Histone serotonylation in dorsal raphe nucleus contributes to stress- and antidepressant-mediated gene expression and behavior.

Mood disorders are an enigmatic class of debilitating illnesses that affect millions of individuals worldwide. While chronic stress clearly increases incidence levels of mood disorders, including major depressive disorder (MDD), stress-mediated disruptions in brain function that precipitate these illnesses remain largely elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding direct roles for serotonin in the precipitation and treatment of affective disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this non-canonical phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress, as well as in DRN of human MDD patients, to examine the impact of stress exposures/MDD diagnosis on H3K4me3Q5ser dynamics, as well as associations between the mark and depression-related gene expression. We additionally assessed stress-induced/MDD-associated regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy in mice to reduce H3K4me3Q5ser levels in DRN and examine its impact on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to attenuate stress-mediated gene expression and behavior. Corresponding patterns of H3K4me3Q5ser regulation were observed in MDD subjects on vs. off ADs at their time of death. These findings thus establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity, observations of which may be of clinical relevance to human MDD and its treatment.

Chronic Stress Exposure Alters the Gut Barrier: Sex-Specific Effects on Microbiota and Jejunum Tight Junctions.

Background: Major depressive disorder (MDD) is the leading cause of disability worldwide. Of individuals with MDD, 30% to 50% are unresponsive to common antidepressants, highlighting untapped causal biological mechanisms. Dysfunction in the microbiota-gut-brain axis has been implicated in MDD pathogenesis. Exposure to chronic stress disrupts blood-brain barrier integrity; still, little is known about intestinal barrier function in these conditions, particularly for the small intestine, where absorption of most foods and drugs takes place. Methods: We investigated how chronic social or variable stress, two mouse models of depression, impact the jejunum intestinal barrier in males and females. Mice were subjected to stress paradigms followed by analysis of gene expression profiles of intestinal barrier-related targets, fecal microbial composition, and blood-based markers. Results: Altered microbial populations and changes in gene expression of jejunum tight junctions were observed depending on the type and duration of stress, with sex-specific effects. We used machine learning to characterize in detail morphological tight junction properties, identifying a cluster of ruffled junctions in stressed animals. Junctional ruffling is associated with inflammation, so we evaluated whether lipopolysaccharide injection recapitulates stress-induced changes in the jejunum and observed profound sex differences. Finally, lipopolysaccharide-binding protein, a marker of gut barrier leakiness, was associated with stress vulnerability in mice, and translational value was confirmed on blood samples from women with MDD. Conclusions: Our results provide evidence that chronic stress disrupts intestinal barrier homeostasis in conjunction with the manifestation of depressive-like behaviors in a sex-specific manner in mice and, possibly, in human depression.

Sex, hormones and cerebrovascular function: from development to disorder.

Proper cerebrovascular development and neurogliovascular unit assembly are essential for brain growth and function throughout life, ensuring the continuous supply of nutrients and oxygen. This involves crucial events during pre- and postnatal stages through key pathways, including vascular endothelial growth factor (VEGF) and Wnt signaling. These pathways are pivotal for brain vascular growth, expansion, and blood-brain barrier (BBB) maturation. Interestingly, during fetal and neonatal life, cerebrovascular formation coincides with the early peak activity of the hypothalamic-pituitary-gonadal axis, supporting the idea of sex hormonal influence on cerebrovascular development and barriergenesis.Sex hormonal dysregulation in early development has been implicated in neurodevelopmental disorders with highly sexually dimorphic features, such as autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD). Both disorders show higher prevalence in men, with varying symptoms between sexes, with boys exhibiting more externalizing behaviors, such as aggressivity or hyperactivity, and girls displaying higher internalizing behaviors, including anxiety, depression, or attention disorders. Indeed, ASD and ADHD are linked to high prenatal testosterone exposure and reduced aromatase expression, potentially explaining sex differences in prevalence and symptomatology. In line with this, high estrogen levels seem to attenuate ADHD symptoms. At the cerebrovascular level, sex- and region-specific variations of cerebral blood flow perfusion have been reported in both conditions, indicating an impact of gonadal hormones on the brain vascular system, disrupting its ability to respond to neuronal demands.This review aims to provide an overview of the existing knowledge concerning the impact of sex hormones on cerebrovascular formation and maturation, as well as the onset of neurodevelopmental disorders. Here, we explore the concept of gonadal hormone interactions with brain vascular and BBB development to function, with a particular focus on the modulation of VEGF and Wnt signaling. We outline how these pathways may be involved in the underpinnings of ASD and ADHD. Outstanding questions and potential avenues for future research are highlighted, as uncovering sex-specific physiological and pathological aspects of brain vascular development might lead to innovative therapeutic approaches in the context of ASD, ADHD and beyond.

Characterizing the blood-brain barrier and gut barrier with super-resolution imaging: opportunities and challenges.

Brain and gut barriers have been receiving increasing attention in health and diseases including in psychiatry. Recent studies have highlighted changes in the blood-brain barrier and gut barrier structural properties, notably a loss of tight junctions, leading to hyperpermeability, passage of inflammatory mediators, stress vulnerability, and the development of depressive behaviors. To decipher the cellular processes actively contributing to brain and gut barrier function in health and disease, scientists can take advantage of neurophotonic tools and recent advances in super-resolution microscopy techniques to complement traditional imaging approaches like confocal and electron microscopy. Here, we summarize the challenges, pros, and cons of these innovative approaches, hoping that a growing number of scientists will integrate them in their study design exploring barrier-related properties and mechanisms.

A gut feeling: The stressed brain drives intestinal inflammation.

Communication between the central nervous system and the periphery contributes to stress responses and mood disorders. In a recent issue of Cell, Schneider et al. report that psychological stress exacerbates gut inflammation and dysmotility by modifying enteric glia and neurons.

Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior.

Background: Major depressive disorder (MDD), along with related mood disorders, is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of mood disorders, stress-mediated disruptions in brain function that precipitate these illnesses remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of mood disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures. Methods: We employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics, as well as associations between the mark and stress-induced gene expression. We additionally assessed stress-induced regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy to reduce H3K4me3Q5ser levels in DRN and examine the impact on stress-associated gene expression and behavior. Results: We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to rescue stress-mediated gene expression and behavior. Conclusions: These findings establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity in DRN.

Barrier-environment interactions along the gut-brain axis and their influence on cognition and behaviour throughout the lifespan.

Environment is known to substantially alter mental state and behaviour across the lifespan. Biological barriers such as the blood-brain barrier (BBB) and gut barrier (GB) are major hubs for communication of environmental information. Alterations in the structural, social and motor environment at different stages of life can influence function of the BBB and GB and their integrity to exert behavioural consequences. Importantly, each of these environmental components is associated with a distinct immune profile, glucocorticoid response and gut microbiome composition, creating unique effects on the BBB and GB. These barrier-environment interactions are sensitive to change throughout life, and positive or negative alterations at critical stages of development can exert long-lasting cognitive and behavioural consequences. Furthermore, because loss of barrier integrity is implicated in pathogenesis of mental disorders, the pathways of environmental influence represent important areas for understanding these diseases. Positive environments can be protective against stress- and age-related damage, raising the possibility of novel pharmacological targets. This review summarizes known mechanisms of environmental influence - such as social interactions, structural complexity and physical exercise - on barrier composition, morphology and development, and considers the outcomes and implications of these interactions in the context of psychiatric disorders.

Glutamate shall not pass: a mechanistic role for astrocytic O-GlcNAc transferase in stress and depression.

Major depressive disorder, characterized by aberrant glutamatergic signaling in the prefrontal cortex (PFC), is a leading cause of disability worldwide. Depression is highly comorbid with metabolic disorders, but a mechanistic link is elusive. In this issue of the JCI, Fan and coauthors report that elevated posttranslational modification with the glucose metabolite N-acetylglucosamine (GlcNAc) by O-GlcNAc transferase (OGT) contributed to stress-induced establishment of depression-like behaviors in mice. This effect was specific to medial PFC (mPFC) astrocytes, with glutamate transporter-1 (GLT-1) identified as an OGT target. Specifically, O-GlcNAcylation of GLT-1 resulted in diminished glutamate clearance from excitatory synapses. Further, astrocytic OGT knockdown restored stress-induced deficits in glutamatergic signaling, promoting resilience. These findings provide a mechanistic link between metabolism and depression and have relevance for antidepressant targets.

Environmental conditions of recognition memory testing induce neurovascular changes in the hippocampus in a sex-specific manner in mice.

Experiences are linked to emotions impacting memory consolidation and associated brain neuronal circuits. Posttraumatic stress disorder is an example of strong negative emotions affecting memory processes by flashbacks of past traumas. Stress-related memory deficits are also observed in major depressive disorder (MDD). We recently highlighted that sex-specific blood-brain barrier (BBB) alterations underlie stress responses in mice and human depression. However, little is known about the relationship between emotional valence, memory encoding and BBB gene expression. Here, we investigated the effects of novel object recognition (NOR) test, an experience considered of neutral emotional valence, on BBB properties in dorsal vs ventral hippocampus (HIPP) in the context of various environmental conditions (arena size, handling, age). The HIPP is a brain area central for learning and memory processes with the dorsal and ventral subregions being associated with working memory vs reference memory retrieval, respectively. Expression of genes related to BBB integrity are altered in line with learning and memory processes in a region- and sex-specific manner. We observed correlations between poor learning, anxiety, stress-induced corticosterone release and changes in BBB-associated gene expression. Comparison of BBB transcriptomes between sexes also revealed profound differences at baseline in both ventral and dorsal HIPP. Finