a minimum dispersion of 0.5. The effects of pct_counts_mt and total_counts were regressed out using the scanpy function sc.pp.regress_out . Following this, each genes expression was re-scaled to zero mean and one standard deviation. Dimensionality reduction was initiated utilizing Principle Components Analysis (PCA), retaining the top 75 components for downstream analysis. The four samples were integrated utilizing the harmonypy 0.0.5 python package, with convergence after two iterations. The resulting adjusted PCA matrix was used to calculate a nearest neighborhood graph with the function sc.pp.neighbors , with n_neighbors set to 15. UMAP was run using min_dist set to 0.05, followed by unsupervised clustering using leiden with resolution set to 1.0.

Cell type annotation

UniCell Deconvolve ( ucdeconvolve 0.1.2) was utilized to perform label transfer for cell type annotations. In brief, the allen-mouse-cortex prebuilt reference atlas was utilized as a reference atlas to annotate cell types using the function ucd.tl.select with default parameters. The resulting predictions were mapped to each cell type using the function ucd.utils.assign_top_celltypes , with the groupby parameter set to a higher-resolution unsupervised leiden cluster assignment with resolution set to 4.0.

Following cell type assignment, top differentially expressed genes for each celltype were identified using the scanpy function sc.tl.rank_genes_groups with default parameters.

Gene set enrichment analysis

Differentially expressed genes were calculated using the scanpy function sc.tl.rank_genes_groups , with groupby set to each sample, use_ raw set to True, and reference set to the control sample VEH_NS-18-HIP . For each non-control sample, we extracted the top 500 differentially expressed genes. Subsequently, the gseapy 1.0.3 package was used to query enrichr for the GO_Biological_Process_2021 and GO_Molecular_Function_2021 gene sets, with organism set to mus musculus.

Olink assay

As previously established [ 27 ], protein lysates were prepared from flash-frozen brain samples at a concentration of 1 mg/mL ( N  = 7–9 per group) using Protein Extraction Reagent (Thermo Scientific, 89900) supplemented with protease inhibitors (Thermo Scientific, 78440). Subsequently, all samples underwent analysis using the Olink ® Target 96 Mouse Exploratory Assay (Olink proteomics, MA, USA, 95380). Following this, the samples were sent to the Mount Sinai Human Immune Monitoring Center for assay execution and data collection. The results obtained for the analyzed protein biomarkers were provided in Normalized Protein eXpression (NPX) units.

Statistical analysis

Statistical analysis was conducted, and all data are presented as mean ± SEM. The data were analyzed using two-way ANOVA followed by Tukey’s post hoc analysis (* p  < 0.05, ** p  < 0.01, *** p  < 0.001, **** p  < 0.0001,). GraphPad Prism 8 software (GraphPad Software Inc., CA, USA) was utilized for all statistical analyses.

Permethrin is brain-penetrant and bioavailable

To confirm the permeability of permethrin through the BBB and characterize its temporal properties after exposure, we conducted pharmacokinetic analysis by evaluating parameters such as time of maximum concentration (T max ), the maximum drug concentration (C max ), and area under concentration-time curve (AUC). The time courses of permethrin, comprising a combination of cis- and trans-isomers, along with primary metabolite 3-phenoxybenzoic acid (3-PBA), were assessed in both plasma (Fig.  1 A, B and C) and brain (Fig.  1 D, E and F) over a 48-hour period following a single injection of 200 mg/kg permethrin. We first observed a “double-peak” phenomenon in both plasma and the brain at 2 h and 24 h (Fig.  1 ). Notably, the plasma exhibited a distinctly double-peak curve, a characteristic often associated with entero-hepatic recycling (Fig.  1 A, B and C). This result indicates an increased elimination half-life, contributing to the extended action of permethrin in plasma and brain. The average plasma concentrations of cis- and trans- permethrin reached their peak at 24 h (Fig.  1 A and B). Cis-permethrin displayed a C max of 12655.89 ± 2646.10nM (Fig.  1 B), and trans-permethrin exhibited a C max of 9025.79 ± 3351.66 nM (Fig.  1 A) in the plasma. In contrast, the mean brain concentrations of cis- and trans-permethrin peaked at approximately 2 h, indicating penetration of cis- and trans-permethrin into the brain occurs rapidly (Fig.  1 D and E). For cis-permethrin, the mean C max in the brain was 20637.85 ± 4786.71 nM (Fig.  1 E), and for trans-permethrin, it was 20878.55 ± 3137.16 nM (Fig.  1 D), both of which were higher than the concentrations observed in plasma. Additionally, we analyzed 3-PBA, the primary metabolite of permethrin, considering its rapid metabolism in the liver. As anticipated, a higher C max (Figs.  1 C and 68951.01 ± 12672.51 nM) was observed in the plasma. However, in the brain, the C max of 3-PBA was found to be significantly lower than in the plasma (Figs.  1 F and 668.43 ± 53.35 nM). Notably, we observed a sustained accumulation of 3-PBA in the brain parenchyma extending beyond 48 h. After reaching their peak concentrations, the mean concentration-time profiles of cis-permethrin, trans-permethrin, and 3-PBA indicated a steady decline over a period of 48 h. These findings suggest that both cis- and trans-permethrin rapidly entered the brain from periphery, achieving higher concentrations and indicating a concentrated distribution within the brain.

Brain and Plasma Concentrations over time. ( A ) Plasma levels of trans-Permethrin reached a maximum concentration at 24 h after acute injection (I.P.) of 200 mg/kg of permethrin. ( B ) Plasma levels of cis-Permethrin also reached a maximum concentration at 24 h. ( C ) Similarly, plasma levels of the permethrin metabolite 3-PBA reached a maximum concentration 24 h after injection. ( D ) Brain tissue levels of trans-Permethrin reached a maximum concentration at 2 h after acute injection. ( E ) Brain tissue levels of cis-Permethrin also reached a maximum concentration at 2 h after acute. ( F ) Brain tissue levels of the permethrin metabolite 3-PBA reached a maximum concentration at 24 h after acute injection. In each group, there were 5 mice, and for brain tissue, 2 replicates (separate brain hemispheres) were utilized per time point. The data are presented as means ± SEM

Permethrin exposure primes the onset of depression-like behavior under stress through microglia activation

To examine the effects of permethrin exposure as a priming factor, mice were exposed to permethrin (200 mg/kg) or a vehicle control for 14 days (Fig.  2 A). Mice were subsequently subjected to either stress or gentle handling (no stress) for 7 days (Fig.  2 A). Following our experimental protocol, anxiety-like behaviors and locomotion activity were evaluated using the OFT (Fig.  2 B), while depressive-like behavior was assessed through the FST (Fig.  2 C and D) to examine neuropsychological responses. There were no significant changes in the distance traveled, which is a measure of locomotion activity, or in the time spent in the center zone, which is indicative of anxiety-like behavior, across all experimental groups (Fig.  2 B). In the FST, neither permethrin exposure nor stress exposure alone led to observable behavioral alterations in immobility time when compared to non-stressed mice treated with the vehicle (Fig.  2 C). Interestingly, mice subjected to stress and treated with permethrin exhibited a significant increase in the time spent immobile, in comparison to all other experimental groups (Fig.  2 C, * p  < 0.05, ** p  < 0.01, *** p  < 0.001). This finding suggests that exposure to permethrin acts as a priming factor in the brain, subsequently leading to depression-like behavior in mice under these specific conditions when stress is introduced.

Permethrin primes stress response to induce depressive-like behavior. ( A ) Experimental scheme. ( B - C ) Exposure to permethrin followed by stress induced depressive ( C ) but not anxiety-like ( B , right panel) behaviors as measured via forced swim and open field tests respectively. ( B , left panel) Bar graphs showed locomotion activity with no alterations among all experimental groups. ( D ) Cx3Cr1 CreeEr /hM4Di-DREADD mice expressing the Gi receptor on microglia were used to demonstrate that microglial inhibition via selective ligand JHU 37,160 is sufficient to prevent behavioral changes resulting from permethrin and stress exposure. Statistical analyses were performed using Two-Way ANOVA (* p  < 0.05, ** p  < 0.01, *** p  < 0.001, **** p  < 0.001, compared to permethrin exposure followed by stress). In each group, there were13 mice and each dot represents an individual mouse. Data are expressed as the means ± SEM

Next, we utilized Cx3cr1 CreER/WT : R26 LSL − hM4Di/WT mice to explore the impact of permethrin-induced microglia priming on the observed depression-like behavior. This mouse model is designed to selectively express Gi-inhibitory receptors (Gi-DREADDs) in microglia, controlled by the inducible Cx3cr1 promoter. Mice underwent daily treatment with 0.1 mg/kg of JHU 37160, a novel DREADD agonist known for selectively activating the Gi inhibitory signaling pathway in microglia, throughout the initial 14-day period of permethrin exposure (Fig.  2 A). Following this treatment phase, the mice were then subjected to 7 days of stress, and then the FST was performed (Fig.  2 A). The observed results were consistent with previous behavioral tests (Fig.  2 C), indicating that mice exposed to stress and treated with permethrin displayed a notable increase in the time spent immobile (Fig.  2 D, **** p  < 0.0001). Notably, treatment with JHU 37160 during permethrin exposure effectively blocked depressive like-behavior in the FST (Fig.  2 D, *** p  < 0.01). These result indicates that microglia activation is a key mediator of the depressive-like behavior following exposure to permethrin followed by stress.

Permethrin exposure, followed by stress, induces regional differences in the pleomorphic response of microglia cells

Pro-inflammatory microglia have been observed to undergo deramification, a process characterized by the retraction of their processes, diminished microglial complexity, and the release of inflammatory cytokines [ 28 ]. In order to further investigate the morphometric changes in microglial cells resulting from exposure to permethrin followed by stress, we conducted a detailed analysis of morphology encompassing parameters such as soma volume, branch length, the number of terminal points, and the number of intersecting segments. Additionally, we conducted a comparative analysis across the hippocampus and PFC to assess regional differences in microglial alterations.

Interestingly, the volume of microglia in hippocampus significantly decreased in mice subjected to both permethrin treatment and stress compared to mice exposed only to permethrin (Fig.  3 A and B, ** p  < 0.01). In addition, the mice subjected to permethrin treatment and stress showed a significant decrease in the branch length of microglial processes (Fig.  3 A and C, * p  < 0.05, ** p  < 0.01), accompanied by a noticeable reduction in the number of terminal points in hippocampus (Fig.  3 A and D, * p  < 0.05). Sholl analysis further revealed that microglia from the group exposed to both permethrin and stress exhibited fewer and less expansive branches compared to other experimental groups (Fig.  3 E). Additionally, quantification of the area under the curve further confirmed the significant decrease in microglial branching caused by permethrin and stress (Fig.  3 E and F, * p  < 0.05, ** p  < 0.01). However, no discernible morphological alterations were observed in microglia in the PFC, encompassing soma volume (Fig.  3 G and H), branch length (Fig.  3 G and I), terminal points (Fig.  3 G and J), intersection of segments (Fig.  3 G and K) and area under cover (Fig.  3 G and L).

Alterations in microglial morphology induced by permethrin and stress in brain, specifically in the hippocampus prefrontal cortex. ( A ) Representative immunofluorescence images of IBA-1+ (red) cells in hippocampus. ( B - D ) Bar graphs represented soma volume ( B ), branch length ( C ) and number of terminal points ( D ) per microglia in hippocampus. ( E - F ) Sholl analysis showed that microglia in the group exposed to both permethrin and stress displayed reduced branching complexity compared to other experimental groups. ( E ) Link graph showed the quantification of the number of intersections at increasing radii, with measurements taken at 5 μm intervals. ( F ) Bar graph represented the Area Under the Curve (AUC) of the line graphs shown in ( E ). ( G ) Representative immunofluorescence images of IBA-1 + cells in prefrontal cortex. ( H - J ) Sholl analysis showed that microglia in the prefrontal cortex exhibited no apparent morphological changes. Bar graphs represented soma volume ( H ), branch length ( I ) and number of terminal points ( J ) per microglia in prefrontal cortex. ( K ) Link graph showed the quantification of the number of intersections in the prefrontal cortex. ( L ) Bar graph represented the AUC of the line graphs. The area outlined with a white box in the top panel is magnified in the middle panel. The bottom panel shows representative images of three-dimensional (3D) reconstructions of microglia from the middle panel Scale bars indicate 50 (top panel) and 5 (middle and bottom panel) um. Statistical analyses were performed using Two-Way ANOVA (* p  < 0.05, ** p  < 0.01, compared to permethrin exposure followed by stress. In each group, there were 4-5mice and each dot represents an individual mouse. Data are expressed as the means ± SEM

These findings underscore the importance of regional specificity in understanding neuroinflammatory responses, particularly in the hippocampus, where permethrin treatment acts as a priming factor, subsequently leading to depression-like behavior in mice under stress conditions.

