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Alterations in energy metabolism are associated with depression. However, the role of glycolysis in the pathogenesis of depression and the underlying molecular mechanisms remain unexplored. Through an unbiased proteomic screen coupled with biochemical verifications, we show that the levels of glycolysis and lactate dehydrogenase A (LDHA), a glycolytic enzyme that catalyzes L-lactate production, are reduced in the dorsomedial prefrontal cortex (dmPFC) of stress-susceptible mice in chronic social defeat stress (CSDS) model. Conditional knockout of LDHA from the brain promotes depressive-like behaviors in both male and female mice, accompanied with reduced L-lactate levels and decreased neuronal excitability in the dmPFC. Moreover, these phenotypes could be duplicated by knockdown of LDHA in the dmPFC or specifically in astrocytes. In contrast, overexpression of LDHA reverses these phenotypic changes in CSDS-susceptible mice. Mechanistic studies demonstrate that L-lactate promotes neuronal excitability through monocarboxylic acid transporter 2 (MCT2) and by inhibiting large-conductance Ca2+-activated potassium (BK) channel. Together, these results reveal a role of LDHA in maintaining neuronal excitability to prevent depressive-like behaviors. The role of glycolysis in depression is unclear. Here the authors report a glycolytic deficit under social stress and demonstrate that astrocytic LDHA affects neuronal excitability and depressive-like behaviours via lactate homeostasis in mice. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive neurodegenerative disorder that has been recognized for over 200 years by its clinically dominant motor system impairment. There are prominent non-motor symptoms as well, and among these, psychiatric symptoms of depression and anxiety and cognitive impairment are common and can appear earlier than motor symptoms. Although the neurobiology underlying these particular PD-associated non-motor symptoms is not completely understood, the identification of PARK genes that contribute to hereditary and sporadic PD has enabled genetic models in animals that, in turn, have fostered ever deepening analyses of cells, synapses, circuits, and behaviors relevant to non-motor psychiatric and cognitive symptoms of human PD. Moreover, while it has long been recognized that inflammation is a prominent component of PD, recent studies demonstrate that brain-immune signaling crosstalk has significant modulatory effects on brain cell and synaptic function in the context of psychiatric symptoms. This review provides a focused update on such progress in understanding the neurobiology of PD-related non-motor psychiatric and cognitive symptoms. [ABSTRACT FROM AUTHOR]

[Display omitted] • Stress or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein upregulated MyD88 expression in microglia. • Inducible expression of MyD88 in the mPFC increased stress susceptibility via activation of p38-MAPK/NF-κB signaling pathway. • Knockout or pharmacological inhibition of MyD88 ameliorated depressive-like behavior. • TJ-M2010-5, a novel synthesized targeting inhibitor of MyD88 dimerization, alleviated stress- or SARS-CoV-2 Spike protein-induced depression-type behavioral abnormalities. Increasing evidence supports the pathogenic role of neuroinflammation in psychiatric diseases, including major depressive disorder (MDD) and neuropsychiatric symptoms of Coronavirus disease 2019 (COVID-19); however, the precise mechanism and therapeutic strategy are poorly understood. Here, we report that myeloid differentiation factor 88 (MyD88), a pivotal adaptor that bridges toll-like receptors to their downstream signaling by recruiting the signaling complex called 'myddosome', was up-regulated in the medial prefrontal cortex (mPFC) after exposure to chronic social defeat stress (CSDS) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The inducible expression of MyD88 in the mPFC primed neuroinflammation and conferred stress susceptibility via amplifying immune danger signals, such as high-mobility group box 1 and SARS-CoV-2 spike protein. Overexpression of MyD88 aggravated, whereas knockout or pharmacological inhibition of MyD88 ameliorated CSDS-induced depressive-like behavior. Notably, TJ-M2010-5, a novel synthesized targeting inhibitor of MyD88 dimerization, alleviated both CSDS- and SARS-CoV-2 spike protein-induced depressive-like behavior. Taken together, our findings indicate that inhibiting MyD88 signaling represents a promising therapeutic strategy for stress-related mental disorders, such as MDD and COVID-19-related neuropsychiatric symptoms. [ABSTRACT FROM AUTHOR]

Aims: Central melanocortin 4 receptor (MC4R) has been reported to induce anhedonia via eliciting dysfunction of excitatory synapses. It is evident that metabolic signals are closely related to chronic stress‐induced depression. Here, we investigated that a neural circuit is involved in melanocortin signaling contributing to susceptibility to stress. Methods: Chronic social defeat stress (CSDS) was used to develop depressive‐like behavior. Electrophysiologic and chemogenetic approaches were performed to evaluate the role of paraventricular thalamus (PVT) glutamatergic to nucleus accumbens shell (NAcsh) circuit in stress susceptibility. Pharmacological and genetic manipulations were applied to investigate the molecular mechanisms of melanocortin signaling in the circuit. Results: CSDS increases the excitatory neurotransmission in NAcsh through MC4R signaling. The enhanced excitatory synaptic input in NAcsh is projected from PVT glutamatergic neurons. Moreover, chemogenetic manipulation of PVTGlu‐NAcsh projection mediates the susceptibility to stress, which is dependent on MC4R signaling. Overall, these results reveal that the strengthened excitatory neurotransmission in NAcsh originates from PVT glutamatergic neurons, facilitating the susceptibility to stress through melanocortin signaling. Conclusions: Our results make a strong case for harnessing a thalamic circuit to reorganize excitatory synaptic transmission in relieving stress susceptibility and provide insights gained on metabolic underpinnings of protection against stress‐induced depressive‐like behavior. [ABSTRACT FROM AUTHOR]

Stress is a critical factor in the development of mood and drug use disorders. The social defeat model is not appropriate for female rodents due to their low level of aggression. Therefore, a robust female model of social stress needs to be developed and validated. The aim of the present study was to unravel the long-lasting effects of vicarious social defeat (VSD) on the conditioned rewarding effects of cocaine and ethanol intake in female mice. Although VSD seems to be a good model for inducing behavioral and physiologic endophenotypes induced by stress, there are no studies to date that characterize the effect of VSD on cocaine or alcohol use. The results confirm that VSD females showed an increase in corticosterone levels after a vicarious experience while also displaying an increase in anxiety- and anhedonic-like behaviors. Three weeks after the last VSD, vicariously defeated female mice showed an increased developed preference for a non-effective dose of cocaine in the conditioned place preference (CPP) paradigm and showed an increase in ethanol intake. Our results suggest that female mice vicariously experience a state of distress through the social observation of others suffering from adverse events, confirming the use of VSD as a valid model to study the response to social stress in females. The fact that VSD in females induced a comparable behavioral phenotype to that observed in physically defeated males could indicate a relationship with the higher rate of psychopathologies observed in women. Notwithstanding, more studies are needed to dissect the neurobiological and behavioral peculiarities of the female response to social stress. [ABSTRACT FROM AUTHOR]

Altered activity of the ventral pallidum (VP) underlies disrupted motivation in stress and drug exposure. The VP is a very heterogeneous structure composed of many neuron types with distinct physiological properties and projections. Neuronal PAS 1-positive (Npas11) VP neurons are thought to send projections to brain regions critical for motivational behavior. While Npas11 neurons have been characterized in the globus pallidus external, there is limited information on these neurons in the VP. To address this limitation, we evaluated the projection targets of the VP Npas11 neurons and performed RNA-sequencing on ribosome-associated mRNA from VP Npas11 neurons to determine their molecular identity. Finally, we used a chemogenetic approach to manipulate VP Npas11 neurons during social defeat stress (SDS) and behavioral tasks related to anxiety and motivation in Npas1-Cre mice. We used a similar approach in females using the chronic witness defeat stress (CWDS). We identified VP Npas11 projections to the nucleus accumbens, ventral tegmental area, medial and lateral habenula, lateral hypothalamus, thalamus, medial and lateral septum, and periaqueductal gray area. VP Npas11 neurons displayed distinct translatome representing distinct biological processes. Chemogenetic activation of hM3D(Gq) receptors in VP Npas11 neurons increased susceptibility to a subthreshold SDS and anxiety-like behavior in the elevated plus maze and open field while the activation of hM4D(Gi) receptors in VP Npas11 neurons enhanced resilience to chronic SDS and CWDS. Thus, the activity of VP Npas11 neurons modulates susceptibility to social stressors and anxiety-like behavior. Our studies provide new information on VP Npas11 neuron circuitry, molecular identity, and their role in stress response. [ABSTRACT FROM AUTHOR]

Social disturbance in interpersonal relationships is the primary source of stress in humans. Spexin (SPX, SPX1a in cichlid), an evolutionarily conserved neuropeptide with diverse physiological functions, is up-regulated in the brain during chronic social defeat stress in teleost. On the other hand, repeated exposure to social stress can lead to dysregulation of the monoaminergic system and increase the vulnerability of developing depression. Since dysfunction of the serotonin (5-hydroxytryptamine, 5-HT) system is associated with social stress and the pathophysiology of depression, the present study investigated the regulatory relationship between the central 5-HT system and SPX1a in the male teleost, Nile tilapia (Oreochromis niloticus). To identify stress factors that regulate SPX1a gene expression, cortisol, dexamethasone (DEX), and 5-HT were used to treat tilapia brain primary cultures. Our study shows cortisol and DEX treatment had no effect on SPX1a gene expression, but SPX1a gene expression was down-regulated following 5-HT treatment. Anatomical localization showed a close association between 5-HT immunoreactive projections and SPX1a neurons in the semicircular torus. In addition, 5-HT receptors (5-HT2B) were expressed in SPX1a neurons. SPX1a immunoreactive neurons and SPX1a gene expression were significantly increased in socially defeated tilapia. On the other hand, citalopram (antidepressant, 5-HT antagonist) treatment to socially defeated tilapia normalized SPX1a gene expression to control levels. Taken together, the present study shows that 5-HT is an upstream regulator of SPX1a and that the inhibited 5-HT activates SPX1a during social defeat. [ABSTRACT FROM AUTHOR]

Psychosocial stress precipitates mental illnesses, such as depression, and increases the risk of other health problems, including cardiovascular diseases. In this study, we observed the effects of psychosocial stress on the histopathological features of systemic organs and tissues in a mouse psychosocial stress model, namely the subchronic and mild social defeat stress (sCSDS) model. There were several pathological findings in the tissues of both sCSDS and control mice. Mild fibrosis of the heart was observed in sCSDS mice but not in control mice. Extramedullary hematopoiesis in the spleen and hemorrhage in the lungs were observed in both the control and sCSDS mice. Focal necrosis of the liver was seen only in control mice. Furthermore, putrefactive substances in the blood plasma were analyzed because these metabolites originating from intestinal fermentation might be linked to heart fibrosis. Among them, plasma p-cresyl glucuronide and p-cresyl sulfate concentrations significantly increased owing to subchronic social defeat stress, which might influence cardiac fibrosis in sCSDS mice. In conclusion, several pathological features such as increased cardiac fibrosis and elevated plasma putrefactive substances were found in sCSDS mice. Thus, sCSDS mice are a potential model for elucidating the pathophysiology of psychosocial stress and heart failure. [ABSTRACT FROM AUTHOR]

Introduction: Social stress in adolescents precipitates stress-related emotional disorders. In this study we aimed to investigate oligodendrogenesis in three stress-associated brain regions, medial prefrontal cortex (mPFC), habenula, and amygdala in adolescent mice exposed to social defeat stress. Methods: Four-week-old adolescent mice were subjected to social defeat for 10 days, followed by behavioral tests and evaluations of oligodendroglial proliferation and differentiation. Results: Stressed mice showed reduced social interaction, more stretched approach posture, lower sucrose preference, but no changes in the forced swimming test. EdU labeled proliferative cells, newly formed NG2+EdU + oligodendrocyte precursor cells (OPCs), and Olig2+EdU+ oligodendrocyte lineage cells (OLLs) were significantly decreased in the mPFC and the lateral habenula, but not in the amygdala and the medial habenula in socially defeated mice. APC+Edu+ newly-generated mature oligodendrocytes (OLs) were decreased in the mPFC in stressed mice. However, the total number of NG2+ OPCs, APC+ mature OLs, and Olig2+ OLLs were comparable in all the brain regions examined between stressed and control mice except for a decrease of APC+ mature OLs in the prelimbic cortex of stressed mice. Conclusion: Our findings indicate that adolescent social stress causes emotion-related behavioral changes and region-specific impairment of oligodendrogenesis. [ABSTRACT FROM AUTHOR]

The present study aimed to explore the consequences of a single exposure to a social defeat on dopamine release in the rat nucleus accumbens measured with a fast-scan cyclic voltammetry. We found that 24 h after a social defeat, accumbal dopamine responses, evoked by a high frequency electrical stimulation of the ventral tegmental area, were more profound in socially defeated rats in comparison with non-defeated control animals. The enhanced dopamine release was associated with the prolonged immobility time in the forced swim test. The use of the dopamine depletion protocol revealed no alteration in the reduction and recovery of the amplitude of dopamine release following social defeat stress. However, administration of dopamine D2 receptor antagonist, raclopride (2 mg/kg, i.p.), resulted in significant increase of the electrically evoked dopamine release in both groups of animals, nevertheless exhibiting less manifested effect in the defeated rats comparing to control animals. Taken together, our data demonstrated profound alterations in the dopamine transmission in the association with depressive-like behavior following a single exposure to stressful environment. These voltammetric findings pointed to a promising path for the identification of neurobiological mechanisms underlying stress-promoted behavioral abnormalities. [ABSTRACT FROM AUTHOR]

Background/Aims Chronic psychological stress affects gastrointestinal physiology which may underpin alterations in the immune response and epithelial transport, both functions are partly regulated by enteric nervous system. However, its effects on enteric neuroplasticity are still unclear. This study aims to investigate the effects of chronic unpredictable psychological stress on intestinal motility and prominent markers of enteric function. Methods Adult male C57BL/6J mice were exposed to 19 day of unpredictable stress protocol schedule of social defeat and overcrowding. We investigated the effects on plasma corticosterone, food intake, and body weight. In vivo gastrointestinal motility was assessed by fecal pellet output and by whole-gastrointestinal transit (using the carmine red method). Tissue monoamine level, neural and glial markers, neurotrophic factors, monoamine signaling, and Toll-like receptor expression in the proximal and distal colon, and terminal ileum were also assessed. Results Following chronic unpredictable psychological stress, stressed mice showed increased food intake and body weight gain (P < 0.001), and reduced corticosterone levels (P < 0.05) compared to control mice. Stressed mice had reduced stool output without differences in water content, and showed a delayed gastrointestinal transit compared to control mice (P < 0.05). Stressed mice exhibited decreased mRNA expression of tyrosine hydroxylase (Th), brain-derived neurotrophic factor (Bdnf) and glial cell-derived neurotrophic factor (Gdnf), as well as Toll-like receptor 2 (Tlr2) compared to control (P < 0.05), only proximal colon. These molecular changes in proximal colon were associated with higher levels of monoamines in tissue. Conclusion Unpredictable psychological chronic stress induces region-specific impairment in monoamine levels and neuroplasticity markers that may relate to delayed intestinal transit. [ABSTRACT FROM AUTHOR]

This essay addresses the intersection between the Facebook, Instagram, Twitter, Tik-Tok and Pinterest social media platforms and a contemporary religious leader/teacher who exploited them to rise from subalternity to the status of a deified celebrity. It examines his underprivileged disciples and followers and rival formal and informal levels, within Indian Sufi circles. Employing a combined perspective of ethnography, media studies and textual analysis, I discuss the transformations engendered by this social media celebrity and the impact of neo-liberalism on religious teacher–disciple (peeri–mureedi) relations. I show that this transformation involved a commodification of peeri–mureedi relations, leading to a neoliberal morphing of religious practices into marketable products. In so doing, I provide a critical reading of Mazzarella's social media as "re-enlightened" or "inclusive capitalism" that gives voice, agency and new economic possibilities to capitalism's most marginal subjects, who aspire to break the grip of what I term the "economies of despair". [ABSTRACT FROM AUTHOR]

