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Adolescent social stress has been associated with the vulnerability to developing psychopathological disorders in adulthood that are accompanied by brain inflammatory processes. The purpose of this study is to investigate the dynamic changes of the hippocampal neuroinflammatory mediators, including microglia, astrocyte, and interleukin-6 (IL-6) levels in mice experiencing social defeat stress during adolescence. Adolescent mice were divided into the control group and stress group. Mice in the stress group were exposed to chronic intermittent social defeat for a total of 12 days, and control mice were reared in normal conditions. The hippocampal microglia, astrocyte, and IL-6 levels were measured 24 h and 3 weeks after the end of stress exposure. Microglia activation characterized by increased ionized calcium-binding adapter molecule 1 positive cell numbers or staining area in the CA1 and CA3 regions of the hippocampus were observed 24 h after the end of stress, which did not last into the adulthood. No short-term or long-term alterations of the number of hippocampal CA1 and CA3 glia fibrillary acidic protein astrocytes were found in mice experiencing adolescent social defeat, whereas IL-6 levels were only increased 3 weeks after the end of stress. These data suggested that exposure to chronic social defeat stress led to short-term and long-term neuroinflammatory changes in the hippocampus.

The spleen, an important tissue for the immune system, acts as a filter for blood within the immune system. Accumulating evidence suggests that the spleen affects a number of brain functions in health and diseases via immune modulation. Systemic inflammation or chronic social defeat stress (CSDS) can cause splenomegaly in rodents. Interestingly, the new antidepressant arketamine could normalize splenomegaly and depression-like behaviors in CSDS-susceptible mice. A recent study strongly supports the direct connection pathway between the brain and spleen, whereby the spleen can regulate the humoral immune defense by the two brain regions, such as corticotropin-related neurons in the paraventricular nucleus (PVN) and the central nucleus of the amygdala (CeA). Furthermore, afferent and efferent vagus nerve signaling may contribute to brain and spleen communication. In this article, we review recent findings of the brain-spleen axis in health and diseases.

The social defeat stress model is commonly used to study depression and anxiety disorder, which can significantly affect the structure and function of neurons in the hippocampus; however, the relevant mechanism in neuronal loss has not been clearly defined. In the present study, a social defeat stress model was established in mice to evaluate the impact of social defeat stress on the structure of neurons in the hippocampus using Western blotting, immunofluorescence, Nissl staining, Golgi staining and transmission electron microscopy. The results demonstrated that social defeat stress leads to disruption of homeostasis in the hippocampus and the integrity of mitochondria in hippocampal neurons was markedly affected by enhanced mitophagy and autophagy resulting in inhibition of development and growth. These findings provide new insights into the mechanisms of neuronal development and growth due to social defeat stress, which should help in the development of new strategies to combat the effects of depression and anxiety disorder.

Background: This study tested the hypotheses that (i) the relationship between a history of childhood abuse and severity of psychosis is mediated by loneliness; (ii) the relationship between loneliness and psychosis is mediated by within-person fluctuations in depressive and anxious feelings.Methods: Fifty-nine individuals with non-affective psychotic disorder rated the intensity of loneliness, positive symptoms, and depressive and anxious feelings during repeated moments in daily life (Experience Sampling Method). Childhood abuse was assessed retrospectively using the 'Childhood Experience of Care and Abuse' interview. To test the mediation hypotheses, a multilevel structural equation modeling paradigm was used.Results: As predicted, the relationship between severity of childhood abuse and positive symptoms was mediated by loneliness (b = 0.08, 95% CI [0.02, 0.13], p = 0.005). In turn, the relationship between loneliness and positive symptoms was mediated by within-person fluctuations in both depressive (b = 0.04, 95% CI [0.02, 0.06], p < 0.001) and anxious (b = 0.02, 95% CI [0.01, 0.03], p = 0.002) symptomatology. Depression was a stronger mediator than anxiety (b = 0.02, 95% CI [0.00, 0.04], p = 0.027).Conclusions: Our findings highlight the role of childhood abuse and loneliness in the severity of psychosis in daily life.(c) 2019 Elsevier B.V. All rights reserved.

Growing evidence supports the role of microbiota in regulating gut-brain interactions and, thus, contributing to the pathogenesis of depression and the antidepressant actions. Adipose-derived mesenchymal stem cells (ADSCs), as important members of the stem cell family, were demonstrated to alleviate depression behaviors. However, the role of gut microbiota in ADSCs alleviating depression in chronic social defeat stress (CSDS) model is unknown.To examine the effects of ADSCs on depression symptoms and detect the changes in the composition of gut microbiota.We found that ADSCs administration significantly ameliorated CSDS-induced depression behaviors, which was accompanied by alteration in the gut microbiota. The principal co-ordinates analysis (PCoA) results showed that there was a significant difference between the gut microbiota among the groups. Remarkably, receiver operating characteristic (ROC) curves revealed that order Micrococcales, order Rhizobiales and species Bacteroides acidifaciens are potentially important biomarkers for the antidepressant effects of ADSCs in CSDS model.ADSCs are effective in treating depression behaviors in CSDS model, which might be partly due to the regulation of abnormal composition of gut microbiota. Thus, ADSCs offer a promising therapeutic strategy for treating depression in patients.

We review the still scarce but growing literature on resilience to the effects of social stress on the rewarding properties of drugs of abuse. We define the concept of resilience and how it is applied to the field of drug addiction research. We also describe the internal and external protective factors associated with resilience, such as individual behavioral traits and social support. We then explain the physiological response to stress and how it is modulated by resilience factors. In the subsequent section, we describe the animal models commonly used in the study of resilience to social stress, and we focus on the effects of chronic social defeat (SD), a kind of stress induced by repeated experience of defeat in an agonistic encounter, on different animal behaviors (depression- and anxiety-like behavior, cognitive impairment and addiction-like symptoms). We then summarize the current knowledge on the neurobiological substrates of resilience derived from studies of resilience to the effects of chronic SD stress on depression- and anxiety-related behaviors in rodents. Finally, we focus on the limited studies carried out to explore resilience to the effects of SD stress on the rewarding properties of drugs of abuse, describing the current state of knowledge and suggesting future research directions.

Background Innate immune pre-stimulation can prevent the development of depression-like behaviors in chronically stressed mice; however, whether the same stimulation prevents the development of anxiety-like behaviors in animals remains unclear. We addressed this issue using monophosphoryl lipid A (MPL), a derivative of lipopolysaccharide (LPS) that lacks undesirable properties of LPS but still keeps immune-enhancing activities. Methods The experimental mice were pre-injected intraperitoneally with MPL before stress exposure. Depression was induced through chronic social defeat stress (CSDS). Behavioral tests were conducted to identify anxiety-like behaviors. Real-time polymerase chain reaction (PCR) and biochemical assays were employed to examine the gene and protein expression levels of pro-inflammatory markers. Results A single MPL injection at the dose of 400 and 800 μg/kg 1 day before stress exposure prevented CSDS-induced anxiety-like behaviors, and a single MPL injection (400 μg/kg) five but not 10 days before stress exposure produced similar effect. The preventive effect of MPL on anxiety-like behaviors was also observed in CSDS mice who received a second MPL injection 10 days after the first MPL injection or a 4 × MPL injection 10 days before stress exposure. MPL pre-injection also prevented the production of pro-inflammatory cytokines in the hippocampus and medial prefrontal cortex in CSDS mice, and inhibiting the central immune response by minocycline pretreatment abrogated the preventive effect of MPL on CSDS-induced anxiety-like behaviors and pro-inflammatory cytokine productions in the brain. Conclusions Pre-stimulation of the innate immune system by MPL can prevent chronic stress-induced anxiety-like behaviors and neuroinflammatory responses in the brain in mice.

