Search

BACKGROUND: Several studies involving various suicidal phenotypes based on the strategy of the search of genome-wide associations with single nucleotide polymorphisms have been performed recently. These studies need to be generalized. AIM: To systematize the findings of a number of genome-wide association studies (GWAS) for suicidal phenotypes, annotate the identified markers, analyze their functionality, and possibly substantiate the hypothesis holding that these phenotypes reflect a nonspecific set of gene variants that are relevant as relates to stress-vulnerability as a key endophenotype of suicidal behavior (SB). METHODS: A search on the PubMed and related resources using the combinations “suicide AND GWAS” and “suicidal behavior AND GWAS” was performed. It yielded a total of 34 independent studies and meta-analyses. RESULTS: For the 10 years since such studies emerged, they have undergone significant progress. Estimates of the SNP heritability of SB in some cases are comparable with estimates of heritability based on the twin method. Many studies show a high genetic correlation with the genomic markers of the most common mental disorders (depression, bipolar disorder, schizophrenia, post-traumatic stress disorder). At the same time, a genomic architecture specific to SB is also encountered. Studies utilizing the GWAS strategy have not revealed any associations of SB with candidate genes that had been previously studied in detail (different neurotransmitters, stress response system, polyamines, etc.). Frequently reported findings from various studies belong in three main groups: 1) genes involved in cell interactions, neurogenesis, the development of brain structures, inflammation, and the immune responses; 2) genes encoding receptors for neurotrophins and various components of the intracellular signaling systems involved in synaptic plasticity, embryonic development, and carcinogenesis; and 3) genes encoding various neuro-specific proteins and regulators. CONCLUSION: In general, GWAS in the field of suicidology mainly serve the purpose of a deeper understanding of the pathophysiology of suicidal behavior. However, they also demonstrate growing capability in terms of predicting and preventing suicide, especially when calculating the polygenic risk score among certain populations (psychiatric patients) and in combination with tests of different modalities. From our point of view, there exists a set of markers revealed by the GWAS strategy that seems to point to a leading role played by stress vulnerability, an endophenotype that is formed during early development and which subsequently comes to play the role of key pathogenetic mechanism in SB.

Background: Individuals greatly differ in their responses to acute stress, ranging from resilience to vulnerability that may yield stress-related psychopathology. Stress-related psychopathologies involve, by definition, substantial modifications across multiple behavioural domains, including impaired cognitive, affective and social functioning. Nevertheless, and despite extensive investigation of individual variability in stress responsivity, no study to date simultaneously assessed the impact of acute stress across multiple behavioural domains within a given individual.Objective: To address this critical gap, 84 healthy female participants (mean age 24.45 ± 3.02, range 19-35) underwent an established acute stress induction procedure and completed three behavioural tasks, probing the functional domains of positive, cognitive and social processing, both before and after the acute stress procedure.Method: A novel behavioural profiling algorithm was implemented to identify individuals whose performance was substantially impacted by stress across all three functional domains.Results: Approximately 30% of participants exhibited substantial deviation in their performance from before to after stress in all three tasks, hereon defined as stress-affected. Stress-affected participants did not differ in their psychological and physiological responses to the acute stress procedure from the other stress-unaffected 70% of the sample. However, follow-up assessments in 66 of these participants revealed higher levels of stress six months following the procedure among the stress-affected compared to the stress-unaffected group. Stress-affected individuals also reported more aversive childhood experiences, such that the odds of participants who were sexually abused at an early age to be affected behaviourally by acute stress later in life increased by more than five-fold.Conclusions: Taken together, these findings suggest that being affected by acute stress across multiple functional domains is associated with future stress sensitivity and past childhood sexual abuse. Probing individual differences in the impact of acute stress across domains of functionality may better align with the multi-dimensional nature of stress responsivity, uncovering latent vulnerability.

Hyperactivity of granule cells in the ventral dentate gyrus (vDG) promotes vulnerability to chronic stress. However, which receptors in the vDG could be targeted to inhibit this hyperactivity and confer stress resilience is not known. The serotonin 1A receptor (5-HT 1A R) is a G i protein–coupled inhibitory receptor that has been implicated in stress adaptation, anxiety, depression, and antidepressant responses. 5-HT 1A Rs are highly expressed in the DG, but their potential to promote stress resilience by regulating granule cell activity has never been examined. We exposed male and female mice expressing 5-HT 1A Rs only in DG granule cells to 10 days of chronic social defeat stress (CSDS) and treated them with the 5-HT 1A R agonist 8-OH-DPAT every day 30 minutes before each defeat throughout the CSDS paradigm. We then used whole-cell current clamp recordings, immunohistochemistry for the immediate early gene cFos, corticosterone immunoassays, and behavioral testing to determine how activating 5-HT 1A Rs on granule cells affects DG activity, neuroendocrine stress responses, and avoidance behavior. We found that activating 5-HT 1A Rs hyperpolarized DG granule cells and reduced cFos+ granule cells in the vDG following CSDS, indicating that 5-HT 1A R activation rescued stress-induced vDG hyperactivity. Moreover, 5-HT 1A R activation dampened corticosterone responses to CSDS and prevented the development of stress-induced avoidance in the social interaction test and in the open field test. Our findings show that activating 5-HT 1A Rs on DG granule cells can prevent stress-induced neuronal hyperactivity of the vDG and confer resilience to chronic stress. [ABSTRACT FROM AUTHOR]

Background The high individual variability in coping with stress is often attributed to genetic background differences, sustained environmental conditions, or a combination of both. However, the neural mechanisms underlying coping style variability are still poorly understood. Methods Here we examined the impact of a single extended emotional challenge on coping style variability and the associated involvement of the hippocampus, medial prefrontal cortex (mPFC), and periaqueductal gray (PAG). Male Sprague-Dawley rats (n = 170) were trained in an extended 2-way shuttle avoidance (eTWSA) task for 7 days, and daily avoidance rates were measured. Forced swim test, elevated plus maze, or Morris water maze was tested before or after eTWSA exposure. Excitotoxic lesion of the hippocampal dentate gyrus (DG) was performed by Ibotenic infusion. Transient pharmacological blocking of DG, mPFC, or PAG was performed by muscimol or CNQX+TTX infusion. Results Exposing rats to eTWSA was found to lead to naturally developing dichotomous, not continuous, coping styles, which we termed active avoidance (AA) or reactive escape (RE). Prior emotional responses did not predict the developing coping style. AA was associated with beneficial outcomes, including reduced behavioral despair and improved spatial learning. RE led to impaired spatial retrieval. AA was abolished by lesioning or pharmacological blocking of the DG. RE was prevented by blocking mPFC or PAG. Conclusion The results indicate that a single exposure to a significant emotional challenge can lead, in otherwise healthy individuals, to dichotomous development of an active or reactive coping style with distinctive neural correlates and subsequent behavioral significance. [ABSTRACT FROM AUTHOR]

The lateral habenula (LHb) plays a pivotal role in regulating emotional responses during stress reactions, and its hyperactivity has been associated with depression. Recently it has been demonstrated that chronic early-life stress results in individual differences in stress vulnerability among rodents. However, how synaptic function in the LHb varies between susceptibility and resilience to early life stress remains elusive. In this study, we used a maternal separation model to assign animals with different stress vulnerabilities into groups and investigated the synaptic responses in the LHb. Our findings indicate that synaptic long-term depression (LTD) was impaired and extra-synaptic LTD was enhanced in the LHb of the susceptible group. To mimic the synaptic alteration in stress situations, when administered corticosterone, a stress hormone, the intervention appeared to impair synaptic LTD in the LHb of the control group, through the activation of mineralocorticoid receptors (MR). Indeed, there was an up-regulation of MR mRNA observed in the susceptible group. Following there was an up-regulation of both NR2A and NR2B subunits in the LHb. These results indicated that MR and extra-synaptic NMDA receptors in LHb are critically engaged in the susceptibilities to stress. Furthermore, our findings propose potential therapeutic targets for alleviating stress-related symptoms.

Future missions to Mars will expose astronauts to several physical and psychological challenges, including exposure to space radiation (SR) and periods of social isolation (SI). Each of these stressors, in addition to mission demands, can affect physical and mental health and potentially negatively impact sleep. The effects of inflight stressors may vary with duration and time course, may be additive or compounding, and may vary with individual differences in stress resilience and vulnerability. Determining how individual differences in resilient and vulnerable phenotypes respond to these mission-related stressors and their interactions with sleep will be crucial for understanding and mitigating factors that can impair performance and damage health. Here, we examined the single and compound effects of ground-based analogs of SI and SR on sensorimotor performance on the balance beam (BB) in rats. We also assessed emotional responses during testing on the BB and assessed whether sensorimotor performance and emotion varied with individual differences in stress resiliency using our established animal model in which stress produces different effects on sleep. Results showed differential motor performance and emotion in the BB task between SI and SR, and these varied based on resilient and vulnerable phenotypes. These findings demonstrate that identifying individual responses to stressors that can impact sensorimotor ability and behavior necessary to perform mission-related tasks will be of particular importance for astronauts and future missions. Should similar effects occur in humans, there may be considerable inter-individual variability in the impact that flight stressors have on the mental health of astronauts and their ability to perform mission-related tasks. [ABSTRACT FROM AUTHOR]

Background: Chronic aflatoxin B1 (AFB1) exposure may increase the risk of multiple neuropsychiatric disorders. Stress is considered one of the main contributors to major depressive disorder. Whether and how chronic AFB1 exposure affects vulnerability to stress is unclear. Methods: Mice were exposed for three weeks to AFB1 (100 µg/kg/d) and/or chronic mild stress (CMS). The vulnerability behaviors in response to stress were assessed in the forced swimming test (FST), sucrose preference test (SPT), and tail suspension test (TST). Microglial pyroptosis was investigated using immunofluorescence, enzyme-linked immunosorbent assays, and western blot assay in the hippocampus of mice. Hippocampal neurogenesis and the effects of AFB1-treated microglia on proliferation and differentiation of neural stem/precursor cells (NSPCs) were assessed via immunofluorescence in the hippocampus of mice. Results: Mice exposed to CMS in the presence of AFB1 exhibited markedly greater vulnerability to stress than mice treated with CMS or AFB1 alone, as indicated by reduced sucrose preference and longer immobility time in the forced swimming test. Chronic aflatoxin B1 exposure resulted in changes in the microglial morphology and increase in TUNEL+ microglia and GSDMD+ microglia in the hippocampal dentate gyrus. When mice were exposed to both CMS and AFB1, pyroptosis-related molecules (such as NLRP3, caspase-1, GSDMD-N, and interleukin-1β) were significantly upregulated in the hippocampus. These molecules were also significantly enhanced by AFB1 in primary microglial cultures. AFB1-treated mice showed decrease in the numbers of BrdU+, BrdU-DCX+, and BrdU-NeuN+ cells in the hippocampal dentate gyrus, as well as the percentages of BrdU+ cells that were NeuN+ in the presence or absence of CMS when compared with vehicle-treated mice. The combination of AFB1 and CMS exacerbated these effects to an even greater extent. The number of DCX+ cells correlated negatively with the percentage of ameboid microglia, TUNEL+ microglia and GSDMD+ microglia in the hippocampal dentate gyrus. AFB1-treated microglia suppressed the proliferation and neuronal differentiation of NSPCs in vitro. Conclusion: Chronic AFB1 exposure induces microglial pyroptosis, promoting an adverse neurogenic microenvironment that impairs hippocampal neurogenesis, which may render mice more vulnerable to stress.

Summary: This study examined the role of sleep disturbances and insomnia in the context of stress reactivity in adolescence. One‐hundred and thirty‐five 11–18 year olds (Mage = 14.2 years, SD = 1.9, 52% female) completed the Trier Social Stress Test for Children. Salivary cortisol and subjective stress ratings were collected at six time points, and heart rate as well as heart rate variability were measured pre‐, during and post‐stress induction. Additionally, sleep disturbances and insomnia diagnosis were assessed by a self‐report questionnaire and a sleep interview. Robust mixed models investigated if adolescents with compared with adolescents without (a) sleep disturbances and (b) insomnia differ regarding cortisol, heart rate, heart rate variability and psychological stress reactivity considering gender effects. The results indicated that boys with high sleep disturbances showed higher cortisol activity compared with boys with low sleep disturbances, B = 0.88, p < 0.05. Moreover, in boys with insomnia, heart rate and alpha 1 significantly differ less than in boys without insomnia. These findings support the notion of sex differences regarding the association between poor sleep and increased activity of the hypothalamic–pituitary–adrenal axis, and a less adaptable autonomic nervous system in boys in response to an experimental social stress task. [ABSTRACT FROM AUTHOR]

Stress exposure is a key risk factor for the developmentof depressive-like conditions. However, despite the higher incidence of Major Depressive Disorder in the female population, classical stress-based experimental paradigms have primarily focused on males. In the present study, we used the well-established chronic mild stress (CMS) paradigm to investigate the development of anhedonia, a cardinal symptom of affective disorders, in the female animals and we also studied the potential effect of the antipsychotic drug lurasidone in normalizing the alterations brought about by stress exposure. We found that three weeks of CMS exposure produced a significant reduction of sucrose intake in 50% of the animals (vulnerable, CMS-V), whereas the others were resilient (CMS-R). The development of an anhedonic phenotype in CMS-V was associated with a significant elevation of different immune markers, such as Complement C3 and C4, and inflammatory cytokines, including INFß and Il1ß in dorsal and ventral hippocampus. Interestingly, sub-chronic treatment with the antipsychotic drug lurasidone was able to revert the anhedonic phenotype while normalizing most of the molecular alterations found in rats vulnerable to CMS exposure. This study extends the ability of lurasidone to normalize the anhedonic phenotype in CMS rats also to females. Moreover, we provide novel evidence on lurasidone's potential effectiveness in treating mental disorders characterized by immune-inflammatory dysfunction., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Major depressive disorder is a devastating psychiatric illness that affects approximately 17% of the population worldwide. Astrocyte dysfunction has been implicated in its pathophysiology. Traumatic experiences and stress contribute to the onset of major depressive disorder, but how astrocytes respond to stress is poorly understood. Using Western blotting analysis, we identified that stress vulnerability was associated with reduced astrocytic glucocorticoid receptor (GR) expression in mouse models of depression. We further investigated the functions of astrocytic GRs in regulating depression and the underlying mechanisms by using a combination of behavioral studies, fiber photometry, biochemical experiments, and RNA sequencing methods. GRs in astrocytes were more sensitive to stress than those in neurons. GR absence in astrocytes induced depressive-like behaviors, whereas restoring astrocytic GR expression in the medial prefrontal cortex prevented the depressive-like phenotype. Furthermore, we found that GRs in the medial prefrontal cortex affected astrocytic Ca2+ activity and dynamic ATP (adenosine 5′-triphosphate) release in response to stress. RNA sequencing of astrocytes isolated from GR deletion mice identified the PI3K-Akt (phosphoinositide 3-kinase–Akt) signaling pathway, which was required for astrocytic GR–mediated ATP release. These findings reveal that astrocytic GRs play an important role in stress response and that reduced astrocytic GR expression in the stressed subject decreases ATP release to mediate stress vulnerability. [ABSTRACT FROM AUTHOR]

Future missions to Mars will expose astronauts to several physical and psychological challenges, including exposure to space radiation (SR) and periods of social isolation (SI). Each of these stressors, in addition to mission demands, can affect physical and mental health and potentially negatively impact sleep. The effects of inflight stressors may vary with duration and time course, may be additive or compounding, and may vary with individual differences in stress resilience and vulnerability. Determining how individual differences in resilient and vulnerable phenotypes respond to these mission-related stressors and their interactions with sleep will be crucial for understanding and mitigating factors that can impair performance and damage health. Here, we examined the single and compound effects of ground-based analogs of SI and SR on sensorimotor performance on the balance beam (BB) in rats. We also assessed emotional responses during testing on the BB and assessed whether sensorimotor performance and emotion varied with individual differences in stress resiliency using our established animal model in which stress produces different effects on sleep. Results showed differential motor performance and emotion in the BB task between SI and SR, and these varied based on resilient and vulnerable phenotypes. These findings demonstrate that identifying individual responses to stressors that can impact sensorimotor ability and behavior necessary to perform mission-related tasks will be of particular importance for astronauts and future missions. Should similar effects occur in humans, there may be considerable inter-individual variability in the impact that flight stressors have on the mental health of astronauts and their ability to perform mission-related tasks.

Chronic stress leads to many psychiatric disorders, including social and anxiety disorders that are associated with over-activation of neurons in the basolateral amygdala (BLA). However, not all individuals develop psychiatric diseases, many showing considerable resilience against stress exposure. Whether BLA neuronal activity is involved in regulating an individual's vulnerability to stress remains elusive. In this study, using a mouse model of chronic social defeat stress (CSDS), we divided the mice into susceptible and resilient subgroups based on their social interaction behavior. Using in vivo fiber photometry and in vitro patch-clamp recording, we showed that CSDS persistently (after 20 days of recovery from stress) increased BLA neuronal activity in all the mice regardless of their susceptible or resilient nature, although impaired social interaction behavior was only observed in susceptible mice. Increased anxiety-like behavior, on the other hand, was evident in both groups. Notably, the CSDS-induced increase of BLA neuronal activity correlated well with the heightened anxiety-like but not the social avoidance behavior in mice. These findings provide new insight to our understanding of the role of neuronal activity in the amygdala in mediating stress-related psychiatric disorders. [ABSTRACT FROM AUTHOR]

Background: Several studies involving various suicidal phenotypes based on the strategy of the search of genome-wide associations with single nucleotide polymorphisms have been performed recently. These studies need to be generalized., Aim: To systematize the findings of a number of genome-wide association studies (GWAS) for suicidal phenotypes, annotate the identified markers, analyze their functionality, and possibly substantiate the hypothesis holding that these phenotypes reflect a nonspecific set of gene variants that are relevant as relates to stress-vulnerability as a key endophenotype of suicidal behavior (SB)., Methods: A search on the PubMed and related resources using the combinations "suicide AND GWAS" and "suicidal behavior AND GWAS" was performed. It yielded a total of 34 independent studies and meta-analyses., Results: For the 10 years since such studies emerged, they have undergone significant progress. Estimates of the SNP heritability of SB in some cases are comparable with estimates of heritability based on the twin method. Many studies show a high genetic correlation with the genomic markers of the most common mental disorders (depression, bipolar disorder, schizophrenia, post-traumatic stress disorder). At the same time, a genomic architecture specific to SB is also encountered. Studies utilizing the GWAS strategy have not revealed any associations of SB with candidate genes that had been previously studied in detail (different neurotransmitters, stress response system, polyamines, etc.). Frequently reported findings from various studies belong in three main groups: 1) genes involved in cell interactions, neurogenesis, the development of brain structures, inflammation, and the immune responses; 2) genes encoding receptors for neurotrophins and various components of the intracellular signaling systems involved in synaptic plasticity, embryonic development, and carcinogenesis; and 3) genes encoding various neuro-specific proteins and regulators., Conclusion: In general, GWAS in the field of suicidology mainly serve the purpose of a deeper understanding of the pathophysiology of suicidal behavior. However, they also demonstrate growing capability in terms of predicting and preventing suicide, especially when calculating the polygenic risk score among certain populations (psychiatric patients) and in combination with tests of different modalities. From our point of view, there exists a set of markers revealed by the GWAS strategy that seems to point to a leading role played by stress vulnerability, an endophenotype that is formed during early development and which subsequently comes to play the role of key pathogenetic mechanism in SB., Competing Interests: Conflict of interest: The authors declare no conflicts of interest., (© Authors, 2024.)

Emerging evidence has shown that stress responsivity and psychiatric diseases are associated with alterations in N6-methyladenosine (m6A) mRNA epigenetic modifications. Fat mass and obesity-associated protein (FTO) is an m6A demethylase that has been linked to increased body mass and obesity. Here, we show that tricyclic antidepressants (TCAs) with weight-gain side effects, such as imipramine and amitriptyline, directly increased FTO expression and activated its epigenetic function in the ventral tegmental area (VTA). VTA-specific genetic disruption of FTO increased stress vulnerability and abolished the antidepressant activity of TCAs, whereas erasing m6A modification in the VTA by FTO overexpression or cycloleucine led to significant antidepressant activity. Mechanistically, both transcriptome sequencing and quantitative PCR revealed that overexpression of FTO in the VTA decreased the transcription of stress-related neuropeptides, such as cocaine- and amphetamine-regulated transcript peptide and urocortin, in the social defeat model, which was mimicked by imipramine, suggesting an m6A-dependent transcription mechanism of stress-related neuropeptides may underlie the responses to antidepressant. Collectively, our results demonstrate that inhibiting m6A-dependent transcription of stress-related genes may work as a novel antidepressant strategy and highlight a previously unrecognized activator of FTO-dependent epigenetic function that may be used for the treatment of other neurological diseases.

The presentation of neurogenetic disorders such as 22q11.2 Deletion Syndrome (22q11.2DS) includes broad neuropsychiatric phenotypes that impact functioning and require assessment and treatment. Like in non-syndromal neuropsychiatric disorders, there is heterogeneity in symptom severity and illness course. The study of risk and resilience in the general population has benefited from measurement tools that parse heterogeneity and guide treatment. Suitability of such tools in neurogenetic disorders has not been examined and is essential to establish as prerequisite for examining whether similar processes modulate psychopathology in these populations. We applied the Risk & Resilience Battery assessing intrapersonal, interpersonal, and environmental domains, to 80 patients with 22q11.2DS, 30 from Philadelphia, USA and 50 from Tel-Aviv, Israel. We also evaluated global functioning and obtained self-reports of anxiety and depression. We examined the Risk & Resilience Battery reliability for each factor and used partial correlations to examine relations between the Risk & Resilience Battery factors and clinical measures. Across samples, items within each risk and resilience factor showed good to excellent internal consistency. Higher scores on peer victimization, emotion dysregulation, and hostile close relationships were related to reports of anxiety and depression. Higher levels of self-reliance related to lower anxiety while greater security in close relationships related to lower depression. The Risk & Resilience Battery can be applied to 22q11.2DS samples and advance Gene X Environment research and interventions. • Risk and Resilience factors in the general population are similarly prominent in a neurogenetic syndrome. • These Risk and Resilience factors modulate symptom severity and functioning in a neurogenetic syndrome. • The Risk and Resilience measures can be reliably applied across international sites. [ABSTRACT FROM AUTHOR]

Stressful events during pregnancy impact on the progeny neurodevelopment. However, little is known about preconceptional stress effects. The rat social isolation represents an animal model of chronic stress inducing a variety of dysfunctions. Moreover, social deprivation during adolescence interferes with key neurodevelopmental processes. Here, we investigated the development of behavioural, neurochemical and redox alterations in the male offspring of socially isolated female rats before pregnancy, reared in group (GRP) or in social isolation (ISO) from weaning until young-adulthood. To this aim, females were reared in GRP or in ISO conditions, from PND21 to PND70, when they were mated. Their male offspring was housed in GRP or ISO conditions through adolescence and until PND70, when passive avoidance-PA, novel object recognition-NOR and open field-OF tests were performed. Levels of noradrenaline (NA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), glutamate (GLU) and GABA were assessed in the prefrontal cortex (PFC). Moreover, cortical ROS levels were quantified, as well as NF-kB and the NADPH oxidase NOX2 expression, redox status (expressed as GSH:GSSG ratio) and SOD1 amount. A significant decrease of the latency time in the PA was observed in the offspring of ISO females. In the NOR test, while a significant increase in the exploratory activity towards the novel object was observed in the offspring of GRP females, no significant differences were found in the offspring of ISO females. No significant differences were found in the OF test among experimental groups. Theoffspring of ISO females showed increased NA and 5-HIAA levels, whereas in the offspring persistently housed in isolation condition from weaninguntil adulthood, we detected reduced 5-HT levels and ehnanced 5-HIAA amount. No significant changes in GLU concentrations were detected, while decreased GABA content was observed in the offspring of ISO females exposed to social isolation. Increased ROS levels as well as reduced NF-κB, NOX2 expression were detected in the offspring of ISO females. This was accompanied by reduced redox status and enhanced SOD1 levels. In conclusion, our results suggest that female exposure to chronic social stress before pregnancy might have a profound influence on the offspring neurodevelopment in terms of cognitive, neurochemical and redox-related alterations, identifying this specific time window for possible preventive and therapeutic strategies. • Little is known about the effects of preconceptional stress on the offspring. • The rat social isolation induces a variety of psychotic-like dysfunctions. • The offspring of socially isolated females showed cognitive alterations. • The offspring of socially isolated females developed neurochemical changes. • The offspring of socially isolated females displayed redox-related dysfunctions. [ABSTRACT FROM AUTHOR]

Major depressive disorder is the most common psychiatric disorder worldwide. To understand mechanisms and search for new approaches to treating depression, animal models are crucial. Chronic mild stress (CMS) is the most used animal model of depression. Although CMS is considered a robust model of depression, conflicting results have been reported for emotion-related behaviors, which the intrinsic characteristics of each rodent strain could explain. To further shed light on the impact of genetic background on the relevant parameters commonly addressed in depression, we examined the effect of 4-weeks CMS on anxiety and depression-related behaviors and body weight gain in three strain mice (BALB/c, C57BL/6, and CD1) of both sexes. CMS reduced body weight gain in C57BL/6NCrl and CD1 male mice. C57BL/6 animals exhibited a more pronounced anxious-like behavior than CD1 and BALB/c mice in the light-dark box (LDB) and the elevated plus maze (EPM) tests, whereas BALB/c animals exhibited the more robust depressive-like phenotype in the splash test (ST), tail suspension test (TST) and forced-swimming test (FST). Under CMS, exposure did not affect anxiety-related behaviors in any strain but induced depression-like behaviors strain-dependently. CMS C57BL/6 and CD1 mice of both sexes showed depression-like behaviors, and CMS BALB/c male mice exhibited reduced depressive behaviors in the FST. These results suggest a differential effect of stress, with the C57BL/6 strain being more vulnerable to stress than the CD1 and BALB/c strain mice. Furthermore, our findings emphasize the need for researchers to consider mouse strains and behavioral tests in their CMS experimental designs. • Male and female C57BL/6 mice show a more robust basal anxious-like behavior. • Male and female BALB/c mice show a more robust basal depressive-like behavior. • CMS induces apathy-and-depressive-like behavior in male and female C57BL/6 mice. • CMS induces depressive-like behavior in male and female CD1 mice. • Under CMS, BALB/c mice show from negligible to inverse-expected behavior. [ABSTRACT FROM AUTHOR]

Abstract Introduction Tracking stress‐induced brain activity and connectivity dynamically and examining activity/connectivity‐associated recovery ability after stress might be an effective way of detecting stress vulnerability. Methods Using two widely used stress paradigms, a speech task (social stress) and a mathematical calculation task (mental loading stress), we examined common changes in regional homogeneity (ReHo) and functional connectivity (FC) before, during, and after the two stressful tasks in thirty‐nine college students. A counting breath relaxation task was employed as a contrast task. ReHo and FC were compared between subjects with higher versus lower depression symptoms (assessed by the Beck Depression Inventory, BDI). We developed a recovery index (RI) based on dynamic changes of ReHo/FC to evaluate individuals' ability to recover from a stressful state. To assess RI's usefulness in predicting future depression severity, BDI was also measured at one‐year follow‐up. Results Our results revealed a ReHo decrease after both stressful tasks and a ReHo increase after the relaxation task in bilateral thalamus. The ReHo decrease after both stressful tasks was more significant in the higher BDI than the lower BDI group. Higher ReHo RI of the right thalamus in the higher BDI groups was significantly correlated with lower BDI severity at one‐year follow‐up. Bilateral thalamus also showed increased FC with the default mode network and decreased FC with the executive control network after the stressful tasks. Conclusion These findings highlight the importance of tracking resting activity and connectivity of thalamus dynamically for detecting stress vulnerability.

Modern biological models based on stress-diathesis consider suicide an independent form of behavior, which is the basis for the search for specific genetic markers. The current review embraces all presently existing GWAS studies of suicidal phenotypes (suicidal ideation, attempts, and completed suicides). Fifteen studies based on this strategy and using different approaches to data analysis, including comparisons with existing databases on psychiatric genetics, pathway analysis, protein-protein interactions, functional grouping of genes, and enrichment analysis are discussed. In contrast to the candidate gene studies which intensively discussed associations with neurotransmitter systems of the brain (indol- and catecholamines, GABA, excitatory aminoacids, etc.), GWAS suggest a rather different set of factors. Many findings are among the genes involved in neurodevelopment, neuroplasticity, cell adhesion and migration, proliferation, and intracellular signaling, as well as immune system functioning. We consider that this confirms the relevance of the stress-vulnerability models implying a key role of the early development, which affects neuroplasticity. Stress as a systemic reaction of the organism demonstrates a significant role in the genesis of suicidal behavior. It should be noted that findings of different studies rarely coincide, thus demonstrating heterogeneous findings. This may be due to differences in bioinformatics approaches, description of phenotypes, and design of the study. Future accumulation of data especially considering the ethnic factor, increase in the sample size, and meta-analyses may clarify the polygenic nature of suicidal behavior and identify genetic markers that are valuable for both understanding the pathogenesis of suicidality and suicide prediction and prevention. [ABSTRACT FROM AUTHOR]

The epidemic of the 2019 novel coronavirus SARS-CoV-2, causing the coronavirus disease 2019 (COVID-19) is a global public health emergency with multifaceted severe consequences for people's lives and their mental health. In this article, as members of the European College of Neuropsychopharmacology (ECNP) Resilience, we will discuss the urgent need for a focus on resilience during the current coronavirus pandemic. Resilience is pivotal to cope with stress and vital to stay in balance. We will discuss the importance of resilience at the individual and societal level, but also the implication for patients with a psychiatric condition and health care workers. We not only advocate for an increased focus on mental health during the coronavirus pandemic but also highlight the urgent need of augmenting our focus on resilience and on strategies to enhance it. [ABSTRACT FROM AUTHOR]

This study investigates resting high-frequency heart rate variability as a moderator of the association between early-life adversity and two measures of body adiposity. Data were collected from 149 young adults attending a large university in the Midwestern United States (Mage = 18.8 years; 45% black; 55% white; 56% female). Self-reported early-life adversity was associated with greater waist-to-height ratio and body mass index. The strength of these associations was moderated by high-frequency heart rate variability, such that the link was stronger for individuals with lower heart rate variability. Resting high-frequency heart rate variability thus has potential health significance as a biomarker of stress vulnerability. [ABSTRACT FROM AUTHOR]