Single-cell sequencing provides profiling of distinct brain cell populations

To investigate whether the observed microglial morphometric changes in the hippocampus are accompanied by a genetic profile indicative of neuroinflammation, we conducted single-cell RNA sequencing analysis using 21,566 single nuclei collected from the hippocampus of mice (Figs.  4 , 5 and 6 ).

Characterization of GWI-associated brain cell population through single-cell sequencing. ( A ) UCDSelect was used to project annotations from a reference mouse cortex / hippocampus atlas onto novel dataset. Microglial cluster was confirmed by expression of canonical marker genes, including inpp5d , Tgfbr1 , Apbb1ip . ( B ) Cell density plots for each experimental group depict a uniform distribution of cell density, with increasing intensity of red indicating specificity to the respective condition. ( C ) Differential expression analysis against predicted clusters to identify conserved markers specific to each putative cell annotation

The microglia population exhibits significant enrichment in pathways linked to axon development, calcium ion transport, and neurotransmission. ( A and B ) Bubble plots of Gene Ontology (GO) category enrichment results in microglia cell populations for biological process ( A ) and molecular function ( B ). The color of the points reflects the − log10​ adjust p-value, with more significant p-values appearing as more intensely colored points. The size of each point corresponds to the percentage of gene sets within each GO category, with larger points indicating a higher percentage. ( C ) Venn diagram showing the number of overlapping significantly differentially expressed genes (DEGs) specifically enriched under different conditions: vehicle exposure followed by stress (green), permethrin exposure followed by no stress (red), and permethrin exposure followed by stress (pupple) (left panel). The middle panel shows the number of overlapping DEGs after sorting by an absolute z-score greater than 8.8 in the permethrin exposure followed by stress condition, and then how many genes are shared across the different experimental conditions. The right panel shows the log2 fold change values of selected DEGs expressed in the permethrin exposure followed by stress and permethrin exposure followed by no stress conditions

CA3 neuronal cell population exhibits significant enrichment in pathways linked to synaptic plasticity. ( A ) Venn diagram showing the number of overlapping significantly differentially expressed genes (DEGs) in DG, CA1, CA2, and CA3 regions specifically enriched under different conditions: vehicle exposure followed by stress (green), permethrin exposure followed by no stress (red), and permethrin exposure followed by stress (purple) (left panel). ( B ) Bar graphs represent the number of total genes altered and the proportion of genes represented in the Venn diagram showing the overlapping significantly DEGs within DG, CA1, CA2, and CA3. ( C and D ) Bubble plots of GO category enrichment results in neuronal cell populations in CA3 for biological process ( C ) and molecular function ( D ). The color of the points reflects the − log10 adjust p-value, with more significant p-values appearing as more intensely colored points. The size of each point corresponds to the percentage of gene sets within each GO category, with larger points indicating a higher percentage

UniCell Deconvolve Base (UCDBase) was employed to produce an initial unbiased cell type annotation, assessing cell type fractions across different conditions as previously reported [ 29 ]. Subsequently, UniCell Deconvolve Select (UCDSelect) was utilized to transfer annotations from a reference mouse cortex/hippocampus atlas onto the novel dataset (Fig.  4 A) We then compared the density distribution of cell types by sample, highlighting condition-specific differences in cell type fractions post-batch correction among all experimental groups. It revealed that all experimental groups exhibited a similar density distribution, indicating a consistent profiling of distinct brain cell populations across all groups (Fig.  4 B). The identity of the microglial cluster was confirmed by the expression of canonical microglia marker genes, including inpp5d , Tgfbr1 , Apbb1ip . Additionally, the identity of neuronal cells was confirmed by the expression of canonical neuronal marker genes such as Dsp , Olfr538 , Cpne4m for DG, Galntl6, Gm2164, Gm2115 for CA1, Tafa1,m zfp804a for CA2, Cce1, Mndal, Slc9a4 for CA3 (Fig.  4 C). These results confirm the identity of the identified clusters as microglia and neuronal cells, supported by the expression of canonical marker genes characteristic of each cell type using UCDBase analysis, thereby supporting the accuracy of cell type annotation.

Transcriptome analysis reveals alterations in gene expression specific to microglia following exposure to permethrin, followed by stress

To elucidate the transcriptional networks impacted within microglia populations associated with depression-like behavior in mice exposed to permethrin and/or stress, we conducted a functional enrichment analysis, encompassing biological process (Fig.  5 A) and molecular function (Fig.  5 B). In Fig.  5 A, we compared the biological processes selected based on adjusted p-values of < 0.05. While minimal changes were evident in the stress group, both permethrin exposure alone and in combination with stress showed similar alterations in biological processes. Notably, the permethrin with stress condition exhibited heightened significance and involvement of a greater number of gene sets in the same biological processes compared to permethrin-only group. Specifically, microglia cell population in permethrin with stress group displayed enriched biological processes associated with neuronal development (axon development, axon guidance, and the ephrin receptor signaling pathway), neuronal communication (calcium signaling, synaptic transmission, and glutamate receptor activity), as well as neuronal morphogenesis. In the assessment of molecular functions (Fig.  5 B), a consistent trend emerged where minimal alterations were observed in the stress group, whereas both the permethrin-only and permethrin combined with stress groups exhibited similar patterns. Notably, within the permethrin with stress group, distinct molecular activities were noted, including ionotropic glutamate receptor activity and ligand- or voltage-gated calcium channel activity. These findings underscore parallels in biological processes concerning neuronal signaling, ion channel modulation, and synaptic transmission.

Subsequently, we investigated differentially expressed genes (DEGs) to discern variations between permethrin treatment alone and permethrin treatment with stress. In Fig.  5 C, notable modifications in gene expression were observed, with 2,949 genes in the permethrin and stress group and 2,354 genes in the permethrin-only group exhibiting significant alterations compared to the vehicle group without stress (adjusted p-value < 0.05, Fig.  5 C, left). Moreover, 232 genes were exclusively altered in the permethrin-only group, while 845 genes uniquely changed in the permethrin and stress group, suggesting that the permethrin with stress group exhibited more significant gene alterations. Following, utilizing the absolute Z score, we identified the top 100 genes in the permethrin with stress group (Fig.  5 C, middle). It was observed that only 5 genes such as Dlgap1 , Trank1 , Tafa5 , Calr , Rtn1 were exclusively expressed in the permethrin with stress group (Fig.  5 C, right). Additionally, 87 genes showed differential expression in both groups, with the permethrin with stress group exhibiting a significantly more pronounced increase or decrease in expression compared to the permethrin-only group. Notably, 6 genes such as Epha6 , Lyn , Egfem1 , Faah , Klhl3 and Fat2 displayed the most substantial changes, with their expression levels in the permethrin with stress group being 1.4-fold higher or lower than those observed in the permethrin-only group (Fig.  5 C, right). Overall, the results highlight the potential synergistic impact of permethrin and stress on microglia gene expression, which could contribute to the underlying mechanisms involved in depression-like behavior observed in the animal model (Fig.  2 ).

Permethrin exposure followed by stress induces a significant alteration in gene expression patterns across regionally distinct neuronal populations

To investigate how permethrin exposure followed by stress impacts transcriptional networks in neuronal cells, which functions are potentially mediated by microglia, in hippocampal regions including CA1, CA2, CA3, and DG, we first compared the number of DEGs across groups: permethrin exposure followed by no stress, permethrin exposure followed by stress, and vehicle exposure followed by stress (Fig.  6 A and B). Adjust p-value threshold of 0.05 was used to identify DEGs in CA1, CA2, CA3, and DG of the hippocampus in mice from each group. Interestingly, permethrin exposure followed by stress displayed a significantly higher number of DEGs compared to the other groups in all hippocampal regions (Fig.  6 A). Analysis of hippocampal regions CA1, CA2, CA3, and DG following permethrin exposure and subsequent stress revealed a prominent increase of DEGs, with CA1 exhibiting the most notable rise compared to other regions, followed by CA3. (Fig.  6 A). Given the observed differences in microglial alterations between the permethrin-exposed groups with and without stress (Fig.  5 ), we specifically compared gene expression in these groups. Among hippocampal regions, only CA3 region exhibited a high percentage of unique expression in DEGs in the permethrin exposure followed by stress group. 62.87% were unique to the permethrin with stress group, while 29.89% were common to both permethrin exposed groups (with or without stress), and only 7% were specific to the permethrin without stress group (Fig.  6 B).

To further explore the functional implications of the observed gene expression alterations in CA3 region, we conducted Gene Ontology (GO) enrichment analysis, specifically comparing the permethrin exposure followed by no stress and permethrin exposure followed by stress groups ( p  < 0.05, Fig.  6 C and D). Compared to the permethrin exposure followed by no stress group, the permethrin exposure followed by stress group in CA3 region showed significantly enriched GO terms (Fig.  6 C) related to signal transduction, including modulation of chemical synaptic transmission, regulation of neurotransmitter receptors, and regulation of postsynaptic neurotransmitter receptor activity. Notably, even for shared biological processes, permethrin with stress group displayed a greater number of genes and a more significant level of enrichment. We then focused on the molecular function of DEGs using GO enrichment analysis ( p  < 0.05, Fig.  6 D). GO enrichment analysis of DEGs revealed a significant enrichment for molecular function terms ( p  < 0.05, Fig.  6 D). The permethrin exposure followed by stress group exhibited a notably greater abundance of enriched terms compared to the permethrin exposure followed by no stress group, including synaptotagmin-1 binding, amino acid sodium symporter activity, and volume-sensitive anion channel activity. (Fig.  6 D). Overall, this results indicate that permethrin exposure followed by stress triggered a prominent rise in differentially expressed genes, particularly in CA1 and CA3, with CA3 region exhibiting distinct patterns suggestive of disrupted neuronal communication.

Exposure to permethrin followed by stress altered protein expression associated with neuroinflammation and synaptic plasticity

To investigate the proteomic alterations in mice subjected to permethrin exposure followed by stress, we examined the abundance of a specific set of 92 proteins associated with essential biological functions using proximity extension assay-based Olink technology. We identified significant alterations in the levels of six proteins specifically within the hippocampi of mice exposed to permethrin followed by stress (Fig.  7 ).

Olink proteomic analysis in the GWI mouse model. ( A - F ) Box graphs represented significant changes in protein expression levels of TGFα ( A ), Ahr ( B ), IL-1β ( C ), RGMa ( D ), Snap29 ( E ), and Ddah1 ( F ) in the hippocampus across all experimental groups. Statistical analyses were performed using Two-Way ANOVA (* p  < 0.05; ** p  < 0.01, *** p  < 0.001; **** p  < 0.0001; compared to the permethrin followed by stress group, n  = 7–9 mice for each group). Data are expressed as the means ± SEM

Specifically, there was a notable increase in Transforming growth factor alpha (TGF-α) in mice exposed to permethrin followed by stress compared to other experimental groups (* p  < 0.05, Fig.  7 A). Additionally, Aryl hydrocarbon receptor (Ahr), known for its involvement in regulating microglial activation and neuroinflammation, showed elevated levels in the same mice (**** p  < 0.0001, *** p  < 0.001, ** p  < 0.01, Fig.  7 B). Concurrently, there was a decrease in the expression of Interleukin-1beta (IL-1β) (* p  < 0.05, Fig.  7 C).

