Investigating the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism in participants with major depressive disorder.

Reduced hippocampal volume occurs in major depressive disorder (MDD), potentially due to elevated glucocorticoids from an overactivated hypothalamus-pituitary-adrenal (HPA) axis. To examine this in humans, hippocampal volume and hypothalamus (HPA axis) metabolism was quantified in participants with MDD before and after antidepressant treatment. 65 participants (n = 24 males, n = 41 females) with MDD were treated in a double-blind, randomized clinical trial of escitalopram. Participants received simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) before and after treatment. Linear mixed models examined the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism. Chi-squared tests and multivariable logistic regression examined the association between hippocampus/dentate gyrus volume change direction and hypothalamus activity change direction with treatment. Multiple linear regression compared these changes between remitter and non-remitter groups. Covariates included age, sex, and treatment type. No significant linear association was found between hippocampus/dentate gyrus volume and hypothalamus metabolism. 62% (38 of 61) of participants experienced a decrease in hypothalamus metabolism, 43% (27 of 63) of participants demonstrated an increase in hippocampus size (51% [32 of 63] for the dentate gyrus) following treatment. No significant association was found between change in hypothalamus activity and change in hippocampus/dentate gyrus volume, and this association did not vary by sex, medication, or remission status. As this multimodal study, in a cohort of participants on standardized treatment, did not find an association between hypothalamus metabolism and hippocampal volume, it supports a more complex pathway between hippocampus neurogenesis and hypothalamus metabolism changes in response to treatment.

Effects of ebselen addition on emotional processing and brain neurochemistry in depressed patients unresponsive to antidepressant medication.

Lithium is an effective augmenting agent for depressed patients with inadequate response to standard antidepressant therapy, but numerous adverse effects limit its use. We previously reported that a lithium-mimetic agent, ebselen, promoted a positive emotional bias-an indicator of potential antidepressant activity in healthy participants. We therefore aimed to investigate the effects of short-term ebselen treatment on emotional processing and brain neurochemistry in depressed patients with inadequate response to standard antidepressants. We conducted a double-blind, placebo-controlled 7-day experimental medicine study in 51 patients with major depressive disorder who were currently taking antidepressants but had an inadequate response to treatment. Participants received either ebselen 600 mg twice daily for seven days or identical matching placebo. An emotional testing battery, magnetic resonance spectroscopy and depression and anxiety rating scales were conducted at baseline and after seven days of treatment. Ebselen did not increase the recognition of positive facial expressions in the depressed patient group. However, ebselen increased the response bias towards fear emotion in the signal detection measurement. In the anterior cingulate cortex, ebselen significantly reduced the concentrations of inositol and Glx (glutamate+glutamine). We found no significant differences in depression and anxiety rating scales between visits. Our study did not find any positive shift in emotional bias in depressed patients with an inadequate response to antidepressant medication. We confirmed the ability of ebselen to lower inositol and Glx in the anterior cingulate cortex. These latter effects are probably mediated through inhibition of inositol monophosphatase and glutaminase respectively.

Lower levels of TRAF1 in Brodmann's area 24, but not 46, in bipolar disorders are not detectable in major depressive disorders.

INTRODUCTION: Multiple lines of research implicate inflammation-related pathways in the molecular pathology of mood disorders, with our data suggesting a critical role for aberrant cortical tumour necrosis factor α (TNF)-signaling in the molecular pathology of bipolar disorders (BPD) and major depressive disorders (MDD). METHODS: To extend our understanding of changes in TNF-signaling pathways in mood disorders we used Western blotting to measure levels of tumour necrosis factor receptor associated factor 1 (TRAF1) and transmembrane TNF receptor superfamily member 1B (tmTNFRSF1B) in Brodmann's areas (BA) 24 and 46 from people with BPD and MDD. These proteins are key rate-limiting components within TNF-signaling pathways. RESULTS: Compared to controls, there were higher levels of TRAF1 of large effect size (η = 0.19, Cohen's d = 0.97) in BA 24, but not BA 46, from people with BPD. Levels of TRAF1 were not altered in MDD and levels of tmTNFRSF1B were not altered in either disorder. LIMITATIONS: The cases studied had been treated with psychotropic drugs prior to death which is an unresolvable study confound. Cohort sizes are relatively small but not untypical of postmortem CNS studies. CONCLUSIONS: To facilitate post-synaptic signaling, TRAF1 is known to associate with tmTNFRSF1B after that receptor takes its activated conformation which occurs predominantly after it binds to transmembrane TNF (tmTNF). Simultaneously, when tmTNFRSF1B binds to tmTNF reverse signaling through tmTNF is activated. Hence our findings in BA 24 argues that bidirectional TNF-signaling may be an important component of the molecular pathology of BPD.