Dysregulated GABAergic inhibition in the amygdala has long been implicated in stress-related neuropsychiatric disorders. However, the molecular and circuit mechanisms underlying the dysregulation remain elusive. Here, by using a mouse model of chronic social defeat stress (CSDS), we observed that the dysregulation varied drastically across individual projection neurons (PNs) in the basolateral amygdala (BLA), one of the kernel amygdala subregions critical for stress coping. While persistently reducing the extrasynaptic GABAA receptor (GABAAR)-mediated tonic current in the BLA PNs projecting to the ventral hippocampus (BLA → vHPC PNs), CSDS increased the current in those projecting to the anterodorsal bed nucleus of stria terminalis (BLA → adBNST PNs), suggesting projection-based dysregulation of tonic inhibition in BLA PNs by CSDS. Transcriptional and electrophysiological analysis revealed that the opposite CSDS influences were mediated by loss- and gain-of-function of δ-containing GABAARs (GABAA(δ)Rs) in BLA → vHPC and BLA → adBNST PNs, respectively. Importantly, it was the lost inhibition in the former population but not the augmentation in the latter population that correlated with the increased anxiety-like behavior in CSDS mice. Virally mediated maintenance of GABAA(δ)R currents in BLA → vHPC PNs occluded CSDS-induced anxiety-like behavior. These findings clarify the molecular substrate for the dysregulated GABAergic inhibition in amygdala circuits for stress-associated psychopathology.

The social defeat hypothesis of schizophrenia, which proposes that the chronic experience of outsider status or subordinate position leads to increased striatal dopamine activity and thereby to increased risk, has been criticized. The aims of this paper are to improve the definition of defeat and to integrate the social defeat hypothesis with the neurodevelopmental hypothesis. Marmot advanced the idea that low status is pathogenic in that it is associated with a lack of social participation and a lack of autonomy. Given the similarity with outsider status and subordinate position, we re-define social defeat as low status. From this new perspective it is also likely that pre-schizophrenic impairments (of neurodevelopmental origin or not) are pathogenic in that they contribute to low status. The effect of low status may be enhanced by repeated exposure to humiliation, but few studies have measured this variable. Since most individuals exposed to low status do not develop schizophrenia, we propose that this risk factor increases the risk of disorder in the presence of a poor homeostatic control of dopamine neurons in midbrain and dorsal striatum. This is consistent with studies of healthy subjects which report a negative association between low socio-economic status and dopamine D2/D3 receptor availability in the dorsal striatum. In this new version of the social defeat hypothesis we propose that the combination of low status, repeated humiliation and poor homeostatic control of dopamine neurons in midbrain and dorsal striatum leads to increased striatal dopamine activity and thereby to an increased risk of schizophrenia.

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.

The multifactorial etiology of stress-related disorders necessitates a constant interrogation of the molecular convergences in preclinical models of stress that use disparate paradigms as stressors spanning from environmental challenges to genetic predisposition to hormonal signaling. Using RNA-sequencing, we investigated the genomic signatures in the ventral hippocampus common to mouse models of stress. Chronic oral corticosterone (CORT) induced increased anxiety- and depression-like behavior in wild-type male mice and male mice heterozygous for the gene coding for brain-derived neurotrophic factor Val66Met, a variant associated with genetic susceptibility to stress. In a separate set of male mice, chronic social defeat stress (CSDS) led to a susceptible or a resilient population, whose proportion was dependent on housing conditions, namely standard housing or enriched environment. Rank-rank-hypergeometric overlap (RRHO), a threshold-free approach that ranks genes by their p value and effect size direction, was used to identify genes from a continuous gradient of significancy that were concordant across groups. In mice treated with CORT and in standard-housed susceptible mice, differentially expressed genes (DEGs) were concordant for gene networks involved in neurotransmission, cytoskeleton function, and vascularization. Weighted gene co-expression analysis generated 54 gene hub modules and revealed two modules in which both CORT and CSDS-induced enrichment in DEGs, whose function was concordant with the RRHO predictions, and correlated with behavioral resilience or susceptibility. These data showed transcriptional concordance across models in which the stress coping depends upon hormonal, environmental, or genetic factors revealing common genomic drivers that embody the multifaceted nature of stress-related disorders.

Stressful life events are ubiquitous and well-known to negatively impact mental health. However, in both humans and animal models, there is large individual variability in how individuals respond to stress, with some but not all experiencing long-term adverse consequences. While there is growing understanding of the neurobiological underpinnings of the stress response, much less is known about how neurocircuits shaped by lifetime experiences are activated during an initial stressor and contribute to this selective vulnerability versus resilience. We developed a model of acute social defeat stress (ASDS) that allows classification of male mice into “susceptible” (socially avoidant) versus “resilient” (expressing control-level social approach) one hour after exposure to six minutes of social stress. Using circuit tracing and high-resolution confocal imaging, we explored differences in activation and dendritic spine density and morphology in the prelimbic cortex to basolateral amygdala (PL→BLA) circuit in resilient versus susceptible mice. Susceptible mice had greater PL→BLA recruitment during ASDS and activated PL→BLA neurons from susceptible mice had more and larger mushroom spines compared to resilient mice. We hypothesized identified structure/function differences indicate an overactive PL→BLA response in susceptible mice and used an intersectional chemogenetic approach to inhibit the PL→BLA circuit during or prior to ASDS. We found in both cases that this blocked ASDS-induced social avoidance. Overall, we show PL→BLA structure/function differences mediate divergent behavioral responses to ASDS in male mice. These results support PL→BLA circuit overactivity during stress as a biomarker of trait vulnerability and potential target for prevention of stress-induced psychopathology.

Depression is associated with taste disorders; however, the mechanisms by which mental stress affects taste perception are not well understood. This study aimed to elucidate the effects of psychosocial stress on peripheral taste-sensing systems using a mouse depression model. Male mice were subjected to subchronic and mild social defeat stress (sCSDS). Results showed that sCSDS significantly increased body weight, food and water intake, and social avoidance behavior and that sCSDS did not change reward-seeking behavior on sucrose preference but tended to decrease pheromonal preference for female urine. Furthermore, sCSDS downregulated the mRNA levels of sweet and umami taste receptor subunits, i.e., sweet taste receptor type 1 members 2 and 3 (T1R2 and T1R3), but not the umami taste receptor subunit, i.e., taste receptor type 1 member 1 (T1R1), in the circumvallate papillae of mice. It is known that sucrose preference is mediated by the gut–brain axis without taste perception; thus, it was considered that sCSDS affected the peripheral taste-sensing systems, rather than the central reward systems, which mediate sucrose preference. This is the first study to report that psychosocial stress affects peripheral sweet and umami taste-sensing systems.

Background Major depressive disorder (MDD) is a psychiatric disorder caused by various etiologies. Chronic stress models are used to simulate the heterogeneous pathogenic processes of depression. However, few studies have compared transcriptional features between stress models and MDD patients. Methods We generated hippocampal transcriptional profiles of the chronic social defeat model by RNA sequencing and downloaded raw data of the same brain region from public databases of the chronic unpredictable mild stress model, the learned helplessness model, and MDD patients. Differential expression and gene co-expression analyses were integrated to compare transcriptional features between stress models and MDD patients. Results Each stress model shared 11.4% to 16.3% of differentially expressed genes with MDD patients. Functional analysis at the gene expression level identified altered ensheathment of neurons in both stress models and MDD patients. At the gene network level, each stress model shared 20.9% to 41.6% of co-expressed genes with MDD patients. Functional analysis based on these genes found that axon guidance signaling is the most significantly enriched pathway that was shared by all stress models and MDD patients. Limitations This study was limited by considering only a single brain region and a single sex of stress model animals. Conclusions Our results show that hippocampal transcriptional features of stress models partially overlap with those of MDD patients. The canonical pathways of MDD patients, including ensheathment of neurons, PTEN signaling, and axonal guidance signaling, were shared with all stress models. Our findings provide further clues to understand the molecular mechanisms of depression.