Repulsive guidance molecule A (RGMa), renowned for its capacity to inhibit neurite growth and newborn neuron survival in the adult dentate gyrus, demonstrated notable upregulation in the permethrin followed by stress group compared to the other experimental groups (** p  < 0.01, Fig.  7 D). Additionally, Synaptosomal-associated protein 29 (Snap-29), responsible for impeding SNARE complex disassembly and thereby diminishing synaptic transmission, exhibited heightened expression in the permethrin followed by stress group relative to both the no stress and stress alone groups (** p  < 0.01, * p  < 0.05, Fig.  7 E). Conversely, N(G), N(G)-dimethylarginine dimethylaminohydrolase 1(Ddah1), a hydrolase responsible for regulating genes associated with the synthesis and transportation of acetylcholine, exhibited significant decrease in expression in the permethrin followed by stress group (** p  < 0.01, Fig.  7 F). These findings highlight the multifaceted effects of permethrin exposure followed by stress on both inflammatory responses and synaptic plasticity within the hippocampi of mice, underscoring the complex interplay between microglia activation and neuronal function.

GWI is a complex multi-symptom disorder affecting approximately one third of veterans who served in the first GW [ 30 , 31 ]. These soldiers were exposed to various pesticides, including permethrin, DEET, and chlorpyrifos, as well as chemical weapons, smoke from oil well fires, and fine particulate matter from sandstorms [ 32 ]. Upon returning from combat, affected veterans experienced a range of symptoms such as fatigue, anxiety, gastrointestinal distress, and cognitive and psychiatric disturbances [ 4 ]. High levels of stress reported by many veterans during their service suggest that physical and psychological stress may have synergized with toxin exposure [ 3 ]. Currently, there is no approved therapeutic for GWI, with most treatments focusing on symptom management [ 33 ]. Although the exact cause of GWI has not been identified, permethrin exposure is suspected to play a role [ 34 ]. Understanding the mechanistic factors involved and developing appropriate animal models is crucial for advancing care for this underserved population. Thus, the mouse model used in our current studies to examine interactions between environmental toxin exposure and mild stress could serve as a valuable model for studying GWI. This model may help elucidate the underlying mechanisms and contribute to the development of targeted treatments for veterans suffering from GWI.

The exposome, encompassing the cumulative impact of stressors and environmental exposures experienced throughout an individual’s life, is an emerging area of research with profound implications for neuropsychological health [ 35 ]. In particular, interactions between various low-level or mild exposures represent a potential hazard which may go un-noticed due to the seemingly innocuous effects of individual low-level exposures [ 36 ]. In the present study, we investigated the effects of low-level permethrin exposure at levels below the threshold required for acute intoxication for their potential synergistic interactions with 7 days of mild stress exposure. While chronic stress over a 30 day period is associated with psychiatric and changes in mice, 1 week of stress has not been shown to have neuroinflammatory or behavioral effects [ 23 ]. We revealed a significant increase in depression-like behavior in mice exposed to both permethrin and stress compared to those exposed to either factor alone or controls (Fig.  2 ). This suggests that permethrin exposure acts as a priming factor, sensitizing the brain to subsequent stressors and exacerbating depressive symptoms. Exposure to permethrin triggers a rapid influx of sodium ions into microglia cells, leading to increased intracellular sodium accumulation; prolonged exposure for 24 h activates microglia and results in neuroinflammation by releasing pro-inflammatory cytokines [ 13 ]. In the exploration of microglial functions within the CNS, chemogenetic G protein-coupled receptors (GPCRs), including Gi-signaling (e.g., hM4Di) and Gq-signaling (e.g., hM3Dq) DREADDs, have previously been utilized as sophisticated tools for understanding microglial processes [ 37 ]. Importantly, our chemogenetic modulation experiments via microglia expressing DREADD receptors highlight the pivotal role of microglial activation in mediating this depressive-like behavior, as blockade of microglial activation effectively mitigated the observed behavioral changes (Fig.  2 ). Thus, the ability of permethrin to stimulate neuroinflammation through microglia underscores its potential as a priming factor in enhancing susceptibility to depression.

Consistent with previous research [ 34 ], our results demonstrate that permethrin, including both cis- and trans- isomers, is capable of crossing the blood-brain barrier, but reaches higher concentrations in the plasma (Fig.  1 ). This finding highlights the potential neurotoxicity of permethrin, given its ability to directly interact with CNS components. Exposure to permethrin initiates a rapid and continuous influx of sodium into microglial cells through voltage-gated sodium channels (VGSC) [ 13 ]. Consequently, there is an aberrant accumulation of intracellular sodium, leading to the activation of microglia and the subsequent upregulation of pro-inflammatory cytokine such as tumor necrosis factor alpha (TNFα [ 13 ]. This pro-inflammatory response is characterized by deramification, a phenomenon defined by the retraction of microglial processes [ 38 ]. To elucidate these morphometric changes, a detailed analysis encompassing soma volume, branch length, terminal points, and intersecting segments in microglia was conducted (Fig.  3 ). Hippocampus and PFC engage in a bidirectional interaction that influences cognitive functions and the processing of emotional information [ 39 ]. Functional imaging studies in depression patients have identified significant abnormalities in the structure, activation, and functional connectivity of the hippocampal–PFC circuit [ 40 ]. Specifically, the hippocampus and PFC demonstrate significant changes in microglial morphology in response to various stressors [ 34 , 36 , 37 ]. We revealed significant reductions in microglial volume, branch length, and number of terminal points in the hippocampus of mice exposed to permethrin, followed by stress. We also further confirmed a decrease in microglial branching complexity in the hippocampus following combined exposure through sholl analysis. In contrast, no significant morphological alterations were observed in microglia within the PFC across all parameters analyzed. The observed deramification and reduced complexity of microglia in the hippocampus suggest a potential mechanism underlying the development of depression-like behavior following exposure to permethrin and stress.

We investigated the morphology of microglia in the hippocampus and PFC based on the crucial role of these distinct regions in regulating mood and emotional behavior [ 39 , 40 ]. We observed significant alterations in hippocampal microglial morphology, which may contribute to the development of depressive-like behavior after exposure to permethrin followed by stress. Our study investigated the relationship between microglial changes in the hippocampus and depression-like behavior in order to develop valuable insights into the mechanisms underlying the link between neuroinflammation and mood disorders within the context of GWI. Specifically, our findings showed that morphological alterations are accompanied by transcriptional changes indicative of neuroinflammation, as revealed by single cell RNA sequencing analysis (Figs.  4 , 5 and 6 ). A recent study indicates that UCDBase was established to leverage the entirety of publicly available scRNA-Seq data to construct a unified training corpus for deep learning [ 29 ]. In addition, UCDSelect complements UCDBase by enabling context-specific deconvolution through transfer learning of UCDBase features, incorporating user-defined cell signatures for tailored analyses [ 29 ]. Our analysis validated the identified clusters as microglia and neuronal cells through the cell type-specific marker gene (Fig.  4 ). Functional enrichment analysis indicates a synergistic impact of permethrin and stress on microglia gene expression, with the stress-only group showing minimal changes, while the permethrin-only group exhibits a pattern similar to the permethrin-with-stress group, which displays more pronounced alterations (Fig.  5 ). Specifically, we found that among the top 100 genes, only five, such as Dlgap1 , Trank1 , Tafa5 , Calr , and Rtn1 , were exclusively altered in the permethrin exposure followed by stress group. Dlgap1 , Trank1 , and Tafa5 are established risk genes for neuropsychiatric diseases, with Dlgap1 specifically related to major depressive disorder, Trank1 associated with bipolar disorder, and Tafa5 linked to depressive-like behaviors [ 41 , 42 , 43 ]. Calr is released by microglia following exposure to lipopolysaccharide [ 44 ]. This extracellular calreticulin was observed to induce chemoattraction and activation of microglia, leading to the release of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β, as well as the chemokine (C-C motif) ligand 2 [ 44 ]. In addition, Calr serves as an “eat-me” signal, promoting the engulfment of cells by phagocytes through the interaction with the low-density lipoprotein receptor-related protein 1 [ 45 ]. These findings suggest that these five genes may play a role in modulating microglial activity and contributing to the inflammatory response in the brain, potentially leading to depression-like behavior associated with permethrin exposure as a priming factor. Future research in depth is needed to elucidate the roles of these genes in microglial modulation and neuroinflammation, as well as their contribution to depression-like behavior associated with permethrin exposure.

In this study, we identified significant changes induced within the microglial cell population in response to exposure to permethrin followed by stress. We also identified changes in the expression of genes genes associated with neuronal development, neuronal communication, and neuronal morphogenesis (Fig.  5 ) via functional analysis. Microglia exert a critical role in maintaining synaptic integrity throughout development and adulthood via dynamic sculpting of the synapse [ 46 ]. Aberrant microglial function in the mature brain has been implicated in pathological synaptic loss and dysfunction associated with neuroinflammation, and depression [ 47 , 48 ]. For instance, in depressed patients, the reduction in synapse number and function is linked to microglial engulfment of synapses [ 49 ]. Depressive-like behaviors observed in several chronic stress models have been linked to the specific removal of postsynaptic dendritic spines in targeted branches, along with atrophy of neurons [ 50 ]. To investigate how permethrin exposure followed by stress affects transcriptional networks in different types of neuronal cells, we focused on the hippocampal subregions (CA1, CA2, CA3, and DG). Our analysis revealed a significant increase in DEGs in neurons within these regions after permethrin exposure and subsequent stress. Notably, CA1 showed the most significant increase in DEGs, followed by CA3 (Fig.  6 ). The microglia density in CA3 region of the mouse hippocampus is higher than in both CA1 region and DG [ 51 , 52 ]. CA1 region has a higher microglia density compared to DG [ 52 ]. It has been proposed that this variation in microglial density could influence site-specific vulnerability in the hippocampus and that the uneven distribution of microglia may play a role in regulating hippocampal neuronal activity. These findings suggest that the high density of microglia in CA3 region might be a key factor in the significant alterations in neuronal DEGs observed there following permethrin and stress exposure. Further research is needed to specifically examine how microglia-neuron interactions in the CA3 region are affected by permethrin exposure followed by stress, and to elucidate the mechanisms driving these changes.

Consistent with these findings, our proteomic analysis uncovers alterations in key proteins involved in neuroinflammation and synaptic plasticity within the hippocampi of mice exposed to permethrin followed by stress (Fig.  7 ). Notably, we found the upregulation of pro-inflammatory cytokines such as TGFα and Ahr, underscoring the dysregulated inflammatory response elicited by permethrin exposure and stress (Fig.  7 ). The upregulation of TGF-α has been implicated in the activation of microglia, which are key players in neuroinflammatory processes and may contribute to neuronal damage by activating microglia [ 53 ]. AhR is a critical mediator for peripheral immune functions involving the differentiation of dendritic cells and the tissue-specific proinflammatory gene expression [ 54 , 55 ]. In the brain, AhR is ubiquitously expressed in areas including the cerebral cortex, hippocampus, and cerebellum [ 56 ], and is related to its environmental ligands-associated sensorimotor and cognitive abnormalities based on its aggravation of oxidative stress or excitotoxicity in neurons [ 57 ]. AhR can also directly activate cytokine transcription and AhR increases NOX activity by increasing the expression of p47phox to elicit oxidative stress, which contributes to cytokine transcription such as TNF- α [ 58 ]. Additionally, we found that the expression of synaptic plasticity protein molecules (RGMa, SNAP-29, and Ddah1) in response to permethrin followed by stress (Fig.  7 ). SNAP-29 serves as a negative modulator by slowing the disassembly of the SNARE complex and consequently diminishing synaptic transmission in cultured neurons. This effect is associated with the attenuation of both the recycling process of the SNARE-based fusion machinery and the turnover of synaptic vesicles [ 59 ]. RGMa has been identified to hinder synapse formation by disrupting the expression of presynaptic protein synapsin-1 and postsynaptic protein PSD-95 in cortical neurons. [ 60 ]. Recent study suggests that RGMa regulates neuronal branching through the RhoA pathway, thereby impacting synaptic plasticity. [ 61 ]. RGMa can also inhibit axon growth in CNS through its potential suppression of axon growth by inducing the expression of Rho-associated coiled-coil protein kinase in neurons. [ 62 ]. Additionally, research indicates that mice subjected to an Mg-restricted diet display depression-like behavior and diminished expression of DDAH1, the enzyme responsible for breaking down N, N dimethyl-L-arginine, a significant competitive inhibitor of nitric oxide synthase [ 63 ].

In conclusion, our study demonstrates that permethrin exposure followed by stress induces depression-like behaviors in mice through microglial activation and upregulation of pro-inflammatory cytokines, particularly in the hippocampus. Additional alterations in gene expression, observed through sc sequencing, suggest potential disruptions in neuronal communication mediated by microglial activation. To gain a more thorough understanding of how microglial activation affects specific neuronal communication pathways, further in-depth studies are needed to validate and explore the key molecules or mechanisms identified in this research. Our findings highlight the complexity of GWI pathology, revealing how exposure to chemical toxins and psychological stress during the GW may have produced a pronounced neuroinflammatory response and co-inciding psychiatric symptoms. This complex interaction underscores the need to consider both chemical exposures and psychological stress in understanding the full scope of GWI, which may inform more targeted interventions and treatments for affected individuals.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

The authors extend their sincere thanks to Vassili Tchaikovsky for his invaluable technical support and unwavering assistance, as well as to Josh Palmieri for their exceptional work in administrative duties.

This research was supported in part by the Department of Veteran Affairs grant number BX004583 and Department of Defense grant number W81XWH-19-1-0513. G.M.P. holds a Senior VA Career Scientist Award. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.

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Sean X Naughton and Eun-Jeong Yang contributed equally to this work.

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Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Sean X. Naughton, Eun-Jeong Yang, Umar Iqbal, Kyle Trageser, Sibilla Masieri, Henry Wu, Urdhva Raval & Giulio Maria Pasinetti

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Daniel Charytonowicz & Robert Sebra

Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Molly Estill & Li Shen

Department of Plant Biology, Rutgers University, New Brunswick, NJ, USA

Weiting Lyu, Qing-li Wu & James Simon

Geriatric Research, Education and Clinical Center, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA

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S.N. and E.Y. conceived and designed the study concept, performed all experiments, analyzed and interpreted data, and was instrumental in the writing of the manuscript. U.I. and U.R. performed the immunofluorescence experiment and analyzed data. M.E., D.C., L.S., and R.S. analyzed and interpreted single-cell sequencing data. W.L., Q.W., and J.S. performed pharmacological experiments and analyzed the data. S.M., K.J.T and H.W provided assistance throughout the study. G.M.P. conceived and designed the study concept, and supervised the project. In addition, G.M.P. is the guarantor of this work, as such; he has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors read the final version of the manuscript, revised it critically, and gave final approval of the version submitted.

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12974_2024_3215_MOESM1_ESM.tif

Supplementary Material 1: Supplementary Fig. 1. Quality Control Metrics for snRNA-Seq Samples. (A-C) Violin plots with overlayed scattered strip plots of pre-filtered single-nuclei grouped by individual sample (x-axis), with respect to the percent of total counts per cell originating from either mitochondrial (A), hemoglobin (B), or ribosomal (C) genes (y-axis). (D) Scatterplot colored by individual sample showing individual single-nuclei arranged by total number of gene counts (x-axis) with respect to the total number of unique genes identified with at least one count per nucleus (y-axis). (E) Violin plots with overlayed scattered strip plots of pre-filtered single-nuclei grouped by individual sample (x-axis), with respect to the log-transformed total number of genes counts per nucleus (y-axis). (F) Violin plots with overlayed scattered strip plots of pre-filtered single-nuclei grouped by individual sample (x-axis), with respect to the log-transformed total number of unique genes identified with at least one count per nucleus (y-axis)

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Naughton, S.X., Yang, EJ., Iqbal, U. et al. Permethrin exposure primes neuroinflammatory stress response to drive depression-like behavior through microglial activation in a mouse model of Gulf War Illness. J Neuroinflammation 21 , 222 (2024). https://doi.org/10.1186/s12974-024-03215-3

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REVIEW article

From serotonin to neuroplasticity: evolvement of theories for major depressive disorder.

• Key Laboratory of Psychiatry and Mental Health of Hunan Province, Mental Health Institute, The Second Xiangya Hospital of Central South University, National Clinical Research Center for Mental Disorder, National Technology Institute of Psychiatry, Changsha, China

The serotonin (5-HT) hypothesis of depression has played an important role in the history of psychiatry, yet it has also been criticized for the delayed onset and inadequate efficacy of selective serotonin reuptake inhibitors (SSRIs). With evolvement of neuroscience, the neuroplasticity hypothesis of major depressive disorder (MDD) has been proposed and may provide a better framework for clarification the pathogenesis of MDD and antidepressant efficacy. In this article, we first summarized the evidence challenging the monoamine hypothesis and proposed that the antidepressant efficacy of SSRIs is not derived from elevated monoamine (5-HT, noradrenaline (NE), or dopamine (DA)) concentration or monoamine neurotransmission. Second, we reviewed the role of stress in the pathogenesis of MDD and gave a brief introduction to the neuroplasticity hypothesis of MDD. Third, we explored the possible mechanisms underlying the antidepressant efficacy of typical antidepressants in the context of neuroplasticity theory. Fourth, we tried to provide an explanatory framework for the significant difference in onset of efficacy between typical antidepressants and ketamine. Finally, we provided a brief summarization about this review article and some perspectives for future studies.

Introduction

Major depressive disorder (MDD) is a highly prevalent and highly debilitating psychiatric disorder. MDD is the leading cause of disability worldwide with approximately 350 million people around the world suffering from this disorder, and the disease burden of depression has been considered to become the second highest among all diseases by 2020 ( World Health Organization, 2016 ). However, despite the devastating burden of MDD, the pathogenesis of this complex disorder still remains unclear and the current available treatment for depression is also far from optimal ( Collins et al., 2011 ). Specifically, clinical diagnosis of depression is still suffering from lack of objective diagnostic biomarker ( Jentsch et al., 2015 ) and the overall remission rate of sequenced first-line antidepressant treatments (including drugs and cognitive behavioral therapy) for MDD is only about 60%–70% ( Rush et al., 2006 ). Besides, the first-line drugs recommended for MDD in authentic MDD guidelines (most are selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-noradrenaline reuptake inhibitors (SNRIs)) are often criticized by the delayed onset of efficacy, namely, it takes 2 weeks or longer on average for these drugs to work ( Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Depression, 2004 ; National Institute for Health and Care Excellence, 2009 ; American Psychiatric Association Work Group on Major Depressive Disorder, 2010 ; Bauer et al., 2013 ; Kennedy et al., 2016 ).

The suboptimal clinical practice of MDD calls for deep understanding of the pathogenesis of MDD and development of more potent and fast-acting antidepressants. Although several hypotheses have been proposed for MDD, the monoamine (serotonin (5-HT), noradrenaline (NE) and dopamine (DA)) hypothesis is still the most prevailing hypothesis of MDD since most of the currently available antidepressants work on monoamine transporters or receptors. This hypothesis, initially based on the unintentional findings that chemical compounds inhibiting reuptake (imipramine) or metabolism (iproniazid) of monoamine neurotransmitters (5-HT and NE) would demonstrate antidepressant efficacy ( Hirschfeld, 2000 ; Mulinari, 2012 ), claims that MDD is derived from deficiency of 5-HT and/or NE in the synaptic cleft, and antidepressant efficacy would be achieved by increasing 5-HT and/or NE in synaptic cleft through inhibiting clearance or promoting synthesis and release of these monoamines.

The monoamine hypothesis satiates the intense needs of interpretation for the mechanism of pathogenesis of MDD from academy, pharmacies and public population and has guided the development of new antidepressants in 1980s–2000s. Nevertheless, accounting the complicated and heterogeneous clinical manifestations of MDD to deficiency of a molecule is too simplistic and may misguide our understanding of the complexity of this disorder. Indeed as expected, numerous findings inconsistent with this hypothesis have arisen from daily clinical observations, clinical researches and preclinical studies since the proposal of this hypothesis, among which the most prominent findings are the delayed onset of efficacy and inadequate response/remission rate of typical antidepressants as illustrated above. These findings challenged the monoamine hypothesis on one hand, and promoted the evolvement of theories about depression on the other hand. Specifically, to make up for the shortage of monoamine hypothesis, researchers have proposed monoaminergic receptor hypothesis, signaling hypothesis, neuroplasticity hypothesis, etc. ( Racagni and Popoli, 2008 ). These hypotheses evolved towards a more comprehensive and reasonable understanding of MDD and antidepressant efficacy, and the succeeding hypothesis may be totally different from the initial monoamine hypotheses.

Increased Synaptic Serotonin (or NE, DA) Concentration Does Not Account for The Antidepressant Efficacy of Antidepressants

Several published reviews have casted doubt on the low 5-HT hypothesis of MDD and summarized the evidence inconsistent with this hypothesis ( Lacasse and Leo, 2005 ; Racagni and Popoli, 2008 ; Fischer et al., 2014 ; Andrews et al., 2015 ). One article even hypothesized that depression is a result of elevated 5-HT concentration rather than deficiency of 5-HT ( Andrews et al., 2015 ). The evidence challenging the low 5-HT hypothesis may be summarized as the following three categories: first, the rapid increase of 5-HT concentration in the synaptic cleft of neurons is inconsistent with the clinical delayed onset of antidepressant efficacy; second, lowering the concentration of 5-HT in synaptic cleft through tryptophan depletion ( Ruhé et al., 2007 ) or serotonin transporter (SERT) enhancer (i.e., Tinaptine; Kasper and McEwen, 2008 ) failed to induce depression in healthy subjects, actually long-term antidepressants treatment had been detected to downregulating the total 5-HT concentration in the brain ( Marsteller et al., 2007 ; Bosker et al., 2010 ; Siesser et al., 2013 ), which was contrary to the common sense of low 5-HT in depression; and third, genetic variants associated with potentiated SERT function ( l allele of 5-HTTLPR) have been repeatedly found to be related with reduced risk of depression or better prognosis than variants associated with decreased SERT function ( s allele of 5-HTTLPR; Karg et al., 2011 ). A timeline of historical publications or events supporting or opposing the monoamine hypothesis is shown in Figure 1 .

Figure 1 . Timeline of historical events or publications supporting or opposing the monoamine hypothesis of depression. The blue boxes are events or publications supporting monoamine hypothesis and the yellow boxes are those opposing monoamine hypothesis. The following are the publications: 1. Selikoff et al. (1952) , 2. Davies and Shepherd (1955) , 3. Kuhn (1958) , 4. Schildkraut (1965) , 5. Coppen (1967) , 6. Schildkraut and Kety (1967) , 7. Lapin and Oxenkrug (1969) , 8. Oswald et al. (1972) , 9. Stahl (1984) , 10. Caspi et al. (2003) , 11. Andrews et al. (2015) .

The above findings together put sand in the wheels of low 5-HT hypothesis and indicate that it may not be reasonable to account the antidepressant efficacy of SSRIs to elevated 5-HT concentration or increased 5-HT neurotransmission in the brain. Thus the presumption that depression is caused by deficiency of 5-HT is also lack of solid basis. Actually, as stated in the Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications , “there is no clear and convincing evidence that monoamine deficiency accounts for depression, i.e., there is no “real” monoamine deficit” ( Stahl, 2013 ). Similar opinions or comments from other authentic researchers or publications had been summarized in the impressive article of Lacasse and Leo (2005) . Therefore, the low 5-HT hypothesis, although intriguing, are too simplistic and arbitrary for interpretation of the mechanisms underlying the complex manifestations of MDD.

To address the delayed onset of antidepressant efficacy, scientists further proposed the monoamine receptor hypothesis, which asserts that downregulation or desensitization of somatodendritic monoamine autoreceptor (such as 5-HT 1A ), rather than the elevation of monoamine concentration itself, is the key mechanism of antidepressant efficacy ( Stahl, 2013 ). Since the somatodendritic 5-HT 1A autoreceptor inhibits impulse flow of 5-HT neurons, the downregulation or desensitization of this somatodendritic receptor induced by elevated concentration of 5-HT resulted from antidepressant intake would turn on neuronal impulse flow and bring about increased 5-HT in axonal terminals. The enhanced axonal 5-HT transmission and its subsequent neurobiochemical events, like regulation of gene transcription and protein synthesis, are deemed as the final mediators of antidepressant efficacy. As it takes several days to 2 weeks for the downregulation of 5-HT 1A autoreceptor to happen, the monoamine receptor hypothesis perfectly explained the delayed onset of antidepressant efficacy. However, both the clinical molecular imaging and postmortem studies failed to find consistent evidence supporting alterations of 5-HT 1A in patients with MDD ( Ruhé et al., 2014 ). Besides, 5-HT 1A antagonists also failed to achieve consistent antidepressant efficacy in clinical trials. These research findings all casted doubts on the monoamine receptor hypothesis and calls for better hypothesis for the pathogenesis of depression.

Considering the antidepressant efficacy of electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), transcranial direct-current stimulation (tDCS) and new antidepressant ketamine and its derivatives, a legitimate inference might be that these therapies, although differed in forms and styles, would work on a final common pathway which underlies the pathogenesis of or vulnerability to MDD, and the antidepressant efficacy of these therapies is found on reversing or repairing the alteration of this final common pathway. Since no direct evidence about the association between 5-HT and depression and indirect evidence is highly inconsistent, there is no reason to claim that deficiency of 5-HT may serve as the “final common pathway” of depression. Then what else mechanism would be competent for the “final common pathway” of these diverse therapies? As has been repeated confirmed by preclinical and clinical studies, the relationship between stress and depression is robust and steady-going ( Biegler, 2008 ; Risch et al., 2009 ; Binder and Nemeroff, 2010 ; Young and Korszun, 2010 ; Pizzagalli, 2014 ), thus it is legitimate to deduce that revealing the neurobiological sequelae of stress on the brain and its association with depression might provide insight in exploring the “final common pathway” of depression and antidepressant efficacy. Here we would like to take a brief look at the effect of stress on the brain and its role in the pathogenesis of depression at first.

The Role of Stress in The Pathogenesis of MDD

In the framework of gene X environment for psychiatric disorders, stress is the validated environmental factor accounting to increased risk of development, exacerbation, chronicity and relapse of MDD. Generally, major depressive episodes (MDEs) are associated with about 2.5 times more frequent stressful life events in the period before episode as compared with comparable time period in controls ( Hammen, 2005 ), and one stressful life event would lead to about 1.41-fold increased risk of MDE ( Risch et al., 2009 ). In addition, stress is suggested to be linked with treatment resistance ( Amital et al., 2008 ), poorer prognosis ( Gilman et al., 2013 ) and higher rate of relapse and recurrence ( Monroe and Harkness, 2005 ; Harkness et al., 2014 ) of MDD.

How should stress and depression be linked? Numerous theories has been proposed for interpretation of this phenomenon, among which the vicious circle between the dysregulation of hypothalamic-pituitary-adrenocortical (HPA) axis and morphological and functional deficits of hippocampal formation is considered as the key route between stress and depression. Specifically, the elevation of circulating cortisol during chronic stress response would exert neurotoxic effect on hippocampal neurons through glucocorticoid receptor and its downstream effects, which would result in decreased neurogenesis, synaptogenesis and dendritic spines and increased apoptosis of neurons ( Holsboer and Barden, 1996 ; Holsboer, 2000 ; de Kloet et al., 2005 ). The morphological loss of neurons further leads to functional deficits loss of long-term potentiation (LTP) or long-term depression (LTD) of hippocampus, which gives rise to decreased GABAergic control of the HPA axis from the bed nucleus of stria terminalis (BNST) normally driven by the action of hippocampus ( Holsboer, 2000 ; Egeland et al., 2015 ), and the the disinhibition of HPA axis would inversely exacerbate the morphological and functional loss of hippocampus. Thus, a vicious circle is formed and the hippocampal formation gradually goes to structural atrophy and functional deficit, which are commonly seen in depression.

Apart from the hypercortisolemia and deficits of hippocampal formation, the effect of stress on the biochemical metabolism and neurotransmission is also deemed to partly mediate the link between stress and depression. Biochemically, chronic stress would induce increased release of glutamate ( Sanacora et al., 2012 ) in the hippocampus and prefrontal cortex (PFC), and blunted neurotransmission of 5-HT ( Mahar et al., 2014 ) and DA ( Pizzagalli, 2014 ) in mesocortical monoaminergic circuits. Specifically, chronic stress would downregulate the firing rate of dorsal raphe (DR) 5-HT neurons projecting to PFC and 5-HT 1A receptor sensitivity in PFC, which may be mediated by hypercortisolemia ( Mahar et al., 2014 ). Similarly, diminished basal DA neuron firing in striatum is also observed in rodents exposed to chronic mild stress ( Bekris et al., 2005 ). And, elevated release of glutamate in PFC is repeatedly observed after chronic stress, which is deemed to exert neurotoxic efficacy on the PFC and hippocampus neurons ( Sanacora et al., 2012 ). These neurochemical changes would together result in negative influence on neuroplasticity through blunted neurogenesis, disrupted synaptogenesis, diminished dendritic spines and reduced synaptic connections. Besides, stress would diminish the cell proliferation and promote apoptosis of glial cells ( Rial et al., 2015 ), which is the primary cell responsible for clearance of glutamate in the brain and may be responsible for the atrophy of hippocampus in MDD ( Duman, 2004 ).

The functional and morphological changes of the brain induced by hypercortisolemia resulted from chronic stress are roughly consistent with the neuroimaging findings of abnormalities in MDD, i.e., atrophy and hypofunction of hippocampus and PFC, and hypertrophy and hyperfunction of amygdala ( Andrade and Rao, 2010 ). Interestingly, the alterations in different brain regions may underlie different symptoms of MDD. Specifically, structural and functional alterations in the PFC-amygdala/hippocampus circuit may underlie depressive emotions; abnormalities in the PFC-nucleus accumbens (NAc) circuit may serve as the neural substrate of anhedonia ( Phillips et al., 2015 ); and alterations of medial and dorsolateral PFC may mediate the cognitive dysfunction of MDD ( Thomas and Elliott, 2009 ).

With the accumulated evidence supporting the strong correlation between stress and depression, and findings revealing the efficacy of stress on brain in line with the abnormalities found in MDD, the term “stress-induced depression” or at least “stress-correlated depression” would seem reasonable. As the case stands, the most frequently used and research validated depression animal model is the chronic stress induced depression model ( Czéh et al., 2016 ). Thus, exploring the pathogenesis of MDD in the framework of stress-induced depression may be reasonable and necessary for our comprehending of this complex and heterogeneous psychiatric disorder.

The routes through which stress exert neurobiological effect on the brain as discussed above are all correlated with the growth, maturation, apoptosis and function of neurons. These processes, usually conceptualized as “neuroplasticity”, are of key significance in the pathogenesis of MDD. Therefore, they may also be competent for the role of “final common pathway” of antidepressant efficacy achieved by diverse treatment strategies. Below, we will give a brief introduction to the main contents of the neuroplasticity hypothesis of depression and take typical antidepressants and ketamine as examples to illustrate how neuroplasticity would serve as the “final common pathway” of antidepressant efficacy.

Neuroplasticity Hypothesis of Depression: Main Contents

Although proposed for a long time and has won a lot of attention in academy, there is still no validated definition about the term “neuroplasticity”. Generally, neuroplasticity refers to the ability of neural system to adapt itself to the internal and external stimuli and to respond adaptively to future stimuli ( Cramer et al., 2011 ). The processes of neuroplasticity are complex and the underlying mechanisms have not yet been fully understood, while it is widely accepted that the “neuroplasticity” includes both morphological and functional adaptation. Generally, the morphological neuroplasticity usually refers to neurogenesis, synaptogenesis, dendritic length and branching, spine density etc ( Cramer et al., 2011 ; Egeland et al., 2015 ) and the functional neuroplasticity includes at least four forms: homologous area adaptation, cross-modal reassignment, map expansion and compensatory masquerade ( Grafman, 2000 ). Neuroplasticity is of key significance in brain’s adaptation to stress, and maladaptive neuroplasticity may underlie various psychiatric disorders, such as depression, post-traumatic stress disorder, etc. Usually, the neuroplasticity theory of depression is usually supported by evidence from three domains ( Serafini, 2012 ): (1) decreased neuroplasticity in hippocampus and PFC in depressed patients; (2) decreased concentration of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), in subjects with depression; and (3) antidepressants would elevate the concentration of neurotrophic factors and improve the neuroplasticity in hippocampus and PFC.

In addition, what deserves to be mentioned is the role of “metaplasticity” (a term coined by Abraham and Bear, 1996 , meaning “plasticity of neuroplasticity”) in explaining stress-induced neural plasticity. The “metaplasticity”, or “activity-dependent and persistent change in neuronal state that shapes the direction, duration or magnitude of future synaptic change ( Abraham and Bear, 1996 )” in another way of saying, includes some key functions like preparing synapses for plasticity and learning and regulating synaptic plasticity homeostatically ( Hulme et al., 2013 ). These functions may be achieved through actions on NMDA and metabtropic glutamate receptors (mGluRs) or heterosynaptic metaplasticity mechanisms like synaptic tagging and capture ( Abraham, 2008 ; Hulme et al., 2013 ). Metaplasticity is sensitive to environmental stimuli, like environment enrichment or stress and dysregulation of metaplasticity induced by chronic stress may contribute to induction of depression ( Vose and Stanton, 2017 ). For a detailed description of mechanisms underlying metaplasticity and their clinical relevance, the impressive articles of Abraham and Bear (1996) , Abraham (2008) and Hulme et al. (2013) may be valuable.

As discussed above, with the establishment of stress-induced depression conceptual framework and the key role of neuroplasticity as mediator between stress and depression, neuroplasticity theory would be an optimal choice for understanding the pathogenesis of depression and antidepressant efficacy. Since we have illustrated the role of stress in the pathogenesis of MDD and the changes of brain induced by stress hereinbefore, next we will discuss how the antidepressants work on neuroplasticity.

How Typical Antidepressants Work on Neuroplasticity?

The possible mechanisms of typical antidepressants on neuroplasticity have been reviewed in several articles ( Racagni and Popoli, 2008 ; Andrade and Rao, 2010 ; Serafini, 2012 ; Harmer and Cowen, 2013 ; Hayley and Litteljohn, 2013 ). Briefly, antidepressants may improve neuroplasticity through the following pathways.

First, antidepressants improve neuroplasticity through monoamine neurotransmitters’ stimulation of the postsynaptic monoamine receptors. These receptors are mostly G-protein coupled receptor (GPCR) and would initiate subsequent signaling after stimulation. Specifically, stimulation of these receptors would activate the adenylate cyclase (AC), which would catalyze the ATP to cyclic adenosine monophosphate (cAMP), and cAMP would further activate the cAMP-response element binding protein (CREB) through activation of protein kinase A (PKA; Carlezon et al., 2005 ). The transcription factor CREB is responsible for gene expression of many proteins involved in the neuroplasticity of hippocampus, such as BDNF, glutamate receptor unit 1 (GluR1), etc ( Pittenger and Duman, 2008 ). Since the atrophy of hippocampus has been consistently found to play a key role in the vulnerability, chronicity, and treatment-resistance of MDD ( MacQueen and Frodl, 2011 ), improving the neurogenesis of hippocampus through activation of postsynaptic monoamine receptors may effectively promote depression recovery. This pathway may be abbreviated as the “GPCR-cAMP” pathway. While the “GPCR-cAMP” pathway is commonly seen in other organs or tissues, it is not the major pathway regulating the function of CREB in the brain ( Carlezon et al., 2005 ).

Second, antidepressant would regulate neuroplasticity through reducing release of presynaptic glutamate, especially the depolarization-evoked release of glutamate, in PFC ( Bonanno et al., 2005 ). The possible molecular mechanism of antidepressants on the release of glutamate had been reviewed in the article of Sanacora et al. (2012) . The reduced glutamate release may imply decreased neurotoxic efficacy and strengthened synaptogenesis, synaptic connections and neurogenesis. To be mentioned, chronic antidepressant would also prevent the stress-induced glutamate release, which may underlie the clinical prophylaxic efficacy of maintenance antidepressant treatment for relapse or recurrence of MDE.

Third, antidepressant may work on neuroplasticity through enhancing AMPA to NMDA throughput ( Du et al., 2006 ). Antidepressants may binding to the glycine-binding site of NMDA receptor and inactivate this site ( Paul and Skolnick, 2003 ). The inactivation of NMDA receptor activity would result in inhibition of eukaryotic elongation factor 2 (eEF2) and enhance the expression of BDNF through subsequent signaling ( Monteggia et al., 2013 ). Besides, antidepressant would upregulate the expression of AMPA subunits GluR1 and potentiate the function of AMPA ( Martinez-Turrillas et al., 2002 ). The depolarization of AMPA receptor would activate the voltage-dependent calcium channels (VDCCs) and induce influx of Ca 2+ into cytoplasm, which would further trigger the exocytosis of BDNF. Then the extracellular BDNF would further stimulate its membrane receptor—TrkB and regulate gene expression and neuroplasticity through subsequent signaling ( Yoshii and Constantine-Paton, 2010 ). Thus stimulation of AMPA and inactivation of NMDA would work synergistically to improve neuroplasticity in the brain.

Fourth, antidepressant may improve neuroplasticity directly through LTP-like process. It has been repeatedly revealed that hippocampal synaptic plasticity was suppressed by stress through diminished amount of LTP, while antidepressant would reverse the negative efficacy of stress and potentiate synaptogenesis and synaptic connectivity through inducing LTP-like processes ( Popoli et al., 2002 ; Shakesby et al., 2002 ).

Last but not least, antidepressant may also improve neurogenesis in the hippocampus through activation of the 5-HT 1A receptor ( Santarelli et al., 2003 ).

Despite the role of BDNF in promoting neuroplasticity and neurogenesis in the hippocampus and PFC and mediating the antidepressant efficacy as mentioned above, what needs special attention is that BDNF may also promote neuroplasticity and neurogenesis in the amygdala, ventral tegmental area (VTA) and NAc, which is assumed to provoke depressive-like behaviors or exacerbate depressive symptoms ( Racagni and Popoli, 2008 ; Harmer and Cowen, 2013 ; Hayley and Litteljohn, 2013 ). Thus, the antidepressant efficacy is not totally opposite to the site-specific neurophysiological and neurochemical efficacy of stress on different brain regions, which inhibits neuroplasticity, induces atrophy in hippocampus and PFC and promotes maladaptive neuroplasticity and induces hypertrophy in amygdala. The hypertrophy and elevated activation of amygdala may underline the heightened risk of relapse in recurrent MDD.

Delayed Efficacy of SSRI and Fast Responding Ketamine: Clinical Trial Findings and Possible Interpretations of Discrepancy in Onset

The rapid onset of antidepressant efficacy of ketamine and delayed onset of efficacy in SSRIs treatment is of special interest. A meta-analysis revealed that overall response rate of single dose ketamine after 24 h is about 52.6%, and this efficacy would last about 3 days and decreased gradually with 10.9% of response rate remained at the end of week two after injection ( Newport et al., 2015 ). Repeated ketamine infusions are associated with a relatively higher overall response rate (70.8%), and the efficacy lasts about 18 days on average after the last ketamine injection ( Murrough et al., 2013 ). Although the clinical application of ketamine for depression is limited by its potential of abuse, the significant difference in time of efficacy onset between ketamine and typical antidepressants is of special clinical significance, since rapid onset of efficacy is urgently needed for MDD patients, particularly for those with suicidal ideation. Clarification the mechanisms underlying the discrepancy of efficacy onset between the two genre drugs may be helpful for the development of new antidepressants with rapid onset of efficacy.

The possible mechanism of antidepressant efficacy of ketamine has been summarized in several reviews ( Browne and Lucki, 2013 ; Zunszain et al., 2013 ; Kavalali and Monteggia, 2015 ; Scheuing et al., 2015 ), which all stated that the blockade of NMDA receptor and potentiation of AMPA receptor is of key significance in ketamine’s antidepressant efficacy. NMDA and AMPA are two ionotropic glutamate receptors distributed widely in the brain. Their physiological ligand, glutamate, is the only excitatory neurotransmitter and innervates the majority of neurons in the brain. Neurohistological studies found that 85% of the brain mass are composed of neocortex, and glutamate is the primary neurotransmitter of 80% neocortex neurons and 85% neocortex synapses ( Douglas and Martin, 2007 ). It is not difficult to infer from the above data that glutamate neurons account for so high proportion of the whole brain neurons that some researchers believe that the brain is largely a “glutamatergic excitatory machine” and all brain functions, particularly cognition and emotion are “ultimately mediated by the changes in excitatory transmission (glutamate) and its counterbalance of the inhibitory component (GABA)” ( Sanacora et al., 2012 ).

As discussed above, glutamate is closely related to neuroplasticity in the brain. Release of glutamate may induce rapid LTP and promote synaptogenesis and synaptoconnectomes. Blocking NMDA receptor and activating AMPA receptor may promote the expression of BDNF gene and promote neuroplasticity synergistically. Thus glutamate is the primary system regulating neuroplasticity in the brain. With these arguments, we believe that the fast onset of antidepressant efficacy of ketamine may be explained by the following two reasons: (1) ketamine acts directly on NMDA receptor and indirectly on AMPA receptor, while SSRIs mainly act on SERT and indirectly regulate efficacy of glutamate receptors; although activating the postsynaptic monoamine receptors also plays a role in the neuroplasticity, this pathway is much slower and weaker than direct working on ionotropic glutamate receptors, i.e., NMDA and AMPA, as discussed above; and (2) the glutamate neurons and neurotransmitters account for much higher proportion in number of neurons and synapses than 5-HT neurons (and other monoamine receptors), drugs work on the glutamate system would exert much greater efficacy on the brain than drugs work on the 5-HT system. Namely, ketamine takes a faster speed and shorter route to regulate neuroplasticity than SSRIs, and this is why the fast responding of ketamine and delayed onset of SSRIs would occur.

Summary and Future Perspectives

The monoamine theory of depression originated from the interpretation of the phenomenon observed in clinical practice, and has served as the primary hypothesis of MDD for more than 50 years. The prosperity of low 5-HT hypothesis is contributed to multilateral force coming from public, academy, industry, history, etc, as illustrated in the wonderful article of Mulinari (2012) . However, with new observations and research evidence constantly emerging, this simplistic hypothesis has been intensely challenged and modifications or even totally new hypothesis are needed. Although SSRIs are currently first-line antidepressants in psychiatry practice, new efficacious drugs with rapid onset of efficacy are emerging. And, in theory research area, a paradigm shift has occurred from monoamine hypothesis to glutamate and neuroplasticity theory, which provides a more mature interpretation framework for the complicated psychiatric disorder.

Neuroplasticity hypothesis of MDD evolves from the monoamine hypothesis and tries to address the problems of monoamine hypothesis. This theory starts from the key role of stress in the pathogenesis of MDD, and provides a reasonable framework for the interpretation of the relationship between stress, brain, depression and antidepressant efficacy. Although the molecular mechanisms underlying neuroplasticity are not fully clarified, this hypothesis provides the most promising framework for understanding the pathogenesis of depression and antidepressant efficacy. However, there are some major themes urgently needed for clarification in future studies.

First, the relationship between stress and MDD has been extensively explored, while gene also plays a key role in the pathogenesis of MDD, how the interaction between gene and stress work on neuroplasticity and its relationship with depression pathogenesis and antidepressant efficacy is of special interest for scientists and clinicians.

Second, more comprehensive and detailed understanding of the molecular mechanisms, particularly the interaction between the neurotransmitter receptors and their subsequent signaling pathways, underlying neuroplasticity, depression and antidepressant efficacy is needed. Targets in these signaling pathways may be of special value in new antidepressant development.

Third, the neuroplasticity theory is not exclusive for MDD, it may also account for the pathogenesis of other psychiatric disorders, such as schizophrenia and bipolar disorder. Thus an interesting question is how the alterations in neuroplasticity account for the significantly different symptomatology of these disorders? Exploring answers to this question may help delineating the boundaries of MDD and searching for objective diagnostic biomarkers for MDD.

Author Contributions

LL, YZ and BL co-designed the topic and contributed substantially to the conception of the article. BL performed the literature work, drafted the manuscript and approved the final version of the article. JL, MW and YZ contributed valuable suggestions to the conception of the article and partial literature analysis. LL and YZ critically revised the manuscript and have approved the final version of the article.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

This research was supported by grant from the National Science and Technologic Program of China (2015BAI13B02 to LL), National Basic Research Program of China (+ 2013CB835100 to LL) and National Natural Science Foundation of China (81171286 and 91232714 to LL; 81671353 to YZ).

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Keywords: major depressive disorder, serotonin, neuroplasticity, final common pathway, antidepressant efficacy

Citation: Liu B, Liu J, Wang M, Zhang Y and Li L (2017) From Serotonin to Neuroplasticity: Evolvement of Theories for Major Depressive Disorder. Front. Cell. Neurosci. 11:305. doi: 10.3389/fncel.2017.00305

Received: 05 March 2017; Accepted: 13 September 2017; Published: 28 September 2017.

Reviewed by:

Copyright © 2017 Liu, Liu, Wang, Zhang and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Yan Zhang, [email protected] Lingjiang Li, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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What's the Latest in Depression Treatment?

Exploring the newest depression treatments on the horizon

Psychedelics and Ketamine

• Other Fast-Acting Treatments
• What's on the Horizon

If it’s felt to you like we’re at an inflection point with mental health, you’re not wrong.

Depression rates, which were already on the rise before the pandemic, appear to be higher than ever. One estimate from the World Health Organization (WHO) puts the global increase of people diagnosed with major depressive disorder (MDD) at a more than 25% rate from 2019 to 2020—and this doesn’t even include people who reported feelings of depression but didn’t meet the full criteria for a diagnosis.

Though actual suicide rates were steady or even down in some countries, the same WHO report estimates that in the US, the incidence of suicidal thoughts went up from about 18% to around 30% in 2020 during pandemic stay-at-home orders.

The good news: there’s currently more innovation in mental health treatment than there’s been since the 1980s when selective serotonin uptake inhibitors (SSRIs) were originally introduced. Many of these new treatments work more quickly than those SSRIs, which can sometimes take up to four to six weeks to work.

"It's a time of hope for many people who haven't been helped by current treatments," says Jeffrey Borenstein, MD , who serves as President & CEO of the Brain & Behavior Research Foundation, which funds mental health research grants.

Depression also has a high recurrence rate. After treatment of the first episode of depression, around 50% will experience relapse. The risk for relapse increases for every subsequent episode. Research also suggests that 30.9% of people have treatment-resistant depression . This means an estimated 8.9 million Americans will try one or more treatments for depression without achieving remission.

With this combination of factors, it’s more crucial than ever to find treatments that are effective and work quickly. Read on to learn more about the new depression treatments that are currently being used, ones that are being researched, and where future research might lead.

It’s a time of hope for many people who haven’t been helped by current treatments.

At a Glance

Depression rates are at an all-time high—but new and effective treatments for this common mental health condition are on the horizon. Since the first antidepressants were introduced in the 1950s, more and more options have continued to emerge. Today, there is an increasing interest in the use of psychedelics and ketamine for depression relief. Other fast-acting options include recently introduced antidepressants and transcranial magnetic stimulation (TMS). Options that show promise as future treatments include optogenetics and stem cells.

History of Depression Treatment

In order to understand current and future depression treatment, it's important to know where we’ve come from to get to where we are today—and some of the conventional wisdom we may be in the process of overturning.

The Monoamine Hypothesis 

The first antidepressant, Ipronizaid, was discovered by accident when it was given to patients with tuberculosis. The patients showed a marked improvement in mood. This monoamine oxidase inhibitor (MAOI) works by preventing the body’s monoamine oxidase enzyme from breaking down dopamine , serotonin , and norepinephrine in the brain.

These three neurotransmitters , collectively known as monoamines because of their similar chemical structures, are responsible for key brain processes, including learning, emotion, and memory. 

The idea that the depletion of these neurotransmitters is what leads to depression is known as the monoamine hypothesis. Tricyclic antidepressants and SSRIs have also been thought to have their impact based on this theory.

The Development of TCAs and SSRIs

Tricyclic antidepressants (TCAs) were developed following the introduction of MAOIs in the 1950s. They work by inhibiting the absorption of serotonin and norepinephrine, and blocking acetylcholine, another neurotransmitter.

With the development of MAOIs and TCAs in the 1950s and 1960s, there was a significant lack of research on other types of antidepressants—until Prozac (fluoxetine) was introduced in 1987.

This was the first SSRI—that is, the first antidepressant to work exclusively on blocking the reabsorption of serotonin. Increasing serotonin levels is thought to regulate mood. Additionally, SSRIs carry far fewer side effects than the earlier MAOIs/TCAs—though they are not without side effects.

Even newer classes of antidepressants, such as selective serotonin-norepinephrine reuptake inhibitors (SNRIs) and atypical antidepressants, still were thought to work based on the monoamine hypothesis.

Newer theories believe that the monoamine hypothesis of low levels of dopamine, serotonin, and norepinephrine "causing" depression, and depression being "cured" by increasing these neurotransmitters, oversimplifies the complexity of the neurochemistry of depression.

The Neuroplasticity Hypothesis

More modern theories look at the role of stress in depression and at the neuroplasticity hypothesis. Stress is linked to both an increased risk of major depressive episodes and treatment resistance .

It is thought that chronic stress leads to dysregulation in the hypothalmic-pituitary-adrenocortical (HPA) axis, which controls reactions to stress as well as mood and emotion, among other things. This dysregulation causes impairment in the hippocampus, which controls memory and emotion.

This leads to the neuroplasticity hypothesis of depression. Put simply, neuroplasticity is the brain’s ability to adapt and change to signals both within and outside of the body.

Those with depression show significantly lower levels of neuroplasticity and a decreased ability to adapt to stress.

Looking at depression through the neuroplasticity theory broadens the focus from how a medication might affect someone's brain from looking beyond just levels of neurotransmitters to looking at how well the neurons are communicating with each other at various parts of the process to create neuroplasticity.

BDNF and Glutamate May Be the Future of Depression Treatment

This neuroplasticity theory involves other systems and chemicals within the brain, and two major areas that are receiving particular focus right now in depression treatment are brain-derived neurotrophic factor (BDNF) and glutamate.

BDNF is a chemical in the brain that is associated with cell growth and cell death, and it is thought that lower levels of BDNF lead to lower levels of neuroplasticity, so it is an area that is receiving attention in development of depression treatment.

Glutamate is an "excitatory" neurotransmitter , meaning it is a messenger that stimulates nerve cells to be ready to receive information. It also helps nerve cells better communicate with each other.

It’s being looked at in depression treatment because optimal glutamate functioning may help facilitate, increasing neuroplasticity, so targeting the glutamate system via new treatments such as ketamine or psychedelics may help symptoms.

Timeline of Depression Research History

• 1958: The first antidepressants, Iproniazid (MAOI) and Imipramamine (TCA)
• 1961 MAOIs: Nardil and Partite
• 1961-1980: tricyclic antidepressants—Elavil, Norpramin, Sinequan, Vivactil, Pamelor, Surmontil, Ludiomil
• 1987: Prozac, the first SSRI
• 1991-1998: SSRIs Zoloft, Paxil, Celexa; SNRIs Effexor and Serzone

Psychedelics are currently having a moment in both scientific circles and mainstream media due to their potential for rapid, significant, and long-lasting reduction in symptoms of depression.

A 2016 study of cancer patients found that just a single treatment of psilocybin (aka "magic mushrooms") led to an immediate reduction in measures of depression that were then seen to last up to six months, with nearly 80% of study participants still reporting antidepressant effect. Even in a follow-up study five years later, a majority of the study subjects still reported reduced symptoms of depression.

It’s believed that a combination of the drug's biological effects on the brain as well as the spiritual and mystical experience contribute to the high levels of effectiveness. The experience may give people relief from more existential aspects of depression.

With that said, it so far has only been studied in very controlled clinical environments so it’s not yet known how it might work in the "real world," and a solid framework has not yet been established on how to do this safely. Despite this, the state of Oregon and the cities of Santa Cruz and Oakland, California, among other locale, have decriminalized the use of psilocybin for therapeutic use.

Already, venture capital has been flowing into the psilocybin "market," with investors eager to capitalize on the promise of its healing powers before it has even been widely legalized or approved by the FDA for the treatment of depression. It is estimated that by 2027, psychedelics will be a multibillion-dollar industry.

Psilocybin has already been granted FDA Breakthrough Therapy designation , meaning that drugs that show significant improvement over traditional therapies in treating serious illnesses can be reviewed and approved on an expedited timeline.

However, some safety concerns do exist. In addition to physical side effects, some patients experienced an increase in suicidal behaviors and ideations. Research is also being done on how to remove the hallucinogenic properties of these drugs.

MDMA, also known as ecstasy or Molly in its street forms, has also been granted FDA “breakthrough therapy” status after Phase 2 clinical trials where a whopping 67% of people in the trial—who entered with severe PTSD—no longer qualified for a PTSD diagnosis.

Although clinical research for MDMA for depression has not gotten as far as MDMA for PTSD, MDMA does show promise for treating major depressive disorder—and more than 50% of adults who have a diagnosis of PTSD also have a diagnosis of MDD.

MDMA works by rapidly releasing and increasing levels of serotonin and dopamine in the brain.

MDMA, it is theorized, is so helpful in PTSD because it helps people recall negative memories with the brain's fear response being better regulated. This may lead to greater self-compassion and stay with these memories safely in therapy without getting overwhelmed.

Of all of the "psychedelic" treatments out there, ketamine is currently the only one that is legal for treatment in all 50 states. (Experts cannot agree on whether it is a true psychedelic or not, though it does cause dissociative effects.)

Ketamine was first synthesized in the 1960s as an anesthetic, and early observations showed that ketamine might work similarly to antidepressants. It wasn’t until the 1990s that ketamine would be studied in earnest to treat depression, with the first randomized controlled study showing the promise of ketamine as an antidepressant being released in 2000.

Spravato (esketamine) was approved in 2019 via Fast Track status with the FDA, and it is currently administered as a nose spray that must be consumed under the monitoring of a doctor for safety reasons.

Esketamine specifies a particular type of ketamine molecule that is thought to be more potent at the NMDA glutamate receptor. IV ketamine uses a different part of the molecule and is currently used off-label for depression. It has demonstrated a more significant overall response rate than intranasal ketamine but is more complicated to use.

Ketamine has received such wide attention for several reasons: first of all, it targets a completely different set of neurotransmitters in the brain than previously studied depression treatments and often begins working within hours. It also may quickly reduce suicidal ideation in some cases.

As other treatments target the monoamine system (see above), ketamine is thought to create a surge of glutamate neurotransmission in the brain.

The fact that ketamine can work so quickly on refractory depression has the potential to be a game changer for depression.

However, more research is needed to figure out how to optimally use this agent, as well as to develop agents like ketamine that don't carry the dissociative side effects and are potentially easier and safer for wide use.

Although ketamine is generally well-tolerated, it does have a number of side effects at the time of administration, such as nausea, dizziness, feeling woozy, spacey, numb, and having sensory distortions—though these side effects typically subside quickly.

Arketamine, which uses a different part of the molecule, is currently being studied as well, as it lasts longer and has fewer side effects, including less dissociative side effects. The FDA has given approval for investigational new drug clearance to study how it will work with other medications.

Other Fast-Acting Treatments 

Beyond the psychedelic space, there are several other new depression treatments that are rapid-acting, including a new protocol for TMS therapy as well as a new oral antidepressant.

"The fact that there's these new treatments [and] that [they can] work so rapidly is something we very much need," says Borenstein. "One of the benefits is that they’re rapidly acting to treat suicidal acts and risk, and that has the potential to be a game changer in psychiatry."

One of these treatments is the oral antidepressant Auvelity , approved by the FDA in August 2022. Auvelity may work within a week and targets the glutamate system, similarly to ketamine.

The medication is a combination of buproprion (the active ingredient in Wellbutrin) and dextromethorphan (commonly found in cough syrup). Its approval may open the door for a new class of medications that work to increase glutamate.

Although transcranial magnetic stimulation (TMS) was first approved by the FDA in 2008, newer versions of the protocol are found to produce results in less than a week, compared to six weeks in the older version.

TMS therapy involves using magnetic pulses on the head to treat depression. The pulses are targeted to the area of the brain implicated in depression, and they work to activate these regions. One of the major areas stimulated is the prefrontal cortex, an area of the brain associated with regulating mood.

According to some research, it has been shown to benefit somewhere between 50-60% of those who have not adequately responded to one or more antidepressant treatments.

Typically, TMS treatment takes six weeks of once-daily sessions, a major time commitment. With this Stanford accelerated intelligent neuromodulation therapy (SAINT) protocol, developed at Stanford, people receive 10 treatments per day for five days.

Moreover, according to the Stanford study, nearly 80% of people no longer met criteria for depression, meaning their symptoms were back in the "normal" range. In the "regular" treatment, only about half the people treated improve, with only a third meeting "remission."

"The patients had remission of depression after a few days, which is tremendous," says Borenstein.

One of the theories behind SAINT is that people who didn’t receive a high enough frequency and density of stimulation.

Some key differences in the SAINT protocol:

• Treating people multiple sessions per day with optimally spaced intervals
• Applying higher levels of stimulation (1800 pulses vs 600)
• Precision targeting through FMRI scans that helped the researchers find the precise location in each participant's brain where the stimulation would occur 

The protocol was approved in September 2022 and is expected to launch in 2023.

What's on the Horizon

In Borenstein’s role helming the Brain & Behavior Research Foundation, he has a birds-eye view of innovation going on in mental health research, as the foundation is the nation’s largest private funder of mental health grants.

A few other possible treatment areas he’s excited about:

Optogenetics : This is a way to use light and genetic tools to control the activity of certain neurons. These techniques have been used to map connections in the brain, but there is hope that someday this technique will be able to positively impact specific cellular pathways in depression.

Stem Cells: A theory is currently being studied that stem cells may decrease depression by helping create more neurons that can form more connections in the brain. Current research includes investigating if there are new molecules that can activate stem cells to act in this antidepressant way.

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Compass Pathways. COMPASS Pathways announces positive topline results from groundbreaking phase IIb trial of investigational COMP360 psilocybin therapy for treatment-resistant depression .

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Mitchell JM, Bogenschutz M, Lilienstein A, et al. MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled phase 3 study. Nat Med . 2021;27(6):1025-1033. doi: 10.1038/s41591-021-01336-3

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By Theodora Blanchfield, AMFT Theodora Blanchfield is an Associate Marriage and Family Therapist and mental health writer using her experiences to help others. She holds a master's degree in clinical psychology from Antioch University and is a board member of Still I Run, a non-profit for runners raising mental health awareness. Theodora has been published on sites including Women's Health, Bustle, Healthline, and more and quoted in sites including the New York Times, Shape, and Marie Claire.

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Is the serotonin hypothesis/theory of depression still relevant? Methodological reflections motivated by a recently published umbrella review

Hans-jürgen möller.

Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Nussbaumstr. 7, 80336 Munich, Germany

Peter Falkai

Associated data.

Not applicable.

The serotonin hypothesis of depression was first proposed in 1967, when the first antidepressants were being developed. It was subsequently refined, but for a long time it was criticized as being too one-sided. Later, the hypothesis was replaced by complex neurobiological theories, e.g., the chemical imbalance theory, which included additional neurotransmitters [ 1 ]. Consequently, the critical findings of the recently published umbrella review by Joanna Moncrieff and colleagues [ 2 ], which claim to falsify the serotonin hypothesis, come as no surprise. The publication of these findings is a good reason to carefully examine the content and methodologies of research on this topic and the basic problems associated with falsifying hypotheses and theories. However, for reasons of space, this editorial will discuss only a few of the main methodological aspects.

The umbrella review by Moncrieff et al. summarizes the results of all systematic reviews and meta-analyses on the serotonin hypothesis of depression and subdivides the hypothesis into six areas: serotonin and the 5-hydroxyindoleacetic acid (HIAA) level in body fluids, serotonin receptor activity, serotonin transporter activity, results of tryptophan depletion studies, serotonin transporter gene levels, and the interaction between the serotonin transporter gene and stress. The areas address the main serotonin theory but not all aspects of it. They make the complexity of the topic clear, in particular the fact that the serotonin theory comprises a bundle of related individual hypotheses. Thus, from the perspective of scientific theory, the authors have to confirm or falsify not a single hypothesis but a whole group of hypotheses held together by a complex theory. Testing and perhaps refuting such a complex theory is much more demanding than testing/refuting a single hypothesis.

The umbrella review includes only data from patients and no findings from animal experiments. The exclusion of animal studies limits the scope of the study considerably and is difficult to reconcile with the demands of testing a complex neurobiological theory.

In evidence-based medicine, meta-analyses and systematic reviews are considered to represent the highest evidence level. However, the inherent problems of these methodological approaches are often not adequately considered [ 3 ] and are also not discussed by Moncrieff et al. The main methodological problem of meta-analyses and thus also of the umbrella review is the question of how to decide which studies to include and which to exclude. Systems of formalistic rules exist for selecting studies, but content-related criticisms about study selection are frequently expressed by people with knowledge of the topic (e.g. clinical psychopharmacologists and neuroscientists). One wonders why from among the 360 studies identified by the PRISMA search process as being theoretically relevant, the systematic umbrella review included only 17 in its final evaluation/description. The respective flow diagram gives only a rough idea of the reasons why studies were excluded.

As is the case in many systematic reviews and meta-analyses, the content-related problems of the individual included studies are not discussed. However, these problems should be reviewed critically. It only makes sense to include studies that were well planned and implemented not only with respect to the formal aspects considered by systematic reviews and meta-analyses, but also with respect to their content. Whether and how this latter aspect was assessed remains unclear in the umbrella review because the authors do not discuss it in detail. Therefore, one must assume that such a detailed evaluation was performed not by the authors of the umbrella review but by the authors of the original meta-analyses. However, that was probably not the case in most of the meta-analyses because when selecting empirical studies for inclusion in such analyses, researchers normally check only formal aspects. The aspects that should actually be considered when evaluating studies were presented by Riederer [ 4 ], among others, by using the example of studies related to serotonin/tryptophan and include the following: problems in determining serotonin in plasma HIAA in cerebrospinal fluid; the fact that plasma serotonin does not reflect the serotonin concentration in the brain because serotonin is metabolized at the blood–brain barrier; consideration of the suboccipital/lumbar HIAA gradient when performing a lumbar puncture; and the temporal difference between tryptophan depletion and the effects of serotonin metabolism on the brain.

In addition to systematic reviews and meta-analyses on the serotonin hypothesis, the umbrella review includes several large studies and a large genetic study based on UK-wide data; the former studies summarize data from individual studies without using the strict approach of a systematic review. The authors state that including these studies was the best way to comprehensively portray the evidence. However, this approach is unusual for an umbrella review and methodologically questionable. Although umbrella reviews typically consider previous meta-analyses/systematic review of primary studies and umbrella reviews of meta-analyses/systematic reviews (also termed “meta-umbrella reviews”) separately, Moncrieff et al. summarized these different types of studies together. This approach means that a comparison of effect sizes is potentially unreliable. In addition, the selection criteria for the primary studies are unclear, which opens the door to uncontrolled selection biases: Some primary studies appear to have been included at the expense of others.

The tryptophan-related studies can be used as an example of how problematic the presentation by Moncrieff et al. is in terms of study selection [ 5 ]. Moncrieff et al. included one meta-analysis, one systematic review, and ten recent studies involving healthy volunteers, but they did not include a clinical and molecular imaging study that showed an effect in people with major depressive disorder [ 6 ]. They also omitted several studies included in two meta-analyses that evaluated circulating concentrations of tryptophan, a substance that directly influences central serotonin [ 7 , 8 ].

The umbrella review also contains a number of material errors and misinterpretations, e.g., concerning imaging data on both 5-HT 1A receptor and serotonin transporter protein (SERT) binding [ 5 ]. For example, the statement by Moncrieff et al. [ 2 ] that 5HT 1A receptors are known as autoreceptors mistakenly assumes that 5HT 1A receptors are exclusively pre-synaptic autoreceptors, whereas most of these receptors are post-synaptic 5-HT 1A heteroreceptors. Reduced availability of post-synaptic 5-HT 1A receptors in unmedicated depression would be consistent with decreased 5-HT neurotransmission.

Overall, the included studies in the various relevant areas produced hardly any evidence for the serotonin theory, and at the most, they found weak connections that support only a few aspects of it. Therefore, the authors conclude from their results that their evaluation cannot confirm the serotonin theory of depression. Even though the authors discuss some of the methodological problems of the individual studies and meta-analyses and the reason for the negative results, they believe that their overall result falsifies the serotonin hypothesis, in particular because they consider the umbrella review approach, which summarizes all available reviews and meta-analyses, as the highest level of evidence synthesis.

Even if one initially accepts the result of the umbrella review by Moncrieff et al. [ 2 ], the broad non-confirmation of various sub-hypotheses of the serotonin theory of depression does not mean that the theory is completely false and, consequently, that a neurobiological explanation of depression is refuted. As in other areas of medicine, the serotonin theory has been expanded through various new basic research findings, e.g., neurogenesis and synaptogenesis, neuronal networks, neuroendocrinology, neuroinflammation, and genetics, independent of the serotonergic system, so these aspects must be included in the etiopathological reflections on the cause of the complex disease depression or its subgroups [ 1 ]. Consequently, the studies on the serotonergic system included in the umbrella review represent only part of the complex neurobiological understanding of depression. The serotonin theory can definitely continue to be scientifically relevant as a partial aspect of the theoretical concept of depression and as part of more complex concepts.

Of relevance in this context is the work of the famous science theorist Thomas S. Kuhn, who showed in his studies on the history of science [ 9 ] that in contrast to the falsification theory from the equally famous science theorist Karl Popper—whom we are in no way questioning here—most complex theories, unlike simple hypotheses, cannot be refuted by falsification. Instead, people lose interest in them because of paradigm shifts in the sense that a younger generation of researchers becomes interested in other theories or because highly complex theories characterized by more advanced technologies gain the upper hand. However, until that happens, the theories can retain a certain usefulness for research, even if they are insufficiently proven. These considerations help one understand why, despite being criticized, the serotonin theory is still relevant as an explanation of depression. Depression is characterized neurobiologically by an imbalance of a complex dynamic system involving genetic, epigenetic, environmental, and stress vulnerabilities, and this imbalance initiates a cascade of neurobiological alterations in and beyond serotonergic functioning. All integrally related pathways interact multi-directionally throughout the various phases of depression [ 1 ].

Moncrieff et al. do not limit their argumentation to their critical conclusion about the validity of the serotonin theory of depression. Instead, with the following sentence in the Discussion section they go far beyond the empirical results of their study by drawing conclusions about the use of antidepressant treatment: “The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs” (2, p. 11). This treatment-related conclusion is highly problematic and cannot be directly inferred from the result of the umbrella review. Furthermore, the efficacy of antidepressant treatment, including serotonergic antidepressants, is well supported by the evidence [ 10 ]. In principle, we can view the efficacy of antidepressants independently from the validity of the serotonin theory of depression and simply interpret the serotonin mechanism as a favorable mechanism for achieving antidepressant effects, not as a theory of causality of depression. Interestingly, Moncrieff et al. do not cite studies that prove the efficacy of antidepressants; as far as the serotonergic antidepressants are concerned, such studies could well be discussed as providing ex juvantibus support for the serotonin theory.

The conclusion drawn by Moncrieff et al. [ 2 ] that the usefulness of antidepressant treatment should be questioned—a conclusion that is in line with the position that Joanna Moncrieff has frequently published, especially in the lay press—can have severe negative consequences for the treatment adherence of people with depression. The question we need to ask is whether the results of their umbrella review are strong enough, as far as the methodology and content of the review are concerned, that they allow such a far-reaching conclusion to be drawn or whether this conclusion rather reflects the authors’ own bias.

Open Access funding enabled and organized by Projekt DEAL.

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• 04 September 2024

Found: a brain-wiring pattern linked to depression

• Sara Reardon 0

Sara Reardon is a freelance journalist based in Bozeman, Montana.

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The network of brain cells called the salience network (black) is bigger in people with depression (middle and right columns) than in those without (left column). Credit: C. J. Lynch et al ./ Nature

The symptoms of depression might come and go, but new evidence suggests that the pattern of brain wiring behind it remains the same for life. The largest imaging study 1 of its kind has found that a certain brain network involved in directing attention to stimuli is nearly twice as big in people with depression as it is in the rest of the population — and that it remains that way when a person no longer feels depressed.

The results are a step towards a biological marker for depression, which is at present diagnosed mainly using questionnaires. But the authors say their finding should be validated in more populations before it is used clinically. The study was published today in Nature .

Networking skills

The technique called functional magnetic resonance imaging (fMRI) allows researchers to study the networks of neurons that wire together different parts of the brain and to measure how much communication passes through these networks. Everyone’s brain networks look fairly similar, but each person shows some variation from the average.

Those individual differences are what neuroscientist Charles Lynch and psychiatrist Conor Liston, both at Weill Cornell Medicine in New York City, and their colleagues set out to investigate, hoping to find networks that correlate with depression. But every fMRI scan is just a snapshot of a brain, which limits the technique’s usefulness for studying a dynamic disorder such as depression, Liston says.

The psychedelic escape from depression

So the team turned to existing data sets containing fMRI images of people who had been repeatedly scanned over time: 135 people with major depressive disorder, which causes severe and long-lasting symptoms; and 37 healthy participants. In almost every person with depression, they found, a brain circuit known as the salience network was almost twice as large as it was in controls. The salience network is itself a connector between other brain circuits. It is involved in switching the brain between internal awareness and working memory , and it helps the brain to decide which environmental stimuli and internal emotions it should pay attention to.

At first, the researchers thought the salience network might expand when a person was depressed. So they used fMRI to scan the brains of several other people with depression nearly every week for up to 18 months and assessed how the person was feeling each time. The salience network of each individual was about the same size every time, whether the person was feeling depressed or not. What did change was the amount of activity between brain regions, which decreased when the person was actively depressed. The researchers could even use network activity to predict whether a person would have a depressive episode the following week.

Early warning sign

The results led the scientists to suspect that a larger network puts people at increased risk of depression, rather than being a simple biomarker for it.

To test this, the team turned to the ABCD Study, which aims to track brain development in nearly 12,000 children between the ages of 9 and young adulthood. They identified 57 children who did not have depression before the age of 13 but who developed the disorder as adolescents. At ages at young as nine years, these children already had expanded salience networks compared with their peers. “It’s moving one step closer to cause and effect,” Liston says.

The researchers are unsure what causes the expansion of the network, but they have a few ideas. Large salience networks could be a genetic trait, given that depression is partly heritable . Alternatively, Lynch says, the network might be overused during a depressive episode — if a person was ruminating on negative stimuli, for instance — and grow in response.

Potential benefits

Diego Pizzagalli, a depression researcher at McLean Hospital in Belmont, Massachusetts, is impressed with the consistency of the findings across databases. If the work is replicated, Pizzagalli says, the size of a child’s salience network could one day be used to identify whether they are at risk of depression, and to intervene through therapy to reduce the likelihood of the disease .

Cognitive neuroscientist Caterina Gratton at the University of Illinois Urbana–Champaign is also impressed with the study, and particularly that it tracked individuals over time instead of looking at large numbers of people. “Rather than reading a few pages of many books, we’re reading whole chapters,” she says.

Lynch says that the team is now investigating whether the expanded network correlates with other mental illnesses that share some symptoms with depression, such as bipolar disorder and obsessive compulsive disorder. “It would be very surprising if this [network expansion] were specific to depression, given how heterogeneous depression is,” he says.

Nature 633 , 265-266 (2024)

doi: https://doi.org/10.1038/d41586-024-02857-w

Lynch, C. J. et al. Nature https://doi.org/10.1038/s41586-024-07805-2 (2024).

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