Sleep rebound leads to marked recovery of prolonged sleep deprivation-induced adversities in the stress response and hippocampal neuroplasticity of male rats.

BACKGROUND: Sleep disturbances are not only frequent symptoms, but also risk factors for major depressive disorder. We previously reported that depressed patients who experienced "Hypersomnia" showed a higher and more rapid response rate under paroxetine treatment, but the underlying mechanism remains unclear. The present study was conducted to clarify the beneficial effects of sleep rebound through an experimental "Hypersomnia" rat model on glucocorticoid and hippocampal neuroplasticity associated with antidepressive potency. METHODS: Thirty-four male Sprague-Dawley rats were subjected to sham treatment, 72-h sleep deprivation, or sleep deprivation and subsequent follow-up for one week. Approximately half of the animals were sacrificed to evaluate adrenal weight, plasma corticosterone level, hippocampal content of mRNA isoforms, and protein of the brain-derived neurotrophic factor (Bdnf) gene. In the other half of the rats, Ki-67- and doublecortin (DCX)-positive cells in the hippocampus were counted via immunostaining to quantify adult neurogenesis. RESULTS: Prolonged sleep deprivation led to adrenal hypertrophy and an increase in the plasma corticosterone level, which had returned to normal after one week follow-up. Of note, sleep deprivation-induced decreases in hippocampal Bdnf transcripts containing exons II, IV, VI, and IX and BDNF protein levels, Ki-67-(+)-proliferating cells, and DCX-(+)-newly-born neurons were not merely reversed, but overshot their normal levels with sleep rebound. LIMITATIONS: The present study did not record electroencephalogram or assess behavioral changes of the sleep-deprived rats. CONCLUSIONS: The present study demonstrated that prolonged sleep deprivation-induced adversities are reversed or recovered by sleep rebound, which supports "Hypersomnia" in depressed patients as having a beneficial pharmacological effect.

Exploring the role of neuronal-enriched extracellular vesicle miR-93 and interoception in major depressive disorder.

Major depressive disorder (MDD) is associated with interoceptive processing dysfunctions, but the molecular mechanisms underlying this dysfunction are poorly understood. This study combined brain neuronal-enriched extracellular vesicle (NEEV) technology and serum markers of inflammation and metabolism with Functional Magnetic Resonance Imaging (fMRI) to identify the contribution of gene regulatory pathways, in particular micro-RNA (miR) 93, to interoceptive dysfunction in MDD. Individuals with MDD (n = 41) and healthy comparisons (HC; n = 35) provided blood samples and completed an interoceptive attention task during fMRI. EVs were separated from plasma using a precipitation method. NEEVs were enriched by magnetic streptavidin bead immunocapture utilizing a neural adhesion marker (L1CAM/CD171) biotinylated antibody. The origin of NEEVs was validated with two other neuronal markers - neuronal cell adhesion molecule (NCAM) and ATPase Na+/K+ transporting subunit alpha 3 (ATP1A3). NEEV specificities were confirmed by flow cytometry, western blot, particle size analyzer, and transmission electron microscopy. NEEV small RNAs were purified and sequenced. Results showed that: (1) MDD exhibited lower NEEV miR-93 expression than HC; (2) within MDD but not HC, those individuals with the lowest NEEV miR-93 expression had the highest serum concentrations of interleukin (IL)-1 receptor antagonist, IL-6, tumor necrosis factor, and leptin; and (3) within HC but not MDD, those participants with the highest miR-93 expression showed the strongest bilateral dorsal mid-insula activation during interoceptive versus exteroceptive attention. Since miR-93 is regulated by stress and affects epigenetic modulation by chromatin re-organization, these results suggest that healthy individuals but not MDD participants show an adaptive epigenetic regulation of insular function during interoceptive processing. Future investigations will need to delineate how specific internal and external environmental conditions contribute to miR-93 expression in MDD and what molecular mechanisms alter brain responsivity to body-relevant signals.

Dopaminergic dysfunction in the left putamen of patients with major depressive disorder.

INTRODUCTION: Dopaminergic transmission impairment has been identified as one of the main neurobiological correlates of both depression and clinical symptoms commonly associated with its spectrum such as anhedonia and psychomotor retardation. OBJECTIVES: We examined the relationship between dopaminergic deficit in the striatum, as measured by 123I-FP-CIT SPECT imaging, and specific psychopathological dimensions in patients with major depressive disorder. METHODS: To our knowledge this is the first study with a sample of >120 subjects. After check for inclusion and exclusion criteria, 121 (67 females, 54 males) patients were chosen retrospectively from an extensive 1106 patients database of 123I-FP-CIT SPECT scans obtained at the Nuclear Medicine Unit of Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome. These individuals had undergone striatal dopamine transporter (DAT) assessments based on the recommendation of their referring clinicians, who were either neurologists or psychiatrists. At the time of SPECT imaging, each participant underwent psychiatric and psychometric evaluations. We used the following psychometric scales: Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Snaith Hamilton Pleasure Scale, and Depression Retardation Rating Scale. RESULTS: We found a negative correlation between levels of depression (p = 0.007), anxiety (p = 0.035), anhedonia (p = 0.028) and psychomotor retardation (p = 0.014) and DAT availability in the left putamen. We further stratified the sample and found that DAT availability in the left putamen was lower in seriously depressed patients (p = 0.027) and in patients with significant psychomotor retardation (p = 0.048). CONCLUSION: To our knowledge this is the first study to have such a high number of sample. Our study reveals a pivotal role of dopaminergic dysfunction in patients with major depressive disorder. Elevated levels of depression, anxiety, anhedonia, and psychomotor retardation appear to be associated with reduced DAT availability specifically in the left putamen.

Identifying plasma metabolic characteristics of major depressive disorder, bipolar disorder, and schizophrenia in adolescents.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are classified as major mental disorders and together account for the second-highest global disease burden, and half of these patients experience symptom onset in adolescence. Several studies have reported both similar and unique features regarding the risk factors and clinical symptoms of these three disorders. However, it is still unclear whether these disorders have similar or unique metabolic characteristics in adolescents. We conducted a metabolomics analysis of plasma samples from adolescent healthy controls (HCs) and patients with MDD, BD, and SCZ. We identified differentially expressed metabolites between patients and HCs. Based on the differentially expressed metabolites, correlation analysis, metabolic pathway analysis, and potential diagnostic biomarker identification were conducted for disorders and HCs. Our results showed significant changes in plasma metabolism between patients with these mental disorders and HCs; the most distinct changes were observed in SCZ patients. Moreover, the metabolic differences in BD patients shared features with those in both MDD and SCZ, although the BD metabolic profile was closer to that of MDD than to SCZ. Additionally, we identified the metabolites responsible for the similar and unique metabolic characteristics in multiple metabolic pathways. The similar significant differences among the three disorders were found in fatty acid, steroid-hormone, purine, nicotinate, glutamate, tryptophan, arginine, and proline metabolism. Interestingly, we found unique characteristics of significantly altered glycolysis, glycerophospholipid, and sphingolipid metabolism in SCZ; lysine, cysteine, and methionine metabolism in MDD and BD; and phenylalanine, tyrosine, and aspartate metabolism in SCZ and BD. Finally, we identified five panels of potential diagnostic biomarkers for MDD-HC, BD-HC, SCZ-HC, MDD-SCZ, and BD-SCZ comparisons. Our findings suggest that metabolic characteristics in plasma vary across psychiatric disorders and that critical metabolites provide new clues regarding molecular mechanisms in these three psychiatric disorders.

Profiling Small RNA From Brain Extracellular Vesicles in Individuals With Depression.

BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability with significant mortality risk. Despite progress in our understanding of the etiology of MDD, the underlying molecular changes in the brain remain poorly understood. Extracellular vesicles (EVs) are lipid-bound particles that can reflect the molecular signatures of the tissue of origin. We aimed to optimize a streamlined EV isolation protocol from postmortem brain tissue and determine whether EV RNA cargo, particularly microRNAs (miRNAs), have an MDD-specific profile. METHODS: EVs were isolated from postmortem human brain tissue. Quality was assessed using western blots, transmission electron microscopy, and microfluidic resistive pulse sensing. EV RNA was extracted and sequenced on Illumina platforms. Functional follow-up was performed in silico. RESULTS: Quality assessment showed an enrichment of EV markers, as well as a size distribution of 30 to 200 nm in diameter, and no contamination with cellular debris. Small RNA profiling indicated the presence of several RNA biotypes, with miRNAs and transfer RNAs being the most prominent. Exploring miRNA levels between groups revealed decreased expression of miR-92a-3p and miR-129-5p, which was validated by qPCR and was specific to EVs and not seen in bulk tissue. Finally, in silico functional analyses indicate potential roles for these 2 miRNAs in neurotransmission and synaptic plasticity. CONCLUSION: We provide a streamlined isolation protocol that yields EVs of high quality that are suitable for molecular follow-up. Our findings warrant future investigations into brain EV miRNA dysregulation in MDD.

PGC-1α in the hippocampus mediates depressive-like and stress-coping behaviours and regulates excitatory synapses in the dentate gyrus in mice.

Decreased hippocampal synaptic plasticity is an important pathological change in stress-related mood disorders, including major depressive disorder. However, the underlying mechanism is unclear. PGC-1α, a transcriptional coactivator, is a key factor in synaptic plasticity. We investigated the relationships between changes in hippocampal PGC-1α expression and depressive-like and stress-coping behaviours, and whether they are related to hippocampal synapses. Adeno-associated virus was used to alter hippocampal PGC-1α expression in male C57BL/6 mice. The sucrose preference test and forced swimming test were used to assess their depressive-like and stress-coping behaviours, respectively. Immunohistochemistry and stereology were used to calculate the total number of excitatory synapses in each hippocampal subregion (the cornu ammonis (CA) 1, CA3, and dentate gyrus). Immunofluorescence was used to visualize the changes in dendritic structure. Western blotting was used to detect the expression of hippocampal PGC-1α and mitochondrial-associated proteins, such as UCP2, NRF1 and mtTFAs. Our results showed that mice with downregulated PGC-1α expression in the hippocampus exhibited depressive-like and passive stress-coping behaviours, while mice with upregulated PGC-1α in the hippocampus exhibited increased stress-coping behaviours. Moreover, the downregulation of hippocampal PGC-1α expression resulted in a decrease in the number of excitatory synapses in the DG and in the protein expression of UCP2 in the hippocampus. Alternatively, upregulation of hippocampal PGC-1α yielded the opposite results. This suggests that hippocampal PGC-1α is involved in regulating depressive-like and stress-coping behaviours and modulating the number of excitatory synapses in the DG. This provides new insight for the development of antidepressants.

Role of estrogen in sex differences in memory, emotion and neuropsychiatric disorders.

Estrogen regulates a wide range of neuronal functions in the brain, such as dendritic spine formation, remodeling of synaptic plasticity, cognition, neurotransmission, and neurodevelopment. Estrogen interacts with intracellular estrogen receptors (ERs) and membrane-bound ERs to produce its effect via genomic and non-genomic pathways. Any alterations in these pathways affect the number, size, and shape of dendritic spines in neurons associated with psychiatric diseases. Increasing evidence suggests that estrogen fluctuation causes changes in dendritic spine density, morphology, and synapse numbers of excitatory and inhibitory neurons differently in males and females. In this review, we discuss the role of estrogen hormone in rodents and humans based on sex differences. First, we explain estrogen role in learning and memory and show that a high estrogen level alleviates the deficits in learning and memory. Secondly, we point out that estrogen produces a striking difference in emotional memories in men and women, which leads them to display sex-specific differences in underlying neuronal signaling. Lastly, we discuss that fluctuations in estrogen levels in men and women are related to neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BPD), major depressive disorder (MDD), substance use disorder (SUD), and anxiety disorders.

The reduction of microglial efferocytosis is concomitant with depressive-like behavior in CUMS-treated mice.

BACKGROUND: Microglial efferocytosis plays a crucial role in facilitating and sustaining homeostasis in the central nervous system, and it is involved in neuropsychiatric disorders. How microglial efferocytosis is affected under the condition of major depressive disorder (MDD) remains elusive. In this study, we hypothesized that microglial efferocytosis in the hippocampus is impaired in the chronic unpredicted mild stress (CUMS) model of MDD, which is involved in the development of MDD. METHOD: Depressive-like behavior in adult male mice was induced by CUMS and confirmed by behavioral tests. Microglial efferocytosis was evaluated using immunofluorescence staining of hippocampal slices and primary microglia co-cultured with apoptotic cells. The protein and mRNA levels of phagocytosis-related molecules and inflammation-related cytokines were detected using western blotting and RT-qPCR, respectively. Annexin V was injected to mimic impairment of microglial efferocytosis. TREM2-siRNA was further used on primary microglia to examine efferocytosis-related signaling pathways. RESULTS: Microglia were activated and the expression of proinflammatory cytokines was increased in CUMS mice, while microglial efferocytosis and efferocytosis-related molecules were decreased. Inhibition of the TREM2/Rac1 pathway impaired microglial efferocytosis. Annexin V injection inhibited microglial efferocytosis, increased inflammation in the hippocampus and depressive-like behavior. LIMITATIONS: The potential antidepressant effect of the upregulation of the TREM2/Rac1 pathway was not evaluated. CONCLUSIONS: Impairment of microglial efferocytosis is involved in the development of depressive-like behavior, with downregulation of the TREM2/Rac1 pathway and increased inflammation. These results may increase our understanding of the pathophysiological mechanisms associated with MDD and provide novel targets for therapeutic interventions.

Sub-chronic and mild social defeat stress exposure to C57BL/6J mice increases visceral fat mass and causes accumulation of cholesterol and bile acids in the liver.

Major depressive disorder is accompanied by a high metabolic illness comorbidity and patients with atypical depression are a subgroup with particularly high risk of obesity, dyslipidemia, and metabolic syndrome; however, the underlying mechanisms have not been fully elucidated. In this study, we examined visceral fat deposition, lipid profiles in the liver, and gut microbiota in sub-chronic and mild social defeat stress (sCSDS)-exposed C57BL/6J mice, which exhibit atypical depression-like phenotypes, i.e., increased body weight and food and water intake. We found that visceral fat mass and levels of hepatic cholesterol and bile acids in sCSDS-exposed mice were significantly increased compared to those in controls. The expression of hepatic small heterodimer partner, a negative regulator of cholesterol metabolism, was significantly elevated in sCSDS-exposed mice. We also found that gut microbial diversity and composition including lower relative abundance of Bacteroides spp. and Bifidobacterium spp. in sCSDS-exposed mice were different from those in controls. In addition, relative abundance of Bacteroides spp. and Bifidobacterium spp. was significantly and negatively correlated with body weight, visceral fat mass, and hepatic cholesterol and bile acids levels. These results indicate that sCSDS-exposure induces dysbiosis, and thereby contributes to metabolic disorder development.

Extracellular matrix abnormalities in the hippocampus of subjects with substance use disorder.

Contextual triggers are significant factors contributing to relapse in substance use disorders (SUD). Emerging evidence points to a critical role of extracellular matrix (ECM) molecules as mediators of reward memories. Chondroitin sulfate proteoglycans (CSPGs) are a subset of ECM molecules that form perineuronal nets (PNN) around inhibitory neurons. PNNs restrict synaptic connections and help maintain synapses. Rodent models suggest that modulation of PNNs may strengthen contextual reward memories in SUD. However, there is currently a lack of information regarding PNNs in the hippocampus of people with SUD as well as how comorbidity with major depressive disorder (MDD) may affect PNNs. We used postmortem hippocampal tissues from cohorts of human and nonhuman primates with or without chronic alcohol use to test the hypothesis that PNNs are increased in subjects with SUD. We used histochemical labeling and quantitative microscopy to examine PNNs, and qRT-PCR to examine gene expression for ECM molecules, synaptic markers and related markers. We identified increased densities of PNNs and CSPG-labeled glial cells in SUD, coinciding with decreased expression of the ECM protease matrix metalloproteinase 9 (Mmp9), and increased expression for the excitatory synaptic marker vesicle associated membrane protein 2 (Vamp2). Similar increases in PNNs were observed in monkeys with chronic alcohol self-administration. Subjects with MDD displayed changes opposite to SUD, and subjects with SUD and comorbid MDD had minimal changes in any of the outcome measures examined. Our findings demonstrate that PNNs are increased in SUD, possibly contributing to stabilizing contextual reward memories as suggested by preclinical studies. Our results also point to a previously unsuspected role for CSPG expression in glial cells in SUD. Evidence for increased hippocampal PNNs in SUD suggests that targeting PNNs to weaken contextual reward memories is a promising therapeutic approach for SUD, however comorbidity with MDD is a significant consideration.

RGS4 Actions in Mouse Prefrontal Cortex Modulate Behavioral and Transcriptomic Responses to Chronic Stress and Ketamine.

The signal transduction protein, regulator of G protein signaling 4 (RGS4), plays a prominent role in physiologic and pharmacological responses by controlling multiple intracellular pathways. Our earlier work identified the dynamic but distinct roles of RGS4 in the efficacy of monoamine-targeting versus fast-acting antidepressants. Using a modified chronic variable stress (CVS) paradigm in mice, we demonstrate that stress-induced behavioral abnormalities are associated with the downregulation of RGS4 in the medial prefrontal cortex (mPFC). Knockout of RGS4 (RGS4KO) increases susceptibility to CVS, as mutant mice develop behavioral abnormalities as early as 2 weeks after CVS resting-state functional magnetic resonance imaging I (rs-fMRI) experiments indicate that stress susceptibility in RGS4KO mice is associated with changes in connectivity between the mediodorsal thalamus (MD-THL) and the mPFC. Notably, RGS4KO also paradoxically enhances the antidepressant efficacy of ketamine in the CVS paradigm. RNA-sequencing analysis of naive and CVS samples obtained from mPFC reveals that RGS4KO triggers unique gene expression signatures and affects several intracellular pathways associated with human major depressive disorder. Our analysis suggests that ketamine treatment in the RGS4KO group triggers changes in pathways implicated in synaptic activity and responses to stress, including pathways associated with axonal guidance and myelination. Overall, we show that reducing RGS4 activity triggers unique gene expression adaptations that contribute to chronic stress disorders and that RGS4 is a negative modulator of ketamine actions. SIGNIFICANCE STATEMENT: Chronic stress promotes robust maladaptation in the brain, but the exact intracellular pathways contributing to stress vulnerability and mood disorders have not been thoroughly investigated. In this study, the authors used murine models of chronic stress and multiple methodologies to demonstrate the critical role of the signal transduction modulator regulator of G protein signaling 4 in the medial prefrontal cortex in vulnerability to chronic stress and the efficacy of the fast-acting antidepressant ketamine.

Circulating myeloid-derived MMP8 in stress susceptibility and depression.

Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3, the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

Prolonged stress response induced by chronic stress and corticosterone exposure causes adult neurogenesis inhibition and astrocyte loss in mouse hippocampus.

Chronic stress is a pervasive and complex issue that contributes significantly to various mental and physical health disorders. Using the previously established chronic unpredictable stress (CUS) model, which simulates human stress situations, it has been shown that chronic stress induces major depressive disorder (MDD) and memory deficiency. However, this established model is associated with several drawbacks, such as limited research reproducibility and the inability to sustain stress response. To resolve these issues, we developed a new CUS model (CUS+C) that included exogenous corticosterone exposure to induce continuous stress response. Thereafter, we evaluated the effect of this new model on brain health. Thus, we observed that the use of the CUS+C model decreased body and brain weight gain and induced an uncontrolled coat state as well as depressive-like behavior in adult mice. It also impaired learning memory function and cognitive abilities, reduced adult hippocampal neurogenesis as well as the number of hippocampal astrocytes, and downregulated glial fibrillary acidic protein expression in the brains of adult mice. These findings can promote the utilization and validity of the animal stress model and provide new information for the treatment of chronic stress-induced depressive and memory disorders.

The Neurochemistry of Depression: The Good, The Bad and The Ugly.

A large constellation of experimental evidence suggests that neuroinflammation is involved in the onset of depression and neurodegenerative disorders. Many studies have shown impairments in tryptophan metabolism, the major pathway for the synthesis of serotonin, the mood regulating neurotransmitter. This article reviews the various metabolites generated in the competing pathways of tryptophan metabolism including the kynurenine pathway. Increased synthesis of the neurotoxic compound quinolinic acid occurs at the expense of the synthesis of the neuroprotective metabolite kynurenic acid. This shift in equilibrium plays a critical role in the induction of oxidative stress, neuroinflammation, and neurotoxicity. Sufficient protein intake with adequate amounts of tryptophan along with dietary antioxidants and flavonoids may offer protection against major depressive and neurodegenerative disorders.

Genetic evidence suggests a genetic association between major depressive disorder and reduced cortical gray matter volume: A Mendelian randomization study and mediation analysis.

BACKGROUND: Several studies have suggested an association between major depressive disorder (MDD) and abnormal brain structure. However, it is unclear whether MDD affects cortical gray matter volume, a common indicator of cognitive function. We aimed to determine whether MDD was associated with decreased cortical gray matter volume (GMV) through a Mendelian randomization (MR) study. METHODS: We obtained summary genetic data from a study conducted by the Psychiatric Genomics Consortium, which recruited a total of 480,359 participants (135,458 cases and 344,901 controls). Genetic tools-single nucleotide polymorphisms (SNPs)-of MDD were extracted from the study and their effects on gray matter volumes of the cortex and total brain were evaluated in a large cohort from the UK Biobank (n = 8427). The effects of the SNPs were pooled using inverse variance weighted (IVW) analysis and further tested in several sensitivity analyses. We tested whether C-reactive protein (CRP) levels and interleukin-6 signaling were the mediators of the effects using a multivariate MR model. RESULTS: Thirty-three SNPs were identified and adopted as genetic tools for predicting MDD. IVW analysis showed that MDD was associated with lower overall GMV (beta value -0.106, 95%CI -0.188 to -0.023, p = 0.011) in the frontal pole (left frontal pole, -0.152, 95%CI -0.177 to -0.127, p = 0.013; right frontal pole, -0.133, 95%CI -0.253 to -0.013, p = 0.028). Multivariate and mediation analysis showed that interleukin-6 was an important mediator of GMV reduction. Reverse causality analysis found no evidence that total GMV affected the risk of MDD, but showed that increased left precuneus cortex volume and left posterior cingulate cortex volume were associated with increased risk of MDD. LIMITATIONS: Potential pleiotropic effects and overestimation of real-world effects. Key assumptions for MR analysis may not be satisfactorily met. CONCLUSION: MDD was associated with a reduced GMV, and interleukin-6 might be a mediator of GMV reduction.