Chronic exposure to stress can lead to a variety of mental disorders such as depression. There are many treatment-resistant patients who do not respond adequately to the standard pharmacological treatments. Therefore, the development of novel therapeutic agents is highly expected. In rodents, socially defeated animals that were exposed to repeated physical aggression from other individuals are widely used in this field of research. The social defeat is considered as a stress that mimics human social stress. On the other hand, emotional stress, but not physical stress, is likely to contribute to the pathogenesis and etiology of depression in human. Therefore, there is a gap between the process of pathogenesis and the animal models, and this is one of the reasons why the development of new psychotropic drugs to treat depression has been difficult. Recently, a novel stress model has been introduced, in which mice are subjected to emotional stress without physical distress by witnessing social defeat scenes of their conspecifics. We have investigated the mechanisms by which emotional stress is transmitted by witnessing social defeat in mice, focusing on the insular cortex. In this article, we summarize and discuss the recent advancements in the neural basis of behavioral changes induced by emotional stress. [ABSTRACT FROM AUTHOR]

We recently reported that a neuronal population in the claustrum (CLA) identified under exposure to psychological stressors plays a key role in stress response processing. Upon stress exposure, the main inputs to the CLA come from the basolateral amygdala (BLA); however, the upstream brain regions that potentially regulate both the CLA and BLA during stressful experiences remain unclear. Here by combining activity-dependent viral retrograde labeling with whole brain imaging, we analyzed neurons projecting to the CLA and BLA activated by exposure to social defeat stress. The labeled CLA projecting neurons were mostly ipsilateral, excluding the prefrontal cortices, which had a distinctly labeled population in the contralateral hemisphere. Similarly, the labeled BLA projecting neurons were predominantly ipsilateral, aside from the BLA in the opposite hemisphere, which also had a notably labeled population. Moreover, we found co-labeled double-projecting single neurons in multiple brain regions such as the ipsilateral ectorhinal/perirhinal cortex, entorhinal cortex, and the contralateral BLA. These results suggest that CLA and BLA receive inputs from neuron collaterals in various brain regions during stress, which may regulate the CLA and BLA forming in a stress response circuitry. [ABSTRACT FROM AUTHOR]

During adolescence, microglia are actively involved in neocortical maturation while concomitantly undergoing profound phenotypic changes. Because the teenage years are also a time of experimentation with cannabis, we evaluated whether adolescent exposure to the drug's psychotropic constituent, Δ9-tetrahydrocannabinol (THC), might persistently alter microglia function. We administered THC (5 mg/kg, intraperitoneal) once daily to male and female mice from postnatal day (PND) 30 to PND44 and examined the transcriptome of purified microglia in adult animals (PND70 and PND120) under baseline conditions or following either of two interventions known to recruit microglia: lipopolysaccharide injection and repeated social defeat. We used high-dimensional mass cytometry by time-of-flight to map brain immune cell populations after lipopolysaccharide challenge. Adolescent THC exposure produced in mice of both sexes a state of microglial dyshomeostasis that persisted until young adulthood (PND70) but receded with further aging (PND120). Key features of this state included broad alterations in genes involved in microglia homeostasis and innate immunity along with marked impairments in the responses to lipopolysaccharide- and repeated social defeat–induced psychosocial stress. The endocannabinoid system was also dysfunctional. The effects of THC were prevented by coadministration of either a global CB 1 receptor inverse agonist or a peripheral CB 1 neutral antagonist and were not replicated when THC was administered in young adulthood (PND70–84). Daily low-intensity CB 1 receptor activation by THC during adolescence may disable critical functions served by microglia until young adulthood with potentially wide-ranging consequences for brain and mental health. [ABSTRACT FROM AUTHOR]

NLRP1 inflammasome has been reported to participate in many neurological disorders. Our previous study has demonstrated that NLRP1 inflammasome is implicated in chronic stress-induced depressive-like behaviors in mice. Age has been reported to be related to depression. Here we examine whether NLRP1 inflammasome is involved in the effect of age on depressive disorder. Two chronic stress stimuli, chronic social defeat stress (CSDS) and repeat social defeat stress (RSDS), were used to establish a depression model in mice of different ages. We found that aged mice exhibited worse depressive-like behaviors and locomotor activity compared to young mice. Interestingly, the expression of hippocampal NLRP1 inflammasome complexes and the levels of the inflammatory cytokines were increased in an age-dependent manner. Also, chronic stress-induced increase in the expression of the hippocampal chemokine C-X-C motif ligand 1 (CXCL1), and its cognate receptor, CXC-motif receptor 2 (CXCR2), was more remarkable in aged mice than that in young mice. Moreover, aged mice exhibited lower hippocampal BDNF levels compared to young mice. Hippocampal Nlrp1a knockdown reduced the levels of pro-inflammatory cytokines and the expression of CXCL1/CXCR2, restored BDNF levels, and alleviated chronic stress-induced depressive-like behaviors in aged mice. Our results suggest that NLRP1 inflammasome-CXCL1/CXCR2-BDNF signaling contributes to the effect of age on chronic stress-induced depressive-like behavior in mice. [ABSTRACT FROM AUTHOR]

Although several previous studies have suggested a relationship between sleep and the stress response, the mechanism underlying this relationship remains largely unknown. Here, we show that fibroblast growth factor 21 (FGF21), a lipid metabolism-related hormone, may play a role in this relationship. In this study, we examined differences in the stress response between FGF21 knockout (KO) mice and wild-type (WT) mice after social defeat stress (SDS). When the amount of non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep and wakefulness were averaged over the dark period after SDS, only KO mice showed significant differences in NREM sleep and wakefulness. In the social interaction test, KO mice seemed to be more prone to social avoidance. Our real-time (RT) -PCR results revealed that the mRNA expression of the stress- and sleep-related gene gamma-aminobutyric acid A receptor subunit alpha 2 was significantly lower in WT mice than in KO mice. Moreover, KO mice showed lower plasma levels of ketone bodies, which also affect sleep/wake regulation, than WT mice. These results suggested that FGF21 might influence sleep/wake regulation by inducing production of an anti-stress agent and/or ketone bodies, which may result in resilience to social stress. • Social defeat stress altered sleep only in FGF21 KO mice during the dark period. • In the social interaction test KO mice seemed to be more prone to social avoidance. • The mRNA expression of gabra2 was significantly lower in WT mice after stress. • KO mice showed lower plasma levels of ketone bodies. [ABSTRACT FROM AUTHOR]

Robert M Jaggers,1 Damon J DiSabato,2,3 Brett R Loman,1 Danica Kontic,1 Kyle D Spencer,1,4,5 Jacob M Allen,1 Jonathan P Godbout,2,3 Ning Quan,6 Tamar L Gur,2,7 Michael T Bailey1,2,8 1Center for Microbial Pathogenesis, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, 43205, USA; 2Institute for Behavioral Medicine Research, Columbus, OH, 43210, USA; 3Department of Neuroscience, The Ohio State University, Columbus, OH, 43210, USA; 4Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA; 5Graduate Partnership Program, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, OH, USA; 6Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, FL, 33458, USA; 7Department of Psychiatry, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA; 8Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USACorrespondence: Michael T Bailey, Center for Microbial Pathogenesis, Abigail Wexner Research Institute, W410, Nationwide Children’s Hospital, 700 Children’s Drive, Columbus, OH, 43205, USA, Tel +1 614-722-2764, Email Michael.bailey2@nationwidechildrens.orgPurpose: Commensal microbes are impacted by stressor exposure and are known contributors to cognitive and social behaviors, but the pathways through which gut microbes influence stressor-induced behavioral changes are mostly unknown. A murine social stressor was used to determine whether host–microbe interactions are necessary for stressor-induced inflammation, including neuroinflammation, that leads to reduced cognitive and social behavior.Methods: C57BL/6 male mice were exposed to a paired fighting social stressor over a 1 hr period for 6 consecutive days. Y-maze and social interaction behaviors were tested following the last day of the stressor. Serum cytokines and lipopolysaccharide binding protein (LBP) were measured and the number and morphology of hippocampal microglia determined via immunohistochemistry. Intestinal mucous thickness and antimicrobial peptide expression were determined via fluorescent staining and real-time PCR (respectively) and microbial community composition was assessed using 16S rRNA gene amplicon sequencing. To determine whether the microbiota or the LBP receptor (CD14) are necessary for stressor-induced behavioral changes, experiments were performed in mice treated with a broad-spectrum antibiotic cocktail or in CD14−/− mice.Results: The stressor reduced Y-maze spontaneous alternations, which was accompanied by increased microglia in the hippocampus, increased circulating cytokines (eg, IL-6, TNF-α) and LBP, and reduced intestinal mucus thickness while increasing antimicrobial peptides and cytokines. These stressor-induced changes were largely prevented in mice given broad-spectrum antibiotics and in CD14−/− mice. In contrast, social stressor-induced alterations of social behavior were not microbe-dependent.Conclusion: Stressor-induced cognitive deficits involve enhanced bacterial interaction with the intestine, leading to low-grade, CD14-dependent, inflammation.Keywords: social defeat, stress, microbiome, microglia, cytokines, neuroinflammation, mucus barrier

Psychological stress induces neuroinflammatory responses, which are associated with the pathogenesis of various psychiatric disorders, such as posttraumatic stress disorder and anxiety. Osthole—a natural coumarin isolated from the seeds of the Chinese herb Cnidium monnieri —exerts anti-inflammatory and antioxidative effects on the central nervous system. However, the therapeutic benefits of osthole against psychiatric disorders remain largely unknown. We previously demonstrated that mice subjected to repeated social defeat stress (RSDS) in the presence of aggressor mice exhibited symptoms of posttraumatic stress disorder, such as social avoidance and anxiety-like behaviors. In this study, we investigated the therapeutic effects of osthole and the underlying molecular mechanisms. Osthole exerted therapeutic effects on cognitive behaviors, mitigating anxiety-like behaviors and social avoidance in a mouse model of RSDS. The anti-inflammatory response induced by the oral administration of osthole was strengthened through the upregulation of heme oxygenase-1 expression. The expression of PPARα was inhibited in mice subjected to RSDS. Nonetheless, osthole treatment reversed the inhibition of PPARα expression. We identified a positive correlation between heme oxygenase-1 expression and PPARα expression in osthole-treated mice. In conclusion, osthole has potential as a Chinese herbal medicine for anxiety disorders. When designing novel drugs for psychiatric disorders, researchers should consider targeting the activation of PPARα. • Osthole alleviated repeated social defeat stress-induced maladaptive behaviors. • The protective effects of osthole were active through PPARα upregulation. • Osthole upregulated HO-1 expression likely through the activation of the PPARα. [ABSTRACT FROM AUTHOR]

Erasing traumatic memory during memory reconsolidation is a promising retrieval-extinction strategy for post-traumatic stress disorder (PTSD). Here, we developed an acute social defeat stress (SDS) mouse model with short-term and re-exposure-evoked long-term social avoidance. SDS-associated traumatic memories were identified to be stored in basolateral amygdala (BLA) engram cells. A single intraperitoneal administration of subanesthetic-dose ketamine within, but not beyond, the re-exposure time window significantly alleviates SDS-induced social avoidance, which reduces the activity and quantity of reactivated BLA engram cells. Furthermore, activation or inhibition of dopaminergic projections from the ventral tegmental area to the BLA effectively mimics or blocks the therapeutic effect of re-exposure with ketamine and is dopamine D2 receptor dependent. Single-cell RNA sequencing reveals that re-exposure with ketamine triggered significant changes in memory-related pathways in the BLA. Together, our research advances the understanding of how ketamine mitigates PTSD symptoms and offers promising avenues for developing more effective treatments for trauma-related disorders. [Display omitted] • Ketamine within the re-exposure time window alleviates PTSD-like symptoms • VTA to BLA dopaminergic activation mimics ketamine's therapeutic effects • Effects depend on dopamine D2 receptors and reduce BLA engram cell activity • scRNA-seq shows that ketamine alters memory-related gene expression Tian et al. show that ketamine administered within the re-exposure time window alleviates PTSD-like symptoms by reducing BLA engram cell activity. Activation of the VTA to BLA dopaminergic pathways mimics ketamine's effects, highlighting the potential of combining ketamine with cognitive-behavioral therapy for enhanced PTSD treatment. [ABSTRACT FROM AUTHOR]

Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region. Stress-induced H3K27me1 accumulation occurred at genes that control neuronal excitability and was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which controls H3K27 methylation patterns. Viral VEFS expression changed the transcriptional profile of the NAc, led to social, emotional, and cognitive abnormalities, and altered excitability and synaptic transmission of NAc D1-medium spiny neurons. Together, we describe a novel function of H3K27me1 in the brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility. [Display omitted] • Stress causes lifelong and cell-type-specific enrichment of H3K27me1 in nucleus accumbens • H3K27me1 accumulates across genes involved in neuronal excitability and neurotransmission • Expression of the VEFS domain of SUZ12 selectively induces H3K27me1 enrichment • VEFS expression induces behavioral and transcriptional signatures of stress susceptibility Torres-Berrío et al. establish a novel function of a form of histone methylation—H3K27me1—in the nucleus accumbens, part of the brain's reward circuitry, and demonstrate its role as a "chromatin scar" that mediates lifelong behavioral, physiological, and transcriptional signatures of stress susceptibility in mice. [ABSTRACT FROM AUTHOR]

Arketamine, the (R)-enantiomer of ketamine, exhibits antidepressant-like effects in mice, though the precise molecular mechanisms remain elusive. It has been shown to reduce splenomegaly and depression-like behaviors in the chronic social defeat stress (CSDS) model of depression. This study investigated whether the spleen contributes to the antidepressant-like effects of arketamine in the CSDS model. We found that splenectomy significantly inhibited arketamine's antidepressant-like effects in CSDS-susceptible mice. RNA-sequencing analysis identified the oxidative phosphorylation (OXPHOS) pathway in the prefrontal cortex (PFC) as a key mediator of splenectomy's impact on arketamine's effects. Furthermore, oligomycin A, an inhibitor of the OXPHOS pathway, reversed the suppressive effects of splenectomy on arketamine's antidepressant-like effects. Specific genes within the OXPHOS pathways, such as COX11, UQCR11 and ATP5e, may contribute to these inhibitory effects. Notably, transforming growth factor (TGF)-β1, along with COX11, appears to modulate the suppressive effects of splenectomy and contribute to arketamine's antidepressant-like effects. Additionally, SRI-01138, an agonist of the TGF-β1 receptor, alleviated the inhibitory effects of splenectomy on arketamine's antidepressant-like effects. Subdiaphragmatic vagotomy also counteracted the inhibitory effects of splenectomy on arketamine's antidepressant-like effects in CSDS-susceptible mice. These findings suggest that the OXPHOS pathway and TGF-β1 in the PFC play significant roles in the antidepressant-like effects of arketamine, mediated through the spleen-brain axis via the vagus nerve. • Splenectomy blocked antidepressant effects of arketamine in CSDS model. • Oxidative phosphorylation (OXPHOS) may play a role in the effects of splenectomy on arketamine's actions. • Subdiaphragmatic vagotomy countered the inhibitory effects of splenectomy on arketamine's effects. • Spleen-brain axis via the vagus nerve plays significant roles in the antidepressant-like effects of arketamine. [ABSTRACT FROM AUTHOR]