Chronic stress induces peripheral and intracerebral immune changes and inflammation, contributing to neuropathology and behavioral abnormalities relevant to psychiatric disorders such as depression. Although the pathological implication of many peripheral factors such as pro‐inflammatory cytokines, hormones, and macrophages has been demonstrated, the roles of circulating extracellular vesicles (EVs) for chronic stress mechanisms remain poorly investigated. Here, we report that chronic social defeat stress (CSDS)‐induced social avoidance phenotype, assessed by a previously untested three‐chamber social approach test, can be distinguished by multiple pro‐inflammatory cytokines and EV‐associated molecular signatures in the blood. We found that the expression patterns of miRNAs distinguished the CSDS‐susceptible mice from the CSDS‐resilient mice. Social avoidance behavior scores were also estimated with good accuracy by the expression patterns of multiple EV‐associated miRNAs. We also demonstrated that EVs enriched from the CSDS‐susceptible mouse sera upregulated the production of pro‐inflammatory cytokines in the LPS‐stimulated microglia‐like cell lines. Our results indicate the role of circulating EVs and associated miRNAs in CSDS susceptibility, which may be related to pro‐inflammatory mechanisms underlying stress‐induced neurobehavioral outcomes., Social avoidance behaviors after chronic social defeat stress are accompanied by altered extracellular vesicles (EVs) in the blood, together with increased levels of pro‐inflammatory cytokines. EV‐associated miRNA expression patterns are correlated with social behavioral scores. In addition, EVs are shown to enhance the production of pro‐inflammatory cytokines in cultured microglia‐like cells. Thus, EVs may contribute to pro‐inflammatory responses in socially stressed mice.

PURPOSE: Chronic glucocorticoid release during the stress response has been proposed to initiate certain damages, which in turn produce metabolic disorders. The present study is the first work to test whether maternal separation (MS) would impact the metabolic alterations associated with pancreatic oxidative and inflammatory damages under chronic exposure to social defeat stress (CSDS) in adulthood. METHODS: During the first 2 weeks of life, male Wistar rats were exposed to MS or left undisturbed with their mothers (Std). Starting on postnatal day 50, the animals of each group were either left undisturbed in the standard group housing (Con) or underwent CSDS for 3 weeks. Thus, there were 4 groups (n = 7/group): Std-Con, Ms-Con, Std-CSDS, MS-CSDS. Each animal was weighed and then decapitated so that we could collect trunk blood for assessment of fasting plasma corticosterone, insulin, glucose, lipid profile, and insulin resistance. Plasma and pancreatic catalase activity, reduced glutathione (GSH), malondialdehyde levels and pancreatic interleukin-1 beta (IL-1β) content were also measured. RESULTS: MS-CSDS animals showed elevated plasma corticosterone and insulin levels (P

Background The brain–gut–microbiota axis plays a crucial role in the bidirectional interactions between the brain and the gut. Soluble epoxide hydrolase (coded by the Ephx2 gene) plays an important role in inflammation, which has been implicated in stress-related depression. Ephx2 knock-out (KO) mice exposed to chronic social defeat stress (CSDS) did not show depression-like behaviors, indicating stress resilience. Here we examined whether the brain–gut–microbiota axis influences the resilience in Ephx2 KO mice. Methods Effects of fecal microbiota transplantation (FMT) from CSDS-susceptible (or control) mice in wild-type (WT) mice and Ephx2 KO mice treated with an antibiotic cocktail (ABX) were investigated. Behavioral, biochemical tests and 16S ribosome RNA analysis were performed. Results FMT from CSDS-susceptible mice produced anhedonia-like behavior in ABX-treated WT and Ephx2 KO mice. The 16S ribosome RNA analysis showed that Faecalibaculum rodentium (F. rodentium) may be responsible for the observed anhedonia-like behavior following FMT from CSDS-susceptible mice. Ingestion of F. rodentium for 14 days produced depression- and anhedonia-like behaviors, higher blood levels of interleukin-6, and reduced expression of synaptic proteins in the prefrontal cortex of ABX-treated Ephx2 KO mice. Furthermore, subdiaphragmatic vagotomy blocked the development of these behavioral abnormalities after ingestion of F. rodentium. Limitations Detailed mechanisms are unclear. Conclusions These findings suggest that F. rodentium might contribute to the conversion of resilient Ephx2 KO mice into KO mice with depression-like phenotypes. The brain–gut–microbiota axis via the subdiaphragmatic vagus nerve plays a crucial role in susceptibility and resilience to stress.

(R,S)-ketamine causes rapid-acting and sustained antidepressant effects in treatment-resistant patients with depression although the precise molecular mechanisms underlying its antidepressant action remain unclear. We recently reported that transforming growth factor (TGF)-β1 might contribute to the antidepressant-like effects of (R)-ketamine that is a more potent enantiomer in rodents. Although TrkB signaling plays a role in the antidepressant-like actions of (R,S)-ketamine and its enantiomers, the role of TrkB signaling in the antidepressant effects of TGF-β1 remains unclear. Using behavioral tests such as tail-suspension test (TST), forced swimming test (FST), and 1% sucrose preference test (SPT), we investigated whether a single intranasal administration of the recombinant TGF-β1 (1.5 and 3.0 μg/kg) causes rapid and sustained antidepressant-like effects in a chronic social defeat stress (CSDS) model. Both doses of TGF-β1 significantly attenuated the increased immobility time of TST and FST in the CSDS susceptible mice. High dose of TGF-β1, but not low dose, significantly ameliorated the decreased sucrose preference of SPT in the CSDS susceptible mice. Pretreatment with a TrkB antagonist ANA-12 (0.5 mg/kg) blocked the antidepressant-like effects of TGF-β1 in CSDS susceptible mice. The data suggest that intranasal administration of TGF-β1 could elicit rapid-acting antidepressant-like effects via TrkB stimulation in a CSDS model. Therefore, it is likely that intranasal administration of TGF-β1 would be a novel therapeutic approach for depression.

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 the 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.

Brain α2-containing GABA(A) receptors play a critical role in the modulation of anxiety- and fear-like behavior. However, it is unknown whether these receptors also play a role in modulating resilience to chronic stress, and in which brain areas and cell types such an effect would be mediated. We evaluated the role of α2-containing GABA(A) receptors following chronic social defeat stress using male mice deficient in the α2 subunit globally or conditionally in dopamine D1- or D2-receptor-expressing neurons, e.g., within the nucleus accumbens (NAc). In addition, we examined the effect of the lack of the α2 subunit on intermediates of the glutathione synthesis pathway. We found that α2-containing GABA(A) receptors on D2-receptor-positive but not on D1-receptor-positive neurons promote resiliency to chronic social defeat stress, as reflected in social interaction tests. The pro-resiliency effects of α2-containing GABA(A) receptors on D2-receptor-positive neurons do not appear to be directly related to alterations in anxiety-like behavior, as reflected in the elevated plus-maze, light–dark box, and novel open field tests. Increases in indices of oxidative stress—reflected by increases in cystathionine levels and reductions in GSH/GSSG ratios—were found in the NAc and prefrontal cortex but not in the hippocampus of mice lacking α2-containing GABA(A) receptors. We conclude that α2-containing GABA(A) receptors within specific brain areas and cell populations promote stress resiliency independently of direct effects on anxiety-like behaviors. A potential mechanism contributing to this increased resiliency is the protection that α2-containing GABA(A) receptors provide against oxidative stress in NAc and the prefrontal cortex.

Numerous human clinical studies have suggested that decreased locomotor activity is a common symptom of major depressive disorder (MDD), as well as other psychiatric diseases. In MDD, the midbrain ventral tegmental area (VTA) dopamine (DA) neurons are closely related to regulate the information processing of reward, motivation, cognition, and aversion. However, the neural circuit mechanism that underlie the relationship between VTA-DA neurons and MDD-related motor impairments, especially hypolocomotion, is still largely unknown. Herein, we investigate how the VTA-DA neurons contribute to the hypolocomotion performance in chronic social defeat stress (CSDS), a mouse model of depression-relevant neurobehavioral states. The results show that CSDS could affect the spontaneous locomotor activity of mice, but not the grip strength and forced locomotor ability. Chemogenetic activation of VTA-DA neurons alleviated CSDS-induced hypolocomotion. Subsequently, quantitative whole-brain mapping revealed decreased projections from VTA-DA neurons to substantia nigra pars reticulata (SNr) after CSDS treatment. Optogenetic activation of dopaminergic projection from VTA to SNr with the stimulation of phasic firing, but not tonic firing, could significantly increase the locomotor activity of mice. Moreover, chemogenetic activation of VTA-SNr dopaminergic circuit in CSDS mice could also rescued the decline of locomotor activity. Taken together, our data suggest that the VTA-SNr dopaminergic projection mediates CSDS-induced hypolocomotion, which provides a theoretical basis and potential therapeutic target for MDD.

Major depressive disorder (MDD) is a common and serious psychiatric disease that involves brain inflammation. Bifidobacterium breve is commonly used as a probiotic and was shown to improve colitis and allergic diseases by suppressing the inflammatory response. Heat-sterilized B. breve has beneficial effects on inflammation. We hypothesize, therefore, that this probiotic might reduce depression symptoms. We tested this is a mouse model of social defeat stress. C57BL/6J mice exposed to chronic social defeat stress (CSDS) for five consecutive days developed a mild depression-like behavior characterized by a social interaction impairment. CSDS also altered the gut microbiota composition, such as increased abundance of Bacilli, Bacteroidia, Mollicutes, and Verrucomicrobiae classes and decreased Erysipelotrichi class. The prophylactic effect of heat-sterilized B. breve as a functional food ingredient was evaluated on the depression-like behavior in mice. The supplementation started two weeks before and lasted two weeks after the last exposure to CSDS. Two weeks after CSDS, the mice showed deficits in social interaction and increased levels of inflammatory cytokines, including interleukin-1β (IL-1β) in the prefrontal cortex (PFC) and hippocampus (HIP). Heat-sterilized B. breve supplementation significantly prevented social interaction impairment, suppressed IL-1β increase in the PFC and HIP, and modulated the alteration of the gut microbiota composition induced by CSDS. These findings suggest that heat-sterilized B. breve prevents depression-like behavior and IL-1β expression induced by CSDS through modulation of the gut microbiota composition in mice. Therefore, heat-sterilized B. breve used as an ingredient of functional food might prevent MDD.

Depression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.

Mood dysregulation refers to the inability of a person to control their negative emotions, and it is linked to various stressful experiences. Dysregulated neural synaptic plasticity and actin-filament dynamics are important regulators of stress response in animal models. However, until now, there is no evidence to differential the mechanisms of synaptic plasticity and actin-filament dynamics in stress susceptibility and stress-resistant. Here we found that depression-like behaviour was observed in the susceptible group following chronic social defeat stress (CSDS) exposure, but not in stress-resistant mice. High-frequency stimulation-induced long-term potentiation (LTP) was impaired in the CSDS-induced depression-susceptible group. Further, the levels of pro-brain derived neurotrophic factor (BDNF), mature BDNF, PSD-95, phosphorylated CaMKII, and phosphorylated Cofilin, an actin-filament dynamics regulator, were reduced in CSDS-induced depression-susceptible mice unlike in stress-resistant mice. These results demonstrate that synaptic plasticity-related molecules, such as BDNF and phosphorylated Cofilin, are important for maintaining synaptic functions and structure in mice that experience more stress.

The global number of patients with depression increases in correlation to exposure to social stress. Chronic stress does not trigger depression in all individuals, as some remain resilient. The underlying molecular mechanisms that contribute to stress sensitivity have been poorly understood, although revealing the regulation of stress sensitivity could help develop treatments for depression. We previously found that striatal Shati/Nat8l, an N-acetyltransferase, was increased in a depression mouse model. We investigated the roles of Shati/Nat8l in stress sensitivity in mice and found that Shati/Nat8l and brain-derived neurotrophic factor (BDNF) levels in the dorsal striatum were increased in stress-susceptible mice but not in resilient mice exposed to repeated social defeat stress (RSDS). Knockdown of Shati/Nat8l in the dorsal striatum induced resilience to RSDS. In addition, blockade of BDNF signaling in the dorsal striatum by ANA-12, a BDNF-specific receptor tropomyosin-receptor-kinase B (TrkB) inhibitor, also induced resilience to stress. Shati/Nat8l is correlated with BDNF expression after RSDS, and BDNF is downstream of Shati/Nat8l pathways in the dorsal striatum; Shati/Nat8l is epigenetically regulated by BDNF via histone acetylation. Our results demonstrate that striatal Shati/Nat8l-BDNF pathways determine stress sensitivity through epigenetic regulation. The striatal Shati/Nat8l-BDNF pathway could be a novel target for treatments of depression and could establish a novel therapeutic strategy for depression patients.

Paternal stress can induce long-lasting changes in germ cells potentially propagating heritable changes across generations. To date, no studies have investigated differences in transmission patterns between stress-resilient and stress-susceptible mice. We tested the hypothesis that transcriptional alterations in sperm during chronic social defeat stress (CSDS) transmit increased susceptibility to stress phenotypes to the next generation. We demonstrate differences in offspring from stressed fathers that depend on paternal category (resilient vs susceptible) and offspring sex. Importantly, artificial insemination (AI) reveals that sperm mediates some of the behavioral phenotypes seen in offspring. Using RNA-sequencing (RNA-seq), we report substantial and distinct changes in the transcriptomic profiles of sperm following CSDS in susceptible versus resilient fathers, with alterations in long noncoding RNAs (lncRNAs) predominating especially in susceptibility. Correlation analysis revealed that these alterations were accompanied by a loss of regulation of protein-coding genes by lncRNAs in sperm of susceptible males. We also identify several co-expression gene modules that are enriched in differentially expressed genes (DEGs) in sperm from either resilient or susceptible fathers. Taken together, these studies advance our understanding of intergenerational epigenetic transmission of behavioral experience. SIGNIFICANCE STATEMENT This manuscript contributes to the complex factors that influence the paternal transmission of stress phenotypes. By leveraging the segregation of males exposed to chronic social defeat stress (CSDS) into either resilient or susceptible categories we were able to identify the phenotypic differences in the paternal transmission of stress phenotypes across generations between the two lineages. Importantly, this work also alludes to the significance of both long noncoding RNAs (lncRNAs) and protein coding genes (PCGs) mediating the paternal transmission of stress. The knowledge gained from these data are of particular interest in understanding the risk for the development of psychiatric disorders such as anxiety and depression.

Objectives Several studies show that severe social stressors, e.g., in the form of exposure to workplace bullying in humans, is associated with negative mental health effects such as depression and anxiety among those targeted. However, the understanding of the underlying biological mechanisms that may explain the relationship between exposure to bullying and such negative health outcomes is scarce. The analyses presented here focus on understanding the role of the β2-adrenergic receptors (ADRB2) on this association. Methods First, a resident-intruder paradigm was used to investigate changes in circulating norepinephrine (NE) in rat serum induced by repeated social defeat and its relationship with subsequent social behavior. Second, the direct effects of the stress-hormones NE and cortisol, i.e., synthetic dexamethasone (DEX), on the ADRB2 expression (qPCR) and monocyte chemoattractant protein-1 (MCP-1) release (immunoassay) was examined in cultured EL-1 cells. Third, in a probability sample of 1052 Norwegian employees, the 9-item short version of the Negative Acts Questionnaire—Revised (S-NAQ) inventory, Hopkins Symptom Checklist and genotyping (SNP TaqMan assay) were used to examine the association between social stress in the form of workplace bullying and anxiety moderated by the ADRB2 genotype (rs1042714) in humans. Results The present study showed a clear association between reduced social interaction and increased level of circulating NE in rats previously exposed to repeated social defeat. Parallel cell culture work, which was performed to examine the direct effects of NE and DEX on ADRB2, demonstrated ADRB2 downregulation and MCP-1 upregulation in cultured EL-1 cells. Genotyping with regard to the ADRB2 genotype; rs1042714 CC vs CG/GG, on human saliva samples, showed that individuals with CC reported more anxiety following exposure to bullying behaviors as compared to the G carriers. Conclusion We conclude that workplace bullying promotes anxiety and threaten well-being through an ADRB2 associated mechanism.

There is growing evidence for a main role of environment in the occurrence of mental disorders such as a psychosocial risk factor, for example, childhood trauma, discrimination linked to minority status, or migrant status. One hypothesis is that social adversity factors influence the risk of schizophrenia through a common pathway: social defeat which could be defined as the impotence of a subject in the face of a situation of social adversity, with a consequential experience of devaluation on the social scale. This review proposes to explain the animal model of social defeat which provides an overview of the neurobiological consequences of chronic stress. Then, we expose this topic in humans, the assessment methods, and its psychopathological field. Finally, we expose epidemiologic and neurobiological evidences, in particular the dopaminergic sensitization process, which provide evidence of a significant role of social defeat in schizophrenia risk due to exposure to psychosocial factors. This etiopathogenic hypothesis has several issues. First, a common pathway to several environmental risk factors could allow an ethiopathogenic model more parcimonious for schizophrenia. It could also allow the assessment and prevention of adversity factors involved in social defeat so as to finally improve the outcome of subjects who have an individual risk for schizophrenia.

Functional lateralization of the prefrontal cortex has been implicated in stress and emotional disorders, yet underlying gene expression changes remains unknown. Here, we report molecular signatures lateralized by chronic social defeats between the two medial prefrontal cortices (mPFCs). Stressed mice show 526 asymmetrically expressed genes between the mPFCs. This cortical asymmetry selectively occurs in stressed mice with depressed social activity, but not in resilient mice with normal behavior. We have isolated highly asymmetric genes including connective tissue growth factor (CTGF), a molecule that modulates wound healing at the periphery. Knockdown of CTGF gene in the right mPFC by shRNA led to a stress-resistant behavioral phenotype. Overexpression of CTGF in the right mPFC using viral transduction induces social avoidance while the left mPFC thereof prevent stress-induced social avoidance. Our study provides a molecular window into the mechanism of stress-induced socioemotional disorders, which can pave the way for new interventions by targeting cortical asymmetry. Supplementary Information The online version contains supplementary material available at 10.1186/s13041-021-00802-w.

Traumatic events during childhood/early adolescence can cause long-lasting physiological and behavioral changes with increasing risk for psychiatric conditions including psychosis. Genetic factors and trauma (and their type, degree of repetition, time of occurrence) are believed to influence how traumatic experiences affect an individual. Here, we compared long-lasting behavioral effects of repeated social defeat stress (SD) applied during either peripuberty or late adolescence in adult male WT and Gclm-KO mice, a model of redox dysregulation relevant to schizophrenia. As SD disrupts redox homeostasis and causes oxidative stress, we hypothesized that KO mice would be particularly vulnerable to such stress. We first found that peripubertal and late adolescent SD led to different behavioral outcomes. Peripubertal SD induced anxiety-like behavior in anxiogenic environments, potentiated startle reflex, and increased sensitivity to the NMDA-receptor antagonist, MK-801. In contrast, late adolescent SD led to increased exploration in novel environments. Second, the long-lasting impact of peripubertal but not late adolescent SD differed in KO and WT mice. Peripubertal SD increased anxiety-like behavior in anxiogenic environments and MK-801-sensitivity mostly in KO mice, while it increased startle reflex in WT mice. These suggest that a redox dysregulation during peripuberty interacts with SD to remodel the trajectory of brain maturation, but does not play a significant role during later SD. As peripubertal SD induced persisting anxiety- and fear-related behaviors in male mice, we then investigated anxiety in a cohort of 89 early psychosis male patients for whom we had information about past abuse and clinical assessment during the first year of psychosis. We found that a first exposure to physical/sexual abuse (analogous to SD) before age 12, but not after, was associated with higher anxiety at 6-12 months after psychosis onset. This supports that childhood/peripuberty is a vulnerable period during which physical/sexual abuse in males has wide and long-lasting consequences.

In mice, social defeat stress (SDS), an ethological model for psychosocial stress, induces sleep. Such sleep could enable resilience, but how stress promotes sleep is unclear. Activity-dependent tagging revealed a subset of ventral tegmental area γ-aminobutyric acid (GABA)–somatostatin (VTA Vgat-Sst ) cells that sense stress and drive non–rapid eye movement (NREM) and REM sleep through the lateral hypothalamus and also inhibit corticotropin-releasing factor (CRF) release in the paraventricular hypothalamus. Transient stress enhances the activity of VTA Vgat-Sst cells for several hours, allowing them to exert their sleep effects persistently. Lesioning of VTA Vgat-Sst cells abolished SDS-induced sleep; without it, anxiety and corticosterone concentrations remained increased after stress. Thus, a specific circuit allows animals to restore mental and body functions by sleeping, potentially providing a refined route for treating anxiety disorders.

Major depressive disorder is a complex psychiatric disorder with a high prevalence rate worldwide. Previous studies have demonstrated the involvement of the prelimbic cortex (PL) in mediating depressive-like behavior, however, the exact molecular mechanism taking place in the PL remains unclear. In the present study, we conducted high-throughput sequencing of mRNAs and miRNAs in PL tissue harvested from chronic social defeat stress (CSDS) susceptible male mice. We identified 59 differentially expressed mRNAs and 6 differentially expressed miRNAs, in which 40 mRNAs and 3 miRNAs were up-regulated, while 19 mRNAs and 3 miRNAs were down-regulated. Integrated analysis of miRNA-mRNA networks suggested that GPR35 signaling might be involved in CSDS-induced depressive-like behaviors. RT-PCR and western blot assays validated that Abra, Sell and GPR35 were up-regulated. Functionally, inhibition of GPR35 in the PL ameliorated CSDS-induced depressive-like behaviors. Thus, the present study provided a global view of mRNA and miRNA profiles in the PL of male stress susceptible mice, and suggested that GPR35 signaling was associated with CSDS-induced depressive-like behaviors. These results may be valuable for further investigations of the molecular regulatory mechanisms in stress-induced depression.

Territorial reactive aggression in mice is used to study the biology of aggression-related behavior and is also a critical component of procedures used to study mood disorders, such as chronic social defeat stress. However, quantifying mouse aggression in a systematic, representative, and easily adoptable way that allows direct comparison between cohorts within or between studies remains a challenge. Here, we propose a structural equation modeling approach to quantify aggression observed during the resident-intruder procedure. Using data for 658 sexually experienced CD-1 male mice generated by three research groups across three institutions over a 10-year period, we developed a higher-order confirmatory factor model wherein the combined contributions of latency to the first attack, number of attack bouts, and average attack duration on each trial day (easily observable metrics that require no specialized equipment) are used to quantify individual differences in aggression. We call our final model the Mouse Aggression Detector (MAD) model. Correlation analyses between MAD model factors estimated from multiple large datasets demonstrate generalizability of this measurement approach, and we further establish the stability of aggression scores across time within cohorts and demonstrate the utility of MAD for selecting aggressors which will generate a susceptible phenotype in social defeat experiments. Thus, this novel aggression scoring technique offers a systematic, high-throughput approach for aggressor selection in chronic social defeat stress studies and a more consistent and accurate study of mouse aggression itself.

Despite the high prevalence of major depressive disorder (MDD), understanding of the biological underpinnings remains limited. Rodent models suggest that changes in activity and output of dopamine (DA) neurons in the ventral tegmental area (VTA) are important for depressive-like phenotypes. Additionally, brain inflammatory processes are thought to contribute to MDD pathology and inflammation in the VTA has been linked to changes in VTA DA neuronal activity. Thus, we sought to determine whether there is increased inflammatory signaling in the VTA following forms of chronic stress that induce depressive-like symptoms. First, we subjected male mice to either physical or vicarious chronic social defeat stress (CSDS), paradigms known to induce long-term depressive-like behavior and changes in VTA signaling. Second, we subjected male and female mice to subchronic variable stress (SCVS), a paradigm that induces depressive-like behavior only in female mice. We then isolated mRNA from the VTA and assessed proinflammatory gene regulation via RT-PCR. Our results show that physical, but not vicarious, CSDS increases interleukin 1β (IL-1β) mRNA expression and this inversely correlates with social interaction score. In contrast, IL-1β expression was unchanged in male or female mice following SCVS. No significant increases in VTA ionized calcium binding adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) immunochemistry were detected following CSDS that would be indicative of a robust inflammatory response. In conclusion, we show that chronic stressors distinctively alter expression of proinflammatory genes in the VTA and changes may depend on the severity and time-course of the stress exposure.

Parasitic food-borne diseases and chronic social stress are frequent attributes of day-to-day human life. Therefore, our aim was to model the combined action of chronic Opisthorchis felineus infection and repeated social defeat stress in C57BL/6 mice. Histological examination of the liver revealed inflammation sites, pronounced periductal fibrosis, and cholangiofibrosis together with proliferation of bile ducts and hepatocyte dystrophy in the infected mice, especially in the stress-exposed ones. Simultaneously with liver pathology, we detected significant structural changes in the cerebral cortex. Immunohistochemical analysis of the hippocampus indicated the highest increase in numerical density of Iba 1-, IL-6-, iNOS-, and Arg1-positive cells in mice simultaneously subjected to the two adverse factors. The number of GFAP-positive cells rose during repeated social defeat stress, most strongly in the mice subjected to both infection and stress. Real-time PCR analysis showed that the expression of genes Aif1 and Il6 differed among the analysed brain regions (hippocampus, hypothalamus, and frontal cortex) and depended on the adverse factors applied. In addition, among the brain regions, there was no consistent increase or decrease in these parameters when the two adverse treatments were combined: (i) in the hippocampus, there was upregulation of Aif1 and no change in Il6 expression; (ii) in the hypothalamus, expression levels of Aif1 and Il6 were not different from controls; and (iii) in the frontal cortex, Aif1 expression did not change while Il6 expression increased. It can be concluded that a combination of two long-lasting adverse factors, O. felineus infection and repeated social defeat stress, worsens not only the hepatic but also brain state, as evidenced behaviorally by disturbances of the startle response in mice.

BackgroundLesbian, bisexual, or gay individuals (LBGs) have an increased risk for mental health problems compared to heterosexuals, but this association has sparsely been investigated for psychotic disorders. The aim of this study was: (1) to examine whether LBG sexual orientation is more prevalent in individuals with a non-affective psychotic disorder (NAPD) than in people without a psychotic disorder; and if so, (2) to explore possible mediating pathways.MethodsSexual orientation was assessed in the 6-year follow-up assessment of the Dutch Genetic Risk and Outcome of Psychosis study (GROUP), a case–control study with 1547 participants (582 patients with psychotic disorder, 604 siblings, and 361 controls). Binary logistic regression analyses were used to calculate the risk of patients with a psychotic disorder being LBG, compared to siblings and controls. Perceived discrimination, history of bullying, childhood trauma (CT), and sexual identity disclosure were investigated as potential mediating variables.ResultsThe proportion of individuals with LBG orientation was 6.8% in patients (n = 40), 4.3% in siblings (n = 26), and 2.5% in controls (n = 10). The age- and gender-adjusted odds ratio of LBG for patients was 1.57 (95% CI 1.08–2.27; p = 0.019), compared to siblings and controls. Discrimination, bullying, and CT all partially mediated this association.ConclusionsAdverse social experiences related to sexual minority status may increase the risk for NAPD. Sexual identity, behavior, and difficulties need more attention in everyday clinical practice.

Stress has a major impact on the modulation of metabolism, as previously evidenced by hyperglycemia following chronic social defeat (CSD) stress in mice. Although CSD-triggered metabolic dysregulation might predispose to pre-diabetic conditions, insulin sensitivity remained intact, and obesity did not develop, when animals were fed with a standard diet (SD). Here, we investigated whether a nutritional challenge, a high-fat diet (HFD), aggravates the metabolic phenotype and whether there are particularly sensitive time windows for the negative consequences of HFD exposure. Chronically stressed male mice and controls (CTRL) were kept under (i) SD-conditions, (ii) with HFD commencing post-CSD, or (iii) provided with HFD lasting throughout and after CSD. Under SD conditions, stress increased glucose levels early post-CSD. Both HFD regimens increased glucose levels in non-stressed mice but not in stressed mice. Nonetheless, when HFD was provided after CSD, stressed mice did not differ from controls in long-term body weight gain, fat tissue mass and plasma insulin, and leptin levels. In contrast, when HFD was continuously available, stressed mice displayed reduced body weight gain, lowered plasma levels of insulin and leptin, and reduced white adipose tissue weights as compared to their HFD-treated non-stressed controls. Interestingly, stress-induced adrenal hyperplasia and hypercortisolemia were observed in mice treated with SD and with HFD after CSD but not in stressed mice exposed to a continuous HFD treatment. The present work demonstrates that CSD can reduce HFD-induced metabolic dysregulation. Hence, HFD during stress may act beneficially, as comfort food, by decreasing stress-induced metabolic demands.

Purpose: To explore the effect of miR-195a on nerve cells in the hippocampal region of depressionmodel mice.Methods: A chronic social defeat stress (CSDS) model was used as a depressed mouse model. In vivo, C57BL/6J mice received CSDS treatment or miR-195a antagomir. Depression-like behaviors were evaluated. In vitro, the target relationship between miR-195a and brain-derived neurotrophic factor (BDNF) was validated by luciferase reporter assays in HEK-293 cells. In primary cortical neurons, expression levels of miR-195a and BDNF mRNA were evaluated using quantitative polymerase chain reaction (qPCR). BDNF protein expression was determined by western blotting.Results: The sucrose preference ratio and social contact of the CSDS group were significantly decreased, whereas the immobility time was significantly increased, compared with the control group (p< 0.05). Interestingly, the expression of miR-195a was upregulated in the CSDS group compared with control group (p < 0.05). Bioinformatics prediction and luciferase reporter assay data indicate that miR195a bound the BDNF 3’ untranslated region. BDNF protein expression levels were significantly reduced by miR-195a mimic but increased by miR-195a inhibitor, compared with the negative control mimic group (p < 0.05). In vivo, miR-195a antagomir alleviated depression-like behaviors compared with CSDS group. In addition, miR-195a antagomir restored the expression of BDNF in mouse hippocampus in the CSDS group (p < 0.05).Conclusion: MiR-195a inhibitor ameliorates depression-like behaviors of depressed mice by downregulation of BDNF, whereas upregulation of miR-195a inhibits BDNF expression in mouse hippocampus and may contribute to depression. Keywords: Chronic social defeat stress, Depression, MiR-195, brain-derived neurotrophic factor, BDNF

Chronic stress is a risk factor for a variety of psychiatric disorders, including depression. Although impairments to motivated behavior are a major symptom of clinical depression, little is known about the circuit mechanisms through which stress impairs motivation. Furthermore, research in animal models for depression has focused on impairments to hedonic aspects of motivation, whereas patient studies suggest that impairments to appetitive, goal-directed motivation contribute significantly to motivational impairments in depression. Here, we characterized goal-directed motivation in repeated social defeat stress (R-SDS), a well-established mouse model for depression in male mice. R-SDS impaired the ability to sustain and complete goal-directed behavior in a food-seeking operant lever-press task. Furthermore, stress-exposed mice segregated into susceptible and resilient subpopulations. Interestingly, susceptibility to stress-induced motivational impairments was unrelated to stress-induced social withdrawal, another prominent effect of R-SDS in mouse models. Based on evidence that ventral hippocampus (vHP) modulates sustainment of goal-directed behavior, we monitored vHP activity during the task using fiber photometry. Successful task completion was associated with suppression of ventral hippocampal neural activity. This suppression was diminished after R-SDS in stress-susceptible but not stress-resilient mice. The serotonin selective reuptake inhibitor (SSRI) escitalopram and ketamine both normalized vHP activity during the task and restored motivated behavior. Furthermore, optogenetic vHP inhibition was sufficient to restore motivated behavior after stress. These results identify vHP hyperactivity as a circuit mechanism of stress-induced impairments to goal-directed behavior and a putative biomarker that is sensitive to antidepressant treatments and that differentiates susceptible and resilient individuals.

Background Deficiency in neuronal structural plasticity is involved in the development of major depressive disorder. TWIST1, a helix-loop-helix transcription factor that is essential for morphogenesis and organogenesis, is normally expressed at low levels in mature neurons. However, it is poorly understood what role TWIST1 plays in the brain and whether it is involved in the pathophysiology of depression. Methods Depressive-like behaviors in C57BL/6J mice were developed by chronic social defeat stress. Genetic and pharmacological approaches were used to investigate the role of the TWIST1–miR-214–PPAR-δ signaling pathway in depressive-like behaviors. Molecular biological and morphological studies were performed to define the molecular mechanisms downstream of TWIST1. Results The expression of TWIST1 was positively correlated with depressive behaviors in humans and mice. Chronic stress elevated TWIST1 expression in the medial prefrontal cortex of mice, which was reversed by fluoxetine treatment. While the overexpression of TWIST1 increased susceptibility to stress, the knockdown of TWIST1 prevented the defective morphogenesis of dendrites of pyramidal neurons in layer II/III of the medial prefrontal cortex and alleviated depressive-like behaviors. Mechanistically, this prodepressant property of TWIST1 was mediated, at least in part, through the repression of miR-214–PPAR-δ signaling and mitochondrial function, which was also mimicked by genetic and pharmacological inhibition of PPAR-δ. Conclusions These results suggest that TWIST1 in the medial prefrontal cortex mediates chronic stress–induced dendritic remodeling and facilitates the occurrence of depressive-like behavior, providing new information for developing drug targets for depression therapy.

Circadian rhythms disturbance is widely observable in patients with major depression (MD) and is also associated with depression vulnerability. Of them, disturbed melatonin secretion rhythm is particularly relevant to MD and is strongly phase-locked to core body temperature (CBT) rhythm. Here we aim to study the specific role of each melatonin receptor (MT1 and MT2) subtype in melatonin regulation of circadian CBT and its possible relationship with depressive-like behaviors. MT1-/- , MT2-/- and WT (C57BL/6) mice were used. Anhedonia, using the sucrose intake test, circadian CBT, environmental place preference (EPP) conditioning and vulnerability to chronic social defeat stress (CSDS) procedure were studied. Moreover, the antidepressant effects of reboxetine (15 mg/kg/day, i.p.) for three weeks or ketamine (15 mg/kg i.p. every four days, 4 doses in total) were studied. Further, exposure to ultra-mild stress induced by individual housing for several weeks was also studied in these mice. MT2-/- mice showed anhedonia and lower CBT compared to WT and MT1-/-. In addition, while reward exposure raised nocturnal CBT in WT this increase did not take place in MT2-/- mice. Further, MT2-/- mice showed an enhanced vulnerability to stress-induced anhedonia and social avoidance as well as an impaired acquisition of novelty seeking behavior. Both reboxetine and ketamine reverted anhedonia and induced a clear anti-helpless behavior in the tail suspension test (TST). Reboxetine raised CBT in mice and reverted ultra-mild stress-induced anhedonia. Our findings show a primary role for MT2 receptors in the regulation of circadian CBT as well as anhedonia and suggest that these receptors could be involved in depressive disorders associated to disturbed melatonin function.

In social mammalian species, such as human and mouse, social stress can arise from different social interactions; for example, from encounters with aggressive strangers (whether they be mice or men). Repeated exposure to such stress can lead to various conditions, including depression and anxiety, but different individuals show varying degrees of resilience to such stress. To explore the mechanisms underlying such differential response to stress, Sakamoto et al. from Johns Hopkins University and University of Alabama at Birmingham used a mouse model of chronic 'social defeat' stress (CSDS) to examine molecular changes in the blood following stress. In an article published in this issue of FEBS Open Bio, the authors report how molecular alterations in circulating extracellular vesicles (EVs) influence social behaviours and resilience to chronic social stress. Test mice were classified as resilient or susceptible to social stress and their blood samples were analysed. Their data demonstrated that mice susceptible to CSDS have alterations in the miRNA content of circulating EVs, and these EVs in turn influence the expression of pro-inflammatory cytokines in microglia cells, thereby resulting in social avoidance phenotypes. Since low resilience to social stress may be linked to the progression of several psychiatric disorders, it may ultimately be possible to determine prognosis or likely response to therapy for individuals susceptible to or suffering from such conditions by profiling pro-inflammatory cytokines and EV-associated miRNAs in blood samples.

Introduction. Social defeat (SD) is defined as a feeling of having lost the fight leading to a loss of valuable status or of important personal goals, and has been associated to depression and suicidal behavior, among other disorders. Furthermore, it has been proposed as a mediating variable between social and clinical elements. Objective. To adapt and validate a Spanish version of the Defeat Scale. Method. A back translation into Spanish was carried out. SD, hopelessness, and social well-being were measured in 546 university students ( Mean age = 20.93 years, SD = 2.98; 68.7% females). Results. An exploratory factor analysis offered a two-dimension structure in the scale made up by the dimension defeat and triumph . A confirmatory factor analysis found good fit indicators for the two-dimension model ( df = 89; χ 2 = 188.96; CFI = .942; RMSEA = .061; IFI = .943). Both dimensions present good internal consistency (Cronbach’s alpha > .70). SD was associated to higher levels of hopelessness and lower levels of social well-being. Discussion and conclusion. The Spanish version of the Defeat Scale presents good psychometric properties. Its use can help deepen the understanding of psychopathological phenomena and their link to social elements within the context of Spanish speaking countries.

Adolescent exposure to chronic stress, a risk factor for mood disorders in adulthood, sensitizes the neuroinflammatory response to a subsequent immune challenge. We previously showed that chronic adolescent stress (CAS) in rats led to distinct patterns of neuroimmune priming in adult male and female rats. However, sex differences in the neuroimmune consequences of CAS and their underlying mechanisms are not fully understood. Here we hypothesized that biological sex would dictate differential induction of inflammation-related transcriptomic pathways and immune cell involvement (microglia activation and leukocyte presence) in the hippocampus of male and female rats with a history of CAS. Adolescent rats underwent CAS (six restraint and six social defeat episodes during postnatal days 38–49), and behavioral assessments were conducted in adolescence and adulthood. Neuroimmune measures were obtained following vehicle or a systemic lipopolysaccharide (LPS) challenge in adulthood. CAS led to increased time in the corners of the open field in adolescence. In males, CAS also increased social avoidance. As adults, CAS rats displayed an exaggerated enrichment of the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway and chemokine induction following LPS challenge, and increased number of perivascular CD45(+) cells in the hippocampus. However, CAS females, but not males, showed exaggerated glucocorticoid receptor (GR) pathway enrichment and increased microglial complexity. These results provide further insight to the mechanisms by which peripheral immune events may influence neuroimmune responses differentially among males and females and further demonstrate the importance of adolescent stress in shaping adult responses.

We have reported that SMIP004, an inhibitor of S-phase kinase-associated protein 2 (Skp2), displays antidepressant-like activities in stress-naïve and chronically stressed mice. Here, we investigated the antidepressant-like effect of C1, another inhibitor of Skp2, in mouse models following acute or chronic drug administration at different doses and treatment times by using the tail suspension test (TST), forced swimming test (FST), and social interaction test (SIT). The time- and dose-dependent results showed that the antidepressant-like effect of C1 occurred 8 days after the drug treatment, and C1 produced antidepressant-like activities at the dose of 5 and 10 but not 1 mg/kg in male or female mice. C1 administration (5 mg/kg) also induced antidepressant-like effects in stress-naïve mice in a three-times administration mode within 24 h (24, 5, and 1 h before the test) but not in an acute administration mode (1 h before the test). The C1 and fluoxetine co-administration produced additive effect on depression-like behaviors in stress-naïve mice. The antidepressant-like effect of C1 was not associated with the change in locomotor activity, as no increased locomotor activity was observed in different treatment modes. Furthermore, the long-term C1 treatment (5 mg/kg) was found to ameliorate the depression-like behaviors in chronic social defeat stress-exposed mice, suggesting that C1 can produce antidepressant-like actions in stress conditions. Since C1 is a specific inhibitor of Skp2, our results demonstrate that inhibition of Skp2 might be a potential strategy for the treatment of depression, and Skp2 may be potential target for the development of novel antidepressants.

Aim This study aimed to assess the response of endogenous beta‐hydroxybutyrate to psychological stress, and its association with nucleotide‐binding domain, leucine‐rich repeat, pyrin domain‐containing 3 (NLRP3) inflammasome, and stress‐induced behavior. Methods Male C57BL/6J mice were subjected to 1‐hour restraint stress to examine changes in the endogenous beta‐hydroxybutyrate and active NLRP3 levels in the prefrontal cortex. Subsequently, we created a depression model applying 10‐day social defeat stress to the male C57BL/6J mice. Results One‐hour restraint stress rapidly increased beta‐hydroxybutyrate levels in the blood. The active NLRP3 levels in the prefrontal cortex also increased significantly. A correlation was found between the increased beta‐hydroxybutyrate levels in the blood and the active NLRP3 levels in the prefrontal cortex. The mice exposed to social defeat stress exhibited depression‐ and anxiety‐like behavioral changes in the open field, social interaction, and forced swim tests. There was a correlation between these behavioral changes and endogenous beta‐hydroxybutyrate levels. Among the social defeat model mice, those with high beta‐hydroxybutyrate levels tended to have more depression‐ and anxiety‐like behavior. Conclusions The increased blood beta‐hydroxybutyrate levels due to psychological stress correlate with the active NLRP3 levels in the prefrontal cortex, suggesting that the increased beta‐hydroxybutyrate levels due to stress may reflect a reaction to brain inflammation. In addition, mice with higher blood beta‐hydroxybutyrate levels tend to exhibit increased depression‐ and anxiety‐like behaviors; thus, an increase in blood beta‐hydroxybutyrate levels due to stress may indicate stress vulnerability., Psychological stress increased blood beta‐hydroxybutyrate (BHB) levels. Mice with higher blood BHB levels tend to exhibit increased depression‐ and anxiety‐like behaviors. The increased blood BHB levels correlate with the active NLRP3 levels in the prefrontal cortex, suggesting that increased blood BHB levels may represent stress vulnerability.

Stress-induced depression is common worldwide. NAc, a “reward” center, is recently reported to be critical to confer the susceptibility to chronic social defeat stress (CSDS) and the depression-related outcome. However, the underlying molecular mechanisms have not been well characterized. In this study, we induced depression-like behaviors with CSDS and chronic mild stress in male mice to mimic social and environmental factors, respectively, and observed animal behaviors with social interaction test, tail suspension test, and sucrose preference test. To determine the role of neuronal nitric oxide synthase (nNOS) and its product nitric oxide (NO), we used brain region-specifically nNOS overexpression and stereotaxic injection of NO inhibitor or donor. Moreover, the downstream molecular cyclin-dependent kinase 5 (CDK5) was explored by conditional KO and gene mutation. We demonstrate that nNOS-implicated mechanisms in NAc shell (NAcSh), including increased cell number, increased protein expression levels, and increased specific enzyme activity, contribute the susceptibility to social defeat and the following depression-like behaviors. NAcSh nNOS does not directly respond to chronic mild stress but facilitates the depression-like behaviors. The increased NAcSh nNOS expression after CSDS leads to the social avoidance and depression-like behaviors in defeated mice, which is dependent on the nNOS enzyme activity and NO production. Moreover, we identify the downstream signal in NAcSh. S-nitrosylation of CDK5 by NO contributes to enhanced CDK5 activity, leading to depression-related behaviors in susceptible mice. Therefore, NAcSh nNOS mediates susceptibility to social defeat stress and the depression-like behaviors through CDK5.SIGNIFICANCE STATEMENTStress-induced depression is common worldwide, and chronic exposure to social and psychological stressors is important cause of human depression. Our study conducted with chronic social defeat stress mice models demonstrates that nNOS in NAcSh is crucial to regulate the susceptibility to social defeat stress and the following depression-like behaviors, indicating NAcSh nNOS as the responding molecule to social factors of depression. Moreover, we discover the downstream mechanism of NAcSh nNOS in mediating the susceptibility is NO and S-nitrosylation of CDK5. Thus, NAcSh nNOS mediates susceptibility to social defeat stress through CDK5 is a potential mechanism for depression, which may interpret how the brain transduces social stress exposure into depression.

The Shen Yuan prescription (SY) comprises Panax ginseng (GT) and Polygala tenuifolia (YT), elicited superior antidepressant activity compared with that of GT or YT alone. The aim of this paper is to elucidate the effects of SY treatment on chronic social defeat stress (CSDS)-induced depression-like symptoms and the related mechanism. Our results indicated that SY treatment reverses the depressive-like behaviors induced by CSDS as measured by the social interaction test, sucrose preference test, forced swim test, and tail suspension test. SY decreased the serum levels of CORT and increased hippocampal neurotransmitters (5-HT, DA, and NE) in CSDS mice. Meanwhile, SY upregulated the brain-derived neurotrophic factor (BDNF) signaling pathway and reversed the decreased hippocampal neurogenesis caused by CSDS. In addition, we found that the TrkB antagonist K252a fully blocked the SY effects on behavioral improvement and eliminated the promoting effects of SY on hippocampal neurogenesis and BDNF-TrkB signaling (including the downstream ERK and Akt pathways) activation, thus further demonstrating that BDNF-TrkB signaling was necessary for the SY effects. In conclusion, our study showed that SY acted as an antidepressant in mice exhibiting CSDS-induced depression-like symptoms, and its effect was facilitated by promoting hippocampal neurogenesis and BDNF signaling pathway activation.