There is considerable interest in understanding what makes an individual vulnerable or resilient to the deleterious effects of stressful events. From candidate genes, dopamine (DA) and dopamine transporter (DAT) have been linked to anxiety, depression, and post‐traumatic stress disorder. We investigated role of DAT using the new DAT heterozygous (DAT‐HET) and homozygous mutant (DAT‐KO) rat models of hyperdopaminergia. We studied the impact of two breeding conditions in spontaneous locomotor behavior of female rats. The classical colony, through mating DAT‐HET males × DAT‐HET females (breeding HET–HET), was used. A second WT colony was derived and maintained (breeding WT–WT). Additionally, a subgroup of rats was bred through mating DAT‐KO males × WT females (atypical HET, breeding KO–WT). We studied the effects of genotype and its interaction with maternal care (depending by breeding condition). HET–HET breeding led to reduced activity in HET females compared to WT rats (from WT–WT breeding). However, HET females from KO–WT breeding did not differ so much from WT rats (WT–WT breeding). The maternal‐care impact was then confirmed: HET mothers (breeding HET–HET) showed reduced liking/grooming of pups and increased digging away from nest, compared to WT mothers (breeding WT–WT). In their female offspring (HET, breeding HET–HET vs. WT, breeding WT–WT), isolation plus wet bedding induced higher and more persistent impact on activity of HET rats, even when the stressor was removed. Our results highlight the importance of epigenetic factors (e.g., maternal care) in responses to stress expressed by offspring at adulthood, quite independently of genotype. DAT hypofunction could determinate vulnerability to stressful agents via altered maternal care. [ABSTRACT FROM AUTHOR]

Studies have suggested that chronic social stress specifically downregulates endothelial tight junction protein expression in the nucleus accumbens (NAc), thus increasing blood-brain barrier (BBB) permeability and promoting depression-like behaviors. However, the molecular mechanism underlying the reduction in tight junction protein, particularly in the NAc, is largely uncharacterized. We performed comparative metabolomic profiling of the nucleus accumbens, prefrontal cortex, and hippocampus of social defeat–stressed mice to identify the molecular events that mediate BBB breakdown. We identified the levels of cyclic adenosine monophosphate (cAMP) that were specifically reduced in the NAc and positively correlated with the degree of social avoidance. Replenishing cAMP in the NAc was sufficient to improve BBB integrity and depression-like behaviors. We further found that cAMP levels were markedly decreased in neurons of the NAc, rather than in endothelial cells, astrocytes, or microglia. RNA-sequencing data showed that adenylate cyclase 5 (Adcy5), an enzyme responsible for the synthesis of cAMP from adenosine triphosphate (ATP), was predominantly expressed in the NAc; it also resided exclusively in neurons. Endogenous modulation of cAMP synthesis in neurons through the knockdown of Adcy5 in the NAc regulated the sensitivity to social stress. Moreover, deficient neuronal cAMP production in the NAc decreased the expression of reelin, while supplementary injection of exogenous reelin into the NAc promoted BBB integrity and ameliorated depression-like behaviors. Chronic social stress diminished cAMP synthesis in neurons, thus damaging BBB integrity in the NAc and promoting stress vulnerability. These results characterize neuron-produced cAMP in the NAc as a biological mechanism of neurovascular pathology in social stress. [ABSTRACT FROM AUTHOR]

Background: The TIA1 gene encodes a prion-related RNA-binding protein that regulates stress-dependent synaptic plasticity and fear memory in mice. It is unknown whether genetic variation in human TIA1 is associated with differences in stress- and fear-related behavior in people.Methods: A longitudinal, population-based survey was conducted in Sweden to collect information on demographics, socioeconomic status, exposure to stressful life events and psychiatric symptoms. DNA samples were obtained from study participants to allow genotyping of single-nucleotide polymorphisms in the human TIA1 locus.Results: We identified a single-nucleotide polymorphism in the human TIA1 gene that interacts with exposure to previous-year stressful life events to predict the development of pathological anxiety symptoms in a non-clinical cohort.Limitations: Sample population is limited in both size and scope, and we did not perform functional analysis of allelic variants of TIA1.Conclusions: TIA1 may represent a susceptibility locus for stress-dependent psychopathology. These studies support an evolutionarily conserved role of TIA1 in the mammalian brain, and may provide molecular and genetic insight into the development of stress-related psychiatric conditions such as PTSD and anxiety. [ABSTRACT FROM AUTHOR]

Ten to 20% of western countries population suffers from major depression disorder (MDD). Stressful life events represent the main environmental risk factor contributing to the onset of MDD and other stress-related neuropsychiatric disorders. In this regard, investigating brain physiology of stress response underlying the remarkable individual variability in terms of behavioral outcome may uncover stress-vulnerability pathways as a source of candidate targets for conceptually new antidepressant treatments. Serum response factor (SRF) has been addressed as a stress transducer via promoting inherent experience-induced Immediate Early Genes (IEGs) expression in neurons. However, in resting conditions, SRF also represents a transcriptional repressor able to assemble the core LSD1/CoREST/HDAC2 corepressor complex, including demethylase and deacetylase activities. We here show that dominant negative SRF splicing isoform lacking most part of the transactivation domain, namely SRFΔ5, owes its transcriptional repressive behavior to the ability of assembling LSD1/CoREST/HDAC2 corepressor complex meanwhile losing its affinity for transcription-permissive cofactor ELK1. SRFΔ5 is highly expressed in the brain and developmentally regulated. In the light of its activity as negative modulator of dendritic spine density, SRFΔ5 increase along with brain maturation suggests a role in synaptic pruning. Upon acute psychosocial stress, SRFΔ5 isoform transiently increases its levels. Remarkably, when stress is chronically repeated, a different picture occurs where SRF protein becomes stably upregulated in vulnerable mice but not in resilient animals. These data suggest a role for SRFΔ5 that is restricted to acute stress response, while positive modulation of SRF during chronic stress matches the criteria for stress-vulnerability hallmark. [ABSTRACT FROM AUTHOR]

Major Depressive Disorder (MDD) is a highly debilitating disorder characterized by a persistent feeling of sadness and anhedonia. Traditional antidepressants have a delayed onset of action and lack of efficacy in up to one third of patients, leading to treatment resistant depression (TRD). Recent years have witnessed a revolutionary treatment of TRD with the introduction of the fast-acting antidepressant ketamine. However, ketamine's mechanisms of action are still poorly understood. Here, we used the chronic mild stress animal model of depression on male rats to investigate the involvement of neurotrophic signaling pathways in stress vulnerability/resilience and fast antidepressant response/non-response to acute subanesthetic ketamine. We performed our analysis on both the hippocampus and the prefrontal cortex, two brain areas implicated in stress-related disorders, considering different subcellular fractions. We measured the activation by phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinases (ERKs), glycogen synthase kinase-3 beta (GSK3 β), mammalian target of rapamycin (mTOR), and eukaryotic elongation factor 2 (eEF2), key effectors in the regulation of neuroplasticity and glutamatergic transmission which were previously associated to ketamine's fast antidepressant effect. We showed here for the first time that both stress and ketamine induced brain area and subcellular fraction specific changes in these pathways. Our study represents the first attempt to identify molecular mechanisms underlying the response/non-response to ketamine in an animal model of depression. This approach could give a crucial contribution to the study of etiopathogenetic mechanisms as well as to the identification of novel targets for the development of innovative therapeutic strategies. [Display omitted] • Sucrose preference test allowed to classify the rats stress resilient and vulnerable. • Sucrose preference test allowed to classify the rats ketamine responder/non-responder. • Stress and ketamine induced brain-area and subcellular fraction-specific changes. • Neurotrophic signaling cascades are selectively activated in ketamine responder rats. [ABSTRACT FROM AUTHOR]

Epidemiological evidence identifies early life adversity as a significant risk factor for the development of mood disorders. Much evidence points to the role of early life experience in susceptibility and, to a lesser extent, resilience, to stress in adulthood. While many models of these phenomena exist in the literature, results are often conflicting and a systematic comparison of multiple models is lacking. Here, we compare effects of nine manipulations spanning the early postnatal through peri-adolescent periods, both at baseline and following exposure to chronic social defeat stress in adulthood, in male mice. By applying rigorous criteria across three commonly used measures of depression- and anxiety-like behavior, we identify manipulations that increase susceptibility to subsequent stress in adulthood and other pro-resilient manipulations that mitigate the deleterious consequences of adult stress. Our findings point to the importance of timing of early life stress and provide the foundation for future studies to probe the neurobiological mechanisms of risk and resilience conferred by variation in the early life environment.

Background: Individuals greatly differ in their responses to acute stress, ranging from resilience to vulnerability that may yield stress-related psychopathology. Stress-related psychopathologies involve, by definition, substantial modifications across multiple behavioural domains, including impaired cognitive, affective and social functioning. Nevertheless, and despite extensive investigation of individual variability in stress responsivity, no study to date simultaneously assessed the impact of acute stress across multiple behavioural domains within a given individual. Objective: To address this critical gap, 84 healthy female participants (mean age 24.45 ± 3.02, range 19-35) underwent an established acute stress induction procedure and completed three behavioural tasks, probing the functional domains of positive, cognitive and social processing, both before and after the acute stress procedure. Method: A novel behavioural profiling algorithm was implemented to identify individuals whose performance was substantially impacted by stress across all three functional domains. Results: Approximately 30% of participants exhibited substantial deviation in their performance from before to after stress in all three tasks, hereon defined as stress-affected. Stress-affected participants did not differ in their psychological and physiological responses to the acute stress procedure from the other stress-unaffected 70% of the sample. However, follow-up assessments in 66 of these participants revealed higher levels of stress six months following the procedure among the stress-affected compared to the stress-unaffected group. Stress-affected individuals also reported more aversive childhood experiences, such that the odds of participants who were sexually abused at an early age to be affected behaviourally by acute stress later in life increased by more than five-fold. Conclusions: Taken together, these findings suggest that being affected by acute stress across multiple functional domains is associated with future stress sensitivity and past childhood sexual abuse. Probing individual differences in the impact of acute stress across domains of functionality may better align with the multi-dimensional nature of stress responsivity, uncovering latent vulnerability.

Relatively little is known about the psychophysiological processes underlying the development of socioemotional vulnerabilities that are common among adolescents exposed to child maltreatment. Using a prospective, longitudinal design, we investigated whether trajectories of resting heart period (HP; a physiological correlate of stress vulnerability) across three visits (separated by 6 months) was associated with shyness (a type of socioemotional vulnerability) in adolescent females exposed to child maltreatment (N = 55; M age = 14.07 years). Adolescents' resting HP across visits was best characterized by two latent trajectories: a stable high class (25.5%) and a stable low class (74.5%). The stable low HP trajectory was associated with higher shyness at Time 1 (T1), and HP trajectory moderated the association between T1 and Time 3 (T3) shyness. Females in the stable low HP trajectory demonstrated stability of shyness from T1 to T3, whereas T1 and T3 shyness were unrelated for females in the stable high HP trajectory. We also found that shyness at T1 and T3 was associated with greater levels of anxiety at T3. These findings illustrate heterogeneity in the developmental patterns of resting autonomic activity in adolescent females exposed to child maltreatment; such differences may influence the continuity of some traits linked with socioemotional vulnerability such as shyness. [ABSTRACT FROM AUTHOR]

Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes stress vulnerability in mouse. This occurs through dysfunction of serotonin [5-hydroxytryptamine (5-HT)] 1A receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knock-out (KO) male mice compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HTlAR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT efflux in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was upregulated by the transcription factor PET 1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1ARactivated G-protein-activated inwardly rectifying potassium conductance in D2LR-KO serotonergic neurons. Finally, D2IR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability. [ABSTRACT FROM AUTHOR]

The exposure to stressful experiences during the prenatal period and through the first years of life is known to affect the brain developmental trajectories, leading to an enhanced vulnerability for the development of several psychiatric disorders later in life. However, not all the subjects exposed to the same stressful experience develop a pathologic condition, as some of them, activating coping strategies, become more resilient. The disclosure of mechanisms associated with stress vulnerability or resilience may allow the identification of novel biological processes and potential molecules that, if properly targeted, may prevent susceptibility or potentiate resilience. Over the last years, miRNAs have been proposed as one of the epigenetic mechanisms mediating the long-lasting effects of stress. Accordingly, they are associated with the development of stress vulnerability or resilience-related strategies. Moreover, miRNAs have been proposed as possible biomarkers able to identify subjects at high risk to develop depression and to predict the response to pharmacological treatments. In this review, we aimed to provide an overview of findings from studies in rodents and humans focused on the involvement of miRNAs in the mechanisms of stress response with the final goal to identify distinct sets of miRNAs involved in stress vulnerability or resilience. In addition, we reviewed studies on alterations of miRNAs in the context of depression, showing data on the involvement of miRNAs in the pathogenesis of the disease and in the efficacy of pharmacological treatments, discussing the potential utility of miRNAs as peripheral biomarkers able to predict the treatment response. [ABSTRACT FROM AUTHOR]

Abstract Active adaptation to acute stress is essential for coping with daily life challenges. The stress hormone cortisol, as well as large scale re-allocations of brain resources have been implicated in this adaptation. Stress-induced shifts between large-scale brain networks, including salience (SN), central executive (CEN) and default mode networks (DMN), have however been demonstrated mainly under task-conditions. It remains unclear whether such network shifts also occur in the absence of ongoing task-demands, and most critically, whether these network shifts are predictive of individual variation in the magnitude of cortisol stress-responses. In a sample of 335 healthy participants, we investigated stress-induced functional connectivity changes (delta-FC) of the SN, CEN and DMN, using resting-state fMRI data acquired before and after a socially evaluated cold-pressor test and a mental arithmetic task. To investigate which network changes are associated with acute stress, we evaluated the association between cortisol increase and delta-FC of each network. Stress-induced cortisol increase was associated with increased connectivity within the SN, but with decreased coupling of DMN at both local (within network) and global (synchronization with brain regions also outside the network) levels. These findings indicate that acute stress prompts immediate connectivity changes in large-scale resting-state networks, including the SN and DMN in the absence of explicit ongoing task-demands. Most interestingly, this brain reorganization is coupled with individuals' cortisol stress-responsiveness. These results suggest that the observed stress-induced network reorganization might function as a neural mechanism determining individual stress reactivity and, therefore, it could serve as a promising marker for future studies on stress resilience and vulnerability. Highlight • Acute stress prompts changes in connectivity of the salience and default mode networks in the absence of external task demands. • Following stress, intra-network connectivity of the salience network was increased, while both intra-network and global connectivity of the default mode network was decreased. • This brain reorganization was coupled with the magnitude of individual cortisol stressresponses. [ABSTRACT FROM AUTHOR]

Epidemiological evidence identifies early life adversity as a significant risk factor for the development of mood disorders. Much evidence points to the role of early life experience in susceptibility and, to a lesser extent, resilience, to stress in adulthood. While many models of these phenomena exist in the literature, results are often conflicting and a systematic comparison of multiple models is lacking. Here, we compare effects of nine manipulations spanning the early postnatal through peri-adolescent periods, both at baseline and following exposure to chronic social defeat stress in adulthood, in male mice. By applying rigorous criteria across three commonly used measures of depression- and anxiety-like behavior, we identify manipulations that increase susceptibility to subsequent stress in adulthood and other pro-resilient manipulations that mitigate the deleterious consequences of adult stress. Our findings point to the importance of timing of early life stress and provide the foundation for future studies to probe the neurobiological mechanisms of risk and resilience conferred by variation in the early life environment. [ABSTRACT FROM AUTHOR]

Highlights • Prenatal stress induces dysfunction of the HPA axis. • Prenatal stress decreases hippocampal GR and MR mRNA expression. • Chewing during prenatal stress normalized HPA axis feedback. • Chewing during prenatal stress attenuates stress-induced GR and MR mRNA expression. • Chewing is an effective strategy to cope with prenatal stress. Abstract Objective To investigate whether maternal chewing during prenatal stress alters the responsivity of young offspring to novel stress, we examined the expression of hippocampal glucocorticoid receptors and mineralocorticoid receptors, and the levels of hypothalamic corticotropin-releasing hormone in young adult mouse offspring of dams exposed to restraint stress during pregnancy. Design To induce stress, the dams were placed in a ventilated restraint tube for 45 min each day from day 12 of pregnancy through parturition. While restrained in the tube, one group of dams was provided a wooden stick for chewing. Hippocampal expression of glucocorticoid receptor and mineralocorticoid receptor messenger ribonucleic acid was assessed in 1-month-old pups. Hypothalamic expression of corticotropin-releasing hormone messenger ribonucleic acid was examined before and after exposing the offspring to a novel stressor. Results Prenatal stress significantly decreased hippocampal expression of both glucocorticoid receptor and mineralocorticoid receptor messenger ribonucleic acid in the offspring, and increased the expression of corticotropin-releasing hormone messenger ribonucleic acid in the hypothalamic paraventricular nucleus in the offspring after novel stress exposure. Maternal chewing during exposure to prenatal stress attenuated the decreased hippocampal expression of both glucocorticoid receptor and mineralocorticoid receptor messenger ribonucleic acid, and the increased corticotropin-releasing hormone messenger ribonucleic acid expression in the hypothalamic paraventricular nucleus in the offspring. Conclusions Downregulation of hippocampal glucocorticoid receptor and mineralocorticoid receptor expression in offspring due to prenatal stress, which may be associated with increased susceptibility to novel stress in adulthood, are attenuated by allowing the dams to chew on a wooden stick. [ABSTRACT FROM AUTHOR]

Populations worldwide are increasingly becoming physically inactive, which is related to somatic and psychological health problems that are prevalent in modern society. Recent epidemiological studies have indicated that the associations between physical inactivity and depression are bidirectional. Numerous animal studies have demonstrated that exercise improves hippocampal function. Because the hippocampus is a pivotal brain region that exerts inhibitory control over stress responses by affecting the hypothalamus-pituitary-adrenal axis, enhanced hippocampal function by exercise can increase stress resilience, which helps prevent stress-related depression. In contrast, physical inactivity is difficult to model in animal studies, and little is known about the effects of physical inactivity on the rodent hippocampus. To fill this gap, we previously developed a mouse model of habituated voluntary wheel running cessation as a reverse intervention to control physical activity. We found that reducing physical activity by cessation of wheel running impairs hippocampal neurogenesis in mice. Thus, this review discusses the relevant literature and provides a hypothesis that physical inactivity can be a potential risk factor for stress-related depression as it increases stress vulnerability by impairing hippocampal function.

The lateral habenula (LHb) plays a pivotal role in regulating emotional responses during stress reactions, and its hyperactivity has been associated with depression. Recently it has been demonstrated that chronic early-life stress results in individual differences in stress vulnerability among rodents. However, how synaptic function in the LHb varies between susceptibility and resilience to early life stress remains elusive. In this study, we used a maternal separation model to assign animals with different stress vulnerabilities into groups and investigated the synaptic responses in the LHb. Our findings indicate that synaptic long-term depression (LTD) was impaired and extra-synaptic LTD was enhanced in the LHb of the susceptible group. To mimic the synaptic alteration in stress situations, when administered corticosterone, a stress hormone, the intervention appeared to impair synaptic LTD in the LHb of the control group, through the activation of mineralocorticoid receptors (MR). Indeed, there was an up-regulation of MR mRNA observed in the susceptible group. Following there was an up-regulation of both NR2A and NR2B subunits in the LHb. These results indicated that MR and extra-synaptic NMDA receptors in LHb are critically engaged in the susceptibilities to stress. Furthermore, our findings propose potential therapeutic targets for alleviating stress-related symptoms., Competing Interests: 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. Jihyun Noh reports financial support was provided by Korea Ministry of Science and ICT. Miseon Kang reports financial support was provided by Korea Ministry of Science and ICT., (© 2023 The Authors.)

Etiology of depression and its vulnerability remains elusive. Using a latent profile analysis on dimensional personality traits, we previously identified 3 different phenotypes in the general population, namely stress-resilient, -vulnerable, and -resistant groups. Here we performed microarray-based blood gene expression profiling of these 3 groups (n = 20 for each group) in order to identify genes involved in stress vulnerability as it relates to the risk of depression. Identified differentially expressed genes among the groups were most markedly enriched in ribosome-related pathways. These ribosomal genes, which included ribosomal protein L17 ( RPL17 ) and ribosomal protein L34 ( RPL34 ), were upregulated in relation to the stress vulnerability. Protein-protein interaction and correlational co-expression analyses of the differentially expressed genes/non-coding RNAs consistently showed that functional networks involving ribosomes were affected. The significant upregulation of RPL17 and RPL34 was also observed in depressed patients compared to healthy controls, as confirmed in 2 independent case-control datasets by using pooled microarray data and qPCR experiments (total number of subjects was 122 and 166, respectively). Moreover, the upregulation of RPL17 and RPL34 was most marked in DSM-IV major depressive disorder, followed by in bipolar disorder, and then in schizophrenia, suggesting some diagnostic specificity of these markers as well as their general roles in stress vulnerability. These results suggest that ribosomal genes, particularly RPL17 and RPL34 , can play integral roles in stress vulnerability and depression across nonclinical and clinical conditions. This study presents an opportunity to understand how multiple psychological traits and underlying molecular mechanisms interact to render individuals vulnerable to depression. [ABSTRACT FROM AUTHOR]

Although the benzodiazepine class of drugs has proven useful in treating anxiety symptoms, recent studies yield no consistent empirical support for their use in treating psychiatric disorders. However, animal studies using a fear conditioning paradigm have suggested that benzodiazepines facilitate fear memory extinction, dependent on treatment timing and subject conditions. However, we have no data on the effect of subject conditions. The purpose of this study was to investigate whether the effect of benzodiazepines depends on hypersensitivity to fear-memory processing. We examined the effect of diazepam, a benzodiazepine, on the extracellular dopamine level in the left amygdala of methamphetamine-sensitized, fear-conditioned model rats, using microdialysis and high-performance liquid chromatography. In this model, the dopamine level in the amygdala excessively increases in response to a fear-conditioned stimulus; the phenomenon has been proposed as a biological marker for hypersensitivity to fear-memory processing. Diazepam inhibited this excessive increase. The extent of the inhibitory effect was greater in the sensitized condition. Diazepam alone increased amygdalar dopamine levels under physiological conditions but not under sensitized conditions. Diazepam did not shorten freezing time in any group. These results suggest that diazepam modulates amygdala dopamine with state dependence and that amygdalar dopamine fine-tuning accounts for part of the therapeutic effect of benzodiazepines on fear memory processing. Further investigation is required to identify patients suitable for treatment with benzodiazepines. This is the first report on the pharmacodynamic effects of benzodiazepine on the amygdalar dopamine basal level and on fear memory processing. [ABSTRACT FROM AUTHOR]

Stressful life events are a major factor in the etiology of several diseases, such as cardiovascular, inflammatory and psychiatric disorders (i.e., depression and anxiety), with the two sexes greatly differing in vulnerability. In humans and other animals, physiological and behavioral responses to stress are strongly dependent on gender, and conditions that are stressful for males are not necessarily stressful for females. Hence the need of an animal model of social chronic stress specifically designed for females. In the present study we aimed to compare the effects of two different chronic stress procedures in female mice, by investigating the impact of 4 weeks of nonsocial unpredictable, physical stress by the Chronic Mild Stress paradigm (CMS; Exp.1) or of Social Instability Stress (SIS; Exp.2) on physiological, endocrine and behavioral parameters in adult female mice. CMS had a pronounced effect on females' response to novelty (i.e., either novel environment or novel social stimulus), body weight growth and hormonal profile. Conversely, 4 weeks of social instability did not alter females' response to novelty nor hormonal levels but induced anhedonia. Our findings thus showed that female mice were more sensitive to nonsocial stress due to unpredictable physical environment than to social instability stressors. Neither of these stress paradigms, however, induced a consistent behavioral and physiological stress response in female mice comparable to that induced by chronic stress procedures in male mice, thus confirming the difficulties of developing a robust and validated model of chronic psychosocial stress in female mice. [ABSTRACT FROM AUTHOR]

Chronic aflatoxin B1 (AFB1) exposure may increase the risk of multiple neuropsychiatric disorders. Stress is considered one of the main contributors to major depressive disorder. Whether and how chronic AFB1 exposure affects vulnerability to stress is unclear. Mice were exposed for three weeks to AFB1 (100 µg/kg/d) and/or chronic mild stress (CMS). The vulnerability behaviors in response to stress were assessed in the forced swimming test (FST), sucrose preference test (SPT), and tail suspension test (TST). Microglial pyroptosis was investigated using immunofluorescence, enzyme-linked immunosorbent assays, and western blot assay in the hippocampus of mice. Hippocampal neurogenesis and the effects of AFB1-treated microglia on proliferation and differentiation of neural stem/precursor cells (NSPCs) were assessed via immunofluorescence in the hippocampus of mice. Mice exposed to CMS in the presence of AFB1 exhibited markedly greater vulnerability to stress than mice treated with CMS or AFB1 alone, as indicated by reduced sucrose preference and longer immobility time in the forced swimming test. Chronic aflatoxin B1 exposure resulted in changes in the microglial morphology and increase in TUNEL+ microglia and GSDMD+ microglia in the hippocampal dentate gyrus. When mice were exposed to both CMS and AFB1, pyroptosis-related molecules (such as NLRP3, caspase-1, GSDMD-N, and interleukin-1β) were significantly upregulated in the hippocampus. These molecules were also significantly enhanced by AFB1 in primary microglial cultures. AFB1-treated mice showed decrease in the numbers of BrdU+, BrdU-DCX+, and BrdU-NeuN+ cells in the hippocampal dentate gyrus, as well as the percentages of BrdU+ cells that were NeuN+ in the presence or absence of CMS when compared with vehicle-treated mice. The combination of AFB1 and CMS exacerbated these effects to an even greater extent. The number of DCX+ cells correlated negatively with the percentage of ameboid microglia, TUNEL+ microglia and GSDMD+ microglia in the hippocampal dentate gyrus. AFB1-treated microglia suppressed the proliferation and neuronal differentiation of NSPCs in vitro. Chronic AFB1 exposure induces microglial pyroptosis, promoting an adverse neurogenic microenvironment that impairs hippocampal neurogenesis, which may render mice more vulnerable to stress. • Chronic aflatoxin B1 exposure rendered mice more vulnerable to stress. • Chronic AFB1 exposure reduced the hippocampal neurogenesis of CMS-exposed mice. • Chronic exposure to aflatoxin B1 increases hippocampal microglial pyroptosis of CMS-exposed mice. [ABSTRACT FROM AUTHOR]

Chronic subordinate colony housing (CSC), an established mouse model for chronic psychosocial stress, promotes a microbial signature of gut inflammation, characterized by expansion of Proteobacteria, specifically Helicobacter spp., in association with colitis development. However, whether the presence of Helicobacter spp. during CSC is critically required for colitis development is unknown. Notably, during previous CSC studies performed at Regensburg University (University 1), male specific-pathogen-free (SPF) CSC mice lived in continuous subordination to a physically present and Helicobacter spp.-positive resident. Therefore, it is likely that CSC mice were colonized, during the CSC procedure, with Helicobacter spp. originating from the dominant resident. In the present study we show that employing SPF CSC mice and Helicobacter spp.-free SPF residents at Ulm University (University 2), results in physiological responses that are typical of chronic psychosocial stress, including increased adrenal and decreased thymus weights, decreased adrenal in vitro adrenocorticotropic hormone (ACTH) responsiveness, and increased anxiety-related behavior. However, in contrast to previous studies that used Helicobacter spp.-positive resident mice, use of Helicobacter spp.-negative resident mice failed to induce spontaneous colitis in SPF CSC mice. Consistent with the hypothesis that the latter is due to a lack of Helicobacter spp. transmission from dominant residents to subordinate mice during the CSC procedure, colonization of SPF residents with Helicobacter typhlonius at University 2, prior to the start of the CSC model, rescued the colitis-inducing potential of CSC exposure. Furthermore, using SPF CSC mice and H. typhlonius -free SPF residents at University 1 prevented CSC-induced colitis. In summary, our data support the hypothesis that the presence or absence of exposure to certain pathobionts contributes to individual variability in susceptibility to stress-/trauma-associated pathologies and to reproducibility of stress-related outcomes between laboratories. [ABSTRACT FROM AUTHOR]

Over the past decade, our understanding of the role of stress in serious mental illness has become more sophisticated. In this paper, we revisit the neural diathesis-stress model of schizophrenia that was initially proposed in 1997 and updated in 2008. In light of cumulative research findings, we must now encompass evidence on the premorbid periods of psychosis, and our more nuanced understanding of hypothalamic-pituitary-adrenal (HPA) axis function and its association with neurodevelopmental, epigenetic, neurotransmitter, and inflammatory processes, as well as brain structure and function. Giving consideration to the methodological complexities that have become more apparent as research in this area has burgeoned, the various indices of HPA axis function, and the different stages of illness, we review relevant research published since the 2008 update of the model. We conclude by proposing an extended neural diathesis-stress model that addresses the broader neurobiological context of stress psychobiology in psychosis progression. Implications of this model for best practice, with regards to both future research and treatment strategies, are discussed. [ABSTRACT FROM AUTHOR]

Background: Obese persons have a higher incidence of depression than healthy-weight persons. Several studies indicated that the exposure to a high fat diet (HFD) results in a decrease in hippocampal neurogenesis, which leads to higher stress response and stress-induced depression. Although stress is a risk factor for obesity and depression, no studies to date have investigated the effect of stress on the hippocampal neurogenesis of HFD-induced obese animals. The aim of this study was to elucidate whether or not obese HFD-fed mice are vulnerable to stress-induced depression by investigating hippocampal neurogenesis.Methods: Sixty-four male ICR mice (four weeks of age) were fed a control (N=24) or 45%HFD (N=40) for seven weeks. Of the HFD-fed group, twenty-four mice met the criteria for "diet-induced obesity". The animals were then exposed to three consecutive days of psychological stress using a Communication Box. Half were sacrificed to evaluate the physiological changes, and the other half were perfused to quantify hippocampal neuroblasts/immature neurons by the estimation of doublecortin-immunopositive cells.Results: In the HFD-fed mice, psychological stress resulted in increases in caloric intake and visceral adipose tissue and a significant decrease in doublecortin-positive cells in the dentate gyrus; however, no such differences were found in the control diet-fed group. Limitations Further study using other neurogenic markers to assess the stage-specific changes in hippocampal neurogenesis will be required CONCLUSIONS: Our findings suggest that an HFD-induced decrease in hippocampal newly-born neurons leads to stress vulnerability, which may contribute to a high risk of stress-induced depression for obese persons. [ABSTRACT FROM AUTHOR]