Emerging data has demonstrated that in mature neurons, SorCS2 localizes to the postsynaptic density of dendritic spines and facilitates plasma membrane sorting of TrkB by interacting with it, transmitting positive signaling from BDNF on neurons. Thus, it is possible that SorCS2 plays a role in the pathophysiology of depression by regulating the BDNF-TrkB system. In the present study, SorCS2 expression in different brain regions [hippocampus, medial prefrontal cortex (mPFC), hypothalamus, amygdala, ventral tegmental area (VTA), and nucleus accumbens (NAc)] was thoroughly investigated in the chronic social defeat stress (CSDS) and chronic unpredictable mild stress (CUMS) models of depression. The changes in depressive-like behaviors, the hippocampal BDNF signaling cascade, and amounts of hippocampal immature neurons were further investigated after SorCS2 overexpression by microinjection of the adenovirus associated virus vector containing the coding sequence of mouse SorCS2 (AAV-SorCS2) into the hippocampus of mice exposed to CSDS or CUMS. It was found that both CSDS and CUMS significantly decreased the protein and mRNA expression of SorCS2 in the hippocampus but not in other brain regions. Chronic stress also notably downregulated the level of hippocampal SorCS2-TrkB binding in mice. In contrast, AAV-based genetic overexpression of hippocampal SorCS2 fully reversed the chronic stress-induced not only depressive-like behaviors but also decreased SorCS2-TrkB binding, BDNF signaling pathway, and amounts of immature neurons in the hippocampus of mice. All these results suggest that enhancing the hippocampal SorCS2 expression protects against chronic stress, producing antidepressant-like actions. Hippocampal SorCS2 may participate in depression neurobiology and be a potential antidepressant target. Targeting of proteins to distinct subcellular compartments is essential for neuronal activity and modulated by VPS10P domain receptors which include SorCS2. In mature neurons, SorCS2 localizes to the postsynaptic density of dendritic spines and facilitates plasma membrane sorting of TrkB by interacting with it, transmitting positive signaling from BDNF on neurons. Our study is the first direct evidence preliminarily showing that SorCS2 plays a role in depression neurobiology. It was found that chronic stress induced not only depressive-like behaviors but also decreased SorCS2 expression in the hippocampus. Chronic stress did not affect SorCS2 expression in the mPFC, hypothalamus, amygdala, VTA, or NAc. In contrast, genetic overexpression of hippocampal SorCS2 prevented against chronic stress, producing antidepressant-like actions in mice. Thus, hippocampal SorCS2 is a potential participant underlying depression neurobiology and may be a novel antidepressant target. Our study may also extend the knowledge of the neurotrophic hypothesis of depression. • CSDS and CUMS decreased the expression and function of SorCS2 in the hippocampus but not in other brain regions. • Genetic overexpression of hippocampal SorCS2 produced antidepressant-like effects in the CSDS model. • Hippocampal SorCS2 overexpression also induced evident antidepressant-like actions in the CUMS model. [ABSTRACT FROM AUTHOR]

TPN672MA, an innovative antipsychotic drug candidate currently in clinical trials, acts as a dopamine D 2 /D 3 receptor partial agonist, serotonin 5-HT 1A receptor agonist, and serotonin 5-HT 2A receptor antagonist. Preclinical investigations have demonstrated its potential in treating the core symptoms of schizophrenia. The present study highlights TPN672MA's significant antidepressant-like effects in classical behavioral models, such as the chronic social defeat stress paradigm. The pronounced 5-HT 1A receptor agonism and D 2 /D 3 receptor partial agonism of TPN672MA likely contribute to its therapeutic effects in depression. Additionally, TPN672MA's antidepressant-like efficacy may be linked to its ability to enhance the expression levels of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein-95 (PSD95) in the hippocampus. Furthermore, TPN672MA displayed a more rapid onset of antidepressant-like action. In conclusion, TPN672MA represents a promising new drug candidate for the treatment of symptoms of schizophrenia and depression. [ABSTRACT FROM AUTHOR]

BORLAND, J.M., The effects of different types of social interactions on the electrophysiology of neurons in the nucleus accumbens in rodents, NEUROSCI BIOBEH REV 21(1) XXX-XXX, 2024.-Sociality shapes an organisms' life. The nucleus accumbens is a critical brain region for mental health. In the following review, the effects of different types of social interactions on the physiology of neurons in the nucleus accumbens is synthesized. More specifically, the effects of sex behavior, aggression, social defeat, pair-bonding, play behavior, affiliative interactions, parental behaviors, the isolation from social interactions and maternal separation on measures of excitatory synaptic transmission, intracellular signaling and factors of transcription and translation in neurons in the nucleus accumbens in rodent models are reviewed. Similarities and differences in effects depending on the type of social interaction is then discussed. This review improves the understanding of the molecular and synaptic mechanisms of sociality. • Social behaviors change intracellular signaling pathways and synaptic plasticity. • Sex behavior, aggression and social defeat, but not pair-bonding, increase DeltaFosB. • Unlike sex and aggression, pair-bonding decreases signaling of NAc neurons. • Social defeat cell-type effects (D1/D2-MSNs) opposite of sex and aggression. • Sex and aggression differ in synaptic morphology. [ABSTRACT FROM AUTHOR]

Kappa opioid receptor activation has been linked to stress and anxiety behavior, thus leading to kappa antagonists being popularized in research as potential anxiolytics. However, while these findings may hold true in standard models, the neuromodulatory effects of social defeat may change the behavioral outcome of kappa opioid receptor activation. Previous research has shown that social defeat can lead to hyperactivity of serotonergic neurons in the dorsal raphe nucleus, and that inhibition of this increase blocks the social deficits caused by defeat. Kappa opioid receptor activation in the dorsal raphe nucleus works to decrease serotonergic activity. We injected the kappa opioid receptor U50,488 directly into the dorsal raphe nucleus of male and female, defeat and control adult California mice. Here we show evidence that U50,488 induces anxiety behavior in control male California mice, but helps relieve it in defeated males. Consistent with previous literature, we find little effect in females adding evidence that there are marked and important sex differences in the kappa opioid system.

Increasing predictability of animal models of posttraumatic stress disorder (PTSD) has required active collaboration between clinical and preclinical scientists. Modeling PTSD is challenging, as it is a heterogeneous disorder with ≥20 symptoms. Clinical research increasingly utilizes objective biological measures (e.g., imaging, peripheral biomarkers) or nonverbal behaviors and/or physiological responses to complement verbally reported symptoms. This shift toward more-objectively measurable phenotypes enables refinement of current animal models of PTSD, and it supports the incorporation of homologous measures across species. We reviewed >600 articles to examine the ability of current rodent models to probe biological phenotypes of PTSD (e.g., sleep disturbances, hippocampal and fear-circuit dysfunction, inflammation, glucocorticoid receptor hypersensitivity) in addition to behavioral phenotypes. Most models reliably produced enduring generalized anxiety-like or depression-like behaviors, as well as hyperactive fear circuits, glucocorticoid receptor hypersensitivity, and response to long-term selective serotonin reuptake inhibitors. Although a few paradigms probed fear conditioning/extinction or utilized peripheral immune, sleep, and noninvasive imaging measures, we argue that these should be incorporated more to enhance translation. Data on female subjects, on subjects at different ages across the life span, or on temporal trajectories of phenotypes after stress that can inform model validity and treatment study design are needed. Overall, preclinical (and clinical) PTSD researchers are increasingly incorporating homologous biological measures to assess markers of risk, response, and treatment outcome. This shift is exciting, as we and many others hope it not only will support translation of drug efficacy from animal models to clinical trials but also will potentially improve predictability of stage II for stage III clinical trials.

BackgroundThe neuropeptide oxytocin (OT) is a key regulator of social and emotional behaviors. The effects of OT are context dependent, and it has been proposed that OT increases the salience of both positive and negative social cues. Here we tested whether the bed nucleus of the stria terminalis (BNST) mediates anxiogenic effects of OT.MethodsFirst, we studied the effects of systemic administration of an OT receptor (OTR) antagonist L-368,899 on social behavior in male and female California mice exposed to social defeat. We examined the effect of L-368,899 on G protein activation and used early growth response factor 1 immunohistochemistry to identify potential sites of OTR action. Finally, we examined the effects of L-368,899 infused in the BNST on behavior.ResultsA single dose of systemic L-368,899 increased social approach in stressed female mice and decreased social approach in male mice naïve to defeat. L-368,899 prevented OT activation of G proteins and did not activate G proteins in the absence of OT. Intranasal OT, which reduces social approach in female mice but not male mice, increased early growth response factor 1 immunoreactivity in the nucleus accumbens core and anteromedial BNST in female mice but not in male mice. Stressed female mice that received an infusion of L-368,899 into the anteromedial BNST but not the nucleus accumbens core increased social approach and decreased social vigilance responses.ConclusionsOur results suggest that OTR activation in anteromedial BNST induces a vigilance response in which individuals avoid, yet attend to, unfamiliar social contexts. Our results suggest that OTR antagonists may have unappreciated therapeutic potential for stress-induced psychiatric disorders.

CBG, a non-psychoactive phytocannabinoid, showed beneficial effects on different CNS disorders [[6], [8]]. Among natural products, triterpenoid acids also play a crucial role in CNS disorders, through their capacity to modulate several signaling pathways involved in neuro-inflammation and apoptotic processes. It has been estimated that CNS disorders result in death in one of every nine patients; these disorders include ictus, Parkinson's disease (PD), and Alzheimer's (AD) disease [[1]]. Central nervous system (CNS) disorders represent a public health priority and demand significant scientific efforts for the development and study of new drugs and their possible beneficial effects. [Extracted from the article]

The mu opioid receptor (MOR) and the orphan GPR151 receptor are inhibitory G protein coupled receptors that are enriched in the habenula, a small brain region involved in aversion processing, addiction and mood disorders. While MOR expression in the brain is widespread, GPR151 expression is restricted to the habenula. In a previous report, we created conditional ChrnB4-Cre × Oprm1fl/fl (so-called B4MOR) mice, where MORs are deleted specifically in Chrnb4-positive neurons restricted to the habenula, and shown a role for these receptors in naloxone aversion. Here we characterized the implication of habenular MORs in social behaviors. B4MOR−/− mice and B4MOR+/+ mice were compared in several social behavior measures, including the chronic social stress defeat (CSDS) paradigm, the social preference (SP) test and social conditioned place preference (sCPP). In the CSDS, B4MOR−/− mice showed lower preference for the social target (unfamiliar mouse of a different strain) at baseline, providing a first indication of deficient social interactions in mice lacking habenular MORs. In the SP test, B4MOR−/− mice further showed reduced sociability for an unfamiliar conspecific mouse. In the sCPP, B4MOR−/− mice also showed impaired place preference for their previous familiar littermates after social isolation. We next created and tested Gpr151−/− mice in the SP test, and also found reduced social preference compared to Gpr151+/+ mice. Altogether our results support the underexplored notion that the habenula regulates social behaviors. Also, our data suggest that the inhibitory habenular MOR and GPR151 receptors normally promote social reward, possibly by dampening the aversive habenula activity. [ABSTRACT FROM AUTHOR]

Identification of early biomarkers of stress is important for preventing mood and anxiety disorders. Saliva is an easy-to-collect and non-invasive diagnostic target. The aim of this study was to characterize the changes in salivary whole microRNAs (miRNAs) and metabolites in mice subjected to subchronic and mild social defeat stress (sCSDS). In this study, we identified seven upregulated and one downregulated miRNAs/PIWI-interacting RNA (piRNA) in the saliva of sCSDS mice. One of them, miR-208b-3p, which is reported as a reliable marker for myocardial infarction, was upregulated in the saliva of sCSDS mice. Histological analysis showed frequent myocardial interstitial fibrosis in the heart of such mice. In addition, gene ontology and pathway analyses suggested that the pathways related to energy metabolism, such as the oxidative phosphorylation and the pentose phosphate pathway, were significantly related to the miRNAs affected by sCSDS in saliva. In contrast, salivary metabolites were not significantly changed in the sCSDS mice, which is consistent with our previous metabolomic study on the plasma of sCSDS mice. Taken in the light of previous studies, the present study provides novel potential stress biomarkers for future diagnosis using saliva. [ABSTRACT FROM AUTHOR]

The research on molecular causes of stress-associated psychopathologies is becoming highly important because the number of people with depression, generalized anxiety disorder and posttraumatic stress disorders (PTSDs) is steadily increasing every year. Investigation of molecular mechanisms in animal models opens up broad prospects for researchers, but relevant molecular signatures can differ significantly between patients and animal models. In our work, we for the first time carried out a meta-analysis of transcriptome changes in the prefrontal cortex of C57BL/6 mice after 10 and 30 days of social defeat stress (SDS). We then examined possible correlations of these alterations with transcriptome changes found in post-mortem samples from patients with depression or PTSD. Although transcriptional signatures of human psychiatric disorders and SDS did not overlap substantially, our results allowed us to identify the most reproducible changes seen after SDS of various durations. In addition, we were able to identify the genes involved in susceptibility to SDS after 10 days of stress. Taken together, these data help us to elucidate the molecular changes induced by SDS depending on its duration as well as their relevance to the alterations found in depression or PTSD in humans. [ABSTRACT FROM AUTHOR]

Upon chronic stress, a fraction of individuals shows stress resilience, which can prevent long-term mental dysfunction. The underlying molecular mechanisms are complex and have not yet been fully understood. In this study, we performed a data-driven behavioural stratification together with single-cell transcriptomics of the hippocampus in a mouse model of chronic social defeat stress. Our work revealed that in a sub-group exhibiting molecular responses upon chronic stress, the dorsal hippocampus is particularly involved in neuroimmune responses, angiogenesis, myelination, and neurogenesis, thereby enabling brain restoration and homeostasis after chronic stress. Based on these molecular insights, we applied rapamycin after the stress as a proof-of-concept pharmacological intervention and were able to substantially increase stress resilience. Our findings serve as a data resource and can open new avenues for further understanding of molecular processes underlying stress response and for targeted interventions supporting resilience. [ABSTRACT FROM AUTHOR]

Emotional stress is considered a severe pathogenetic factor of psychiatric disorders. However, the circuit mechanisms remain largely unclear. Using a three-chamber vicarious social defeat stress (3C-VSDS) model in mice, we here show that chronic emotional stress (CES) induces anxiety-like behavior and transient social interaction changes. Dopaminergic neurons of ventral tegmental area (VTA) are required to control this behavioral deficit. VTA dopaminergic neuron hyperactivity induced by CES is involved in the anxiety-like behavior in the innate anxiogenic environment. Chemogenetic activation of VTA dopaminergic neurons directly triggers anxiety-like behavior, while chemogenetic inhibition of these neurons promotes resilience to the CES-induced anxiety-like behavior. Moreover, VTA dopaminergic neurons receiving nucleus accumbens (NAc) projections are activated in CES mice. Bidirectional modulation of the NAc-VTA circuit mimics or reverses the CES-induced anxiety-like behavior. In conclusion, we propose that a NAc-VTA circuit critically establishes and regulates the CES-induced anxiety-like behavior. This study not only characterizes a preclinical model that is representative of the nuanced aspect of CES, but also provides insight to the circuit-level neuronal processes that underlie empathy-like behavior. Using a three-chamber vicarious social defeat stress model in mice, Qi et al. show that chronic emotional stress (CES) induced anxiety-like behavior and transient social interaction changes. Bidirectional modulation of NAc-VTA circuit mimics or reverses the CES-induced anxiety-like behavior. [ABSTRACT FROM AUTHOR]

The article presents a study on distinct forms of regret linked to resilience versus susceptibility to stress regulated by region-specific cyclic adenosine monophosphate response element–binding protein (CREB) function. It provides information on how maladaptive stress response traits relate to forms of counterfactual thinking, which regulate mood disorders.

Recent studies have indicated that some individuals are less affected by stress, and such individuals are called resilient. This study aimed to determine whether the specific phenotype of microglia might be involved in resilience using the social defeat stress paradigm. Male C57BL/6J (B6) mice were attacked by aggressive male ICR mice for five consecutive days. After stress exposure, the social behaviour was reduced in about half of the B6 mice (vulnerable), whereas no such change was observed in the remaining half of the B6 mice (resilient). Anxiety‐like behaviour was increased in vulnerable mice compared with resilient mice and non‐stressed controls. However, depression‐related behaviour was comparable between the three groups. The morphological characteristics of microglia in the CA1 region of the dorsal hippocampus in non‐stressed controls and resilient mice differed from those in vulnerable mice. Interestingly, the voxel densities of GABAergic and glutamatergic synaptic puncta colocalized with microglia were higher in resilient mice than in non‐stressed controls and vulnerable mice. Microglia were then objectively classified into three morphological types by hierarchical cluster analysis. The appearance of type I microglia resembled the so‐called resting ramified microglia and represented the major population of microglia in non‐stressed controls. Type II microglia exhibited a de‐ramified morphology and accounted for 60% of the microglia in vulnerable mice. Type III microglia showed a hyper‐ramified morphology and represented more than half of the microglia in resilient mice. These results suggest that hyper‐ramified microglia in the hippocampus may be associated with stress resilience via the modulation of synaptic transmission. [ABSTRACT FROM AUTHOR]

Increasing evidence has demonstrated that emotional states and intestinal conditions are inter-connected in so-called “brain–gut interactions.” Indeed, many psychiatric disorders are accompanied by gastrointestinal symptoms, such as the irritable bowel syndrome (IBS). However, the functional connection remains elusive, partly because there are few useful experimental animal models. Here, we focused on a highly validated animal model of stress-induced psychiatric disorders, such as depression, known as the chronic vicarious social defeat stress (cVSDS) model mice, which we prepared using exposure to repeated psychological stress, thereafter examining their intestinal conditions. In the charcoal meal test and the capsaicin-induced hyperalgesia test, cVSDS model mice showed a significantly higher intestinal transit ratio and increased visceral pain-related behaviors, respectively. These changes persisted over one month after the stress session. On the other hand, the pathological evaluations of the histological and inflammatory scores of naive and cVSDS model mice did not differ. Furthermore, keishikashakuyakuto—a kampo medicine clinically used for the treatment of IBS—normalized the intestinal motility change in cVSDS model mice. Our results indicate that cVSDS model mice present IBS-like symptoms such as chronic intestinal peristaltic changes and abdominal hyperalgesia without organic lesion. We therefore propose the cVSDS paradigm as a novel animal model of IBS with wide validity, elucidating the correlation between depressive states and intestinal abnormalities. [ABSTRACT FROM AUTHOR]

Depression has become one of the severe mental disorders threatening global human health. In this study, we first used the proteomics approach to obtain the differentially expressed proteins in the liver between naive control and chronic social defeat stress (CSDS) induced depressed mice. We have identified the upregulation of iron binding protein transferrin (TF) in the liver, the peripheral blood, and the brain in CSDS-exposed mice. Furthermore, bioinformatics analysis of the Gene Expression Omnibus (GEO) database from various mouse models of depression revealed the significantly upregulated transcripts of TF and its receptor TfR1 in multiple brain regions in depressed mice. We also used the recombinant TF administration via the tail vein to detect its permeability through the blood-brain barrier (BBB). We demonstrated the permeability of peripheral TF into the brain through the BBB. Together, these results identified the elevated expression of TF and its receptor TfR1 in both peripheral liver and the central brain in CSDS-induced depressed mice, and peripheral administration of TF can be transported into the brain through the BBB. Therefore, our data provide a compelling information for understanding the potential role and mechanisms of the cross-talk between the liver and the brain in stress-induced depression. [ABSTRACT FROM AUTHOR]

Chronic stress has the potential to impair health and may increase the vulnerability for psychiatric disorders. Emerging evidence suggests that specific neurometabolic dysfunctions play a role herein. In mice, chronic social defeat (CSD) stress reduces cerebral glucose uptake despite hyperglycemia. We hypothesized that this metabolic decoupling would be reflected by changes in contact sites between mitochondria and the endoplasmic reticulum, important intracellular nutrient sensors, and signaling hubs. We thus analyzed the proteome of their biochemical counterparts, mitochondria-associated membranes (MAMs) from whole brain tissue obtained from CSD and control mice. This revealed a lack of the glucose-metabolizing enzyme hexokinase 3 (HK3) in MAMs from CSD mice. In controls, HK3 protein abundance in MAMs and also in striatal synaptosomes correlated positively with peripheral blood glucose levels, but this connection was lost in CSD. We conclude that the ability of HK3 to traffic to sites of need, such as MAMs or synapses, is abolished upon CSD and surmise that this contributes to a cellular dysfunction instigated by chronic stress. Key messages: Chronic social defeat (CSD) alters brain glucose metabolism CSD depletes hexokinase 3 (HK3) from mitochondria-associated membranes (MAMs) CSD results in loss of positive correlation between blood glucose and HK3 in MAMs and synaptosomes [ABSTRACT FROM AUTHOR]

Development of neuropsychiatric disorder is associated with stress-related increase in pro-inflammatory cytokines. Chrysophyllum albidum fruit is an edible tropical fruit containing vitamins and phenolic compounds, well known for their anti-inflammatory and antioxidant activities. This study was designed to investigate the neuroprotective effect of C. albidum fruit extract (CAFE) on stress and lipopolysaccharide (LPS)-induced behavioral and neurochemical impairments in mice. Male Swiss mice were divided into 6 groups (n = 6). Groups 1–3 were orally treated daily for 14 days with normal saline (0.1 mL/10 g), CAFE (100 mg/kg) and Ferulic acid (FA, 10 mg/kg), and left in home cage as controls. Groups 4–6 were treated similarly but subjected to repeated social defeat (RSD) stress using the resident-intruder model from days 1–14. The RSD-animals were injected with LPS (125 µg/kg, i.p) 60 min after each RSD session from days 8–14. Neurobehavioral functions: locomotor, cognitive and anxiety-like behaviors were assessed 24 h after the last treatment. Pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α), dopamine, acetylcholinesterase, glutamic acid decarboxylase (GAD), malondialdehyde, nitrites, and reduced glutathione (GSH) were determined in brain tissue. CAFE significantly attenuated RSD and LPS-induced hypolocomotion, cognitive impairment and anxiety-like behavior when compared to the control. Treatment with CAFE also significantly reversed the negative effects of RSD and LPS on pro-inflammatory cytokines, dopamine, acetylcholinesterase, GAD, and oxidative-nitrosative stress levels. The findings clearly indicated that Chrysophyllum albidum fruit demonstrated neuroprotective effects and can play a key role in mitigating against chronic stress and inflammation linked to neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Featured Application: This review summarizes current knowledge regarding the effects of physical activity on the robustness of the circadian system and the benefits for health, performance, and wellbeing. We propagate practical implications of circadian activity rhythms for diagnosis and the advantages of scheduled motor activity. Circadian rhythms are an inherent property of all living systems and an essential part of the external and internal temporal order. They enable organisms to be synchronized with their periodic environment and guarantee the optimal functioning of organisms. Any disturbances, so-called circadian disruptions, may have adverse consequences for health, physical and mental performance, and wellbeing. The environmental light–dark cycle is the main zeitgeber for circadian rhythms. Moreover, regular physical activity is most useful. Not only does it have general favorable effects on the cardiovascular system, the energy metabolism and mental health, for example, but it may also stabilize the circadian system via feedback effects on the suprachiasmatic nuclei (SCN), the main circadian pacemaker. Regular physical activity helps to maintain high-amplitude circadian rhythms, particularly of clock gene expression in the SCN. It promotes their entrainment to external periodicities and improves the internal synchronization of various circadian rhythms. This in turn promotes health and wellbeing. In experiments on Djungarian hamsters, voluntary access to a running wheel not only stabilized the circadian activity rhythm, but intensive wheel running even reestablished the rhythm in arrhythmic individuals. Moreover, their cognitive abilities were restored. Djungarian hamsters of the arrhythmic phenotype in which the SCN do not generate a circadian signal not only have a diminished cognitive performance, but their social memory is also compromised. Voluntary wheel running restored these abilities simultaneously with the reestablishment of the circadian activity rhythm. Intensively exercising Syrian hamsters are less anxious, more resilient to social defeat, and show less defensive/submissive behaviors, i.e., voluntary exercise may promote self-confidence. Similar effects were described for humans. The aim of the present paper is to summarize the current knowledge concerning the effects of physical activity on the stability of the circadian system and the corresponding consequences for physical and mental performance. [ABSTRACT FROM AUTHOR]

Chronic social stress caused by daily agonistic interactions in male mice leads to a mixed anxiety/depression-like disorder that is accompanied by the development of psychogenic immunodeficiency and stimulation of oncogenic processes concurrently with many neurotranscriptomic changes in brain regions. The aim of the study was to identify carcinogenesis- and apoptosis-associated differentially expressed genes (DEGs) in the hypothalamus of male mice with depression-like symptoms and, for comparison, in aggressive male mice with positive social experience. To obtain two groups of animals with the opposite 20-day social experiences, a model of chronic social conflict was used. Analysis of RNA-Seq data revealed similar expression changes for many DEGs between the aggressive and depressed animals in comparison with the control group; however, the number of DEGs was significantly lower in the aggressive than in the depressed mice. It is likely that the observed unidirectional changes in the expression of carcinogenesis- and apoptosis-associated genes in the two experimental groups may be a result of prolonged social stress (of different severity) caused by the agonistic interactions. In addition, 26 DEGs were found that did not change expression in the aggressive animals and could be considered genes promoting carcinogenesis or inhibiting apoptosis. Akt1, Bag6, Foxp4, Mapk3, Mapk8, Nol3, Pdcd10, and Xiap were identified as genes whose expression most strongly correlated with the expression of other DEGs, suggesting that their protein products play a role in coordination of the neurotranscriptomic changes in the hypothalamus. Further research into functions of these genes may be useful for the development of pharmacotherapies for psychosomatic pathologies. [ABSTRACT FROM AUTHOR]

Rationale: There is accumulating evidence to support the idea that brain-derived neurotrophic factor (BDNF) is involved in stress resilience. However, the precise molecular mechanisms underlying resilience in major depressive disorder (MDD) remain unknown. Objective: The objective of this study was to explore the role of methyl CpG binding protein 2 (MeCP2) and the BDNF/tropomyosin-receptor-kinase B (TrkB) signaling pathway in the stress resilience to chronic social defeat stress (CSDS) in mice. Results: We found that the overexpression of MeCP2 inhibited BDNF transcription, resulting in BDNF mRNA and protein downregulation in neuro-2a cells. The overexpression of MeCP2 increased S80-MeCP2 and decreased S421-MeCP2, BDNF, the ratio of S133-cyclic AMP response element binding protein (CREB)/CREB and p-TrkB/TrkB expression in neuro-2a cells. In addition, using the CSDS mouse model, we found that MeCP2 mRNA levels were decreased in the medial prefrontal cortex (mPFC) of resilient mice and increased in the hippocampus of susceptible mice. BDNF exon IV promoter and BDNF mRNA levels were decreased in the mPFC and hippocampus of susceptible mice. Finally, MeCP2 and S80-MeCP2 protein levels were increased in the mPFC and hippocampus of susceptible mice, whereas the protein expression of S421-MeCP2 and BDNF, the ratio of S133-CREB/CREB, and the levels of p-TrkB/TrkB were decreased in susceptible mice. Conclusions: These data suggest that the overexpression of MeCP2 inhibits BDNF transcription in neuro-2a cells. The inhibition of MeCP2 expression and activation of the BDNF/TrkB signaling pathway may confer stress resilience in CSDS mice. [ABSTRACT FROM AUTHOR]

Chronic stress increases activity of the brain's innate immune system and impairs function of the medial prefrontal cortex (mPFC). However, whether acute stress triggers similar neuroimmune mechanisms is poorly understood. Across four studies, we used a Syrian hamster model to investigate whether acute stress drives changes in mPFC microglia in a time-, subregion-, and social status-dependent manner. We found that acute social defeat increased expression of ionized calcium binding adapter molecule 1 (Iba1) in the infralimbic (IL) and prelimbic (PL) and altered the morphology Iba1+ cells 1, 2, and 7 days after social defeat. We also investigated whether acute defeat induced tissue degeneration and reductions of synaptic plasticity 2 days post-defeat. We found that while social defeat increased deposition of cellular debris and reduced synaptophysin immunoreactivity in the PL and IL, treatment with minocycline protected against these cellular changes. Finally, we tested whether a reduced conditioned defeat response in dominant compared to subordinate hamsters was associated with changes in microglia reactivity in the IL and PL. We found that while subordinate hamsters and those without an established dominance relationships showed defeat-induced changes in morphology of Iba1+ cells and cellular degeneration, dominant hamsters showed resistance to these effects of social defeat. Taken together, these findings indicate that acute social defeat alters microglial morphology, increases markers of tissue degradation, and impairs structural integrity in the IL and PL, and that experience winning competitive interactions can specifically protect the IL and reduce stress vulnerability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Chronic stress has been shown to induce hyperglycemia in both peripheral blood and the brain, yet the detailed mechanisms of glucose metabolism under stress remain unclear. Utilizing 13 C 6 -labeled glucose to trace metabolic pathways, our study investigated the impact of stress by chronic social defeat (CSD) on glucose metabolites in the liver and brain one week post-stress. We observed a reduction in 13 C 6 -enrichment of glucose metabolites in the liver, contrasting with unchanged levels in the brain. Notably, hepatic glycogen levels were reduced while lactate concentrations were elevated, suggesting lactate as an alternative energy source during stress. Long-term effects were also examined, revealing normalized blood glucose levels and restored glycogen stores in the liver three weeks post-CSD, despite sustained increases in food intake. This normalization is hypothesized to result from diminished glucagon levels leading to reduced glycogen phosphorylase activity. Our findings highlight a temporal shift in glucose metabolism, with hyperglycemia and glycogen depletion in the liver early after CSD, followed by a later phase of metabolic stabilization. These results underscore the liver's critical role in adapting to CSD and provide insights into the metabolic adjustments that maintain glucose homeostasis under prolonged stress conditions., (© 2024. The Author(s).)

There is a gap in existing knowledge of stress-triggered neurochemical and behavioral adaptations in females. This study was designed to explore the short-term consequences of a single social defeat (SD) on accumbal dopamine (DA) dynamics and related behaviors in female Wistar rats. During the SD procedure, rats demonstrated different stress-handling strategies, which were defined as active and passive coping. The "active" subjects expressed a significantly higher level of activity directed toward handling stress experience, while the "passive" ones showed an escalated freezing pattern. Remarkably, these opposite behavioral manifestations were negatively correlated. Twenty-four hours following the SD exposure, decreased immobility latency in the Porsolt test and cognitive augmentation in the new object recognition evaluation were evident, along with an increase in electrically evoked mesolimbic DA release in passive coping rats. Rats exhibiting an active pattern of responses showed insignificant changes in immobility and cognitive performance as well as in evoked mesolimbic DA response. Furthermore, the dynamics of the decline and recovery of DA efflux under the depletion protocol were significantly altered in the passive but not active female rats. Taken together, these data suggest that female rats with a passive coping strategy are more susceptible to developing behavioral and neurochemical alterations within 24 h after stress exposure. This observation may represent both maladaptive and protective responses of an organism on a short timescale.

The basolateral amygdala (BLA) is increasingly recognized as a key regulator of depression and anxiety-like behaviors. However, the specific contribution of individual BLA neurons to these behaviors remains poorly understood. Building on our previous study, which demonstrated increased activity in glutamatergic BLA neurons in response to aversive stimuli and that enhancing inhibition in the BLA can alleviate depressive-like behaviors, we investigated the role of individual BLA GABAergic neurons (BLA GABA ) in depressive and anxiety-like phenotypes. To address this question, we employed a comprehensive array of techniques, including c-fos staining, fiber photometry recording, optogenetic and chemogenetic manipulation, and behavior analysis. Our findings indicate that BLA GABA neurons show decreased activity during tail suspension and after chronic social defeat stress (CSDS) during social interaction. High-frequency activation of BLA GABA neurons attenuated depressive and anxiety-like behaviors, while low-frequency activation had no effect. Fiber photometry recordings revealed increased activity in BLA GABAergic neurons expressing somatostatin (SST), parvalbumin (PV), and cholecystokinin (CCK) during footshock aversive stimuli. Moreover, we found increased activity in PV and SST neurons and decreased activity in CCK-GABA neurons in the BLA during tail suspension stress. However, after CSDS, BLA PV neurons displayed decreased activity, while SST and CCK neurons showed no changes during the social interaction test. Behavioral analysis demonstrated that chemogenetic inhibition of PV and CCK-GABA neurons induced depressive and anxiety-like behaviors. whereas SST neuron inhibition had no effect. Conversely, chemogenetic activation of BLA PV neurons alleviated depressive behaviors, and activation of BLA CCK-GABA neurons alleviated at least partly both depressive and anxiety-like behaviors. This study provides compelling evidence that BLA PV neurons play a critical role in regulating depressive-like behaviors, and that BLA CCK-GABA neurons are involved, at least in part, in modulating both depressive-like and anxiety-like behaviors in mice., (© 2024. The Author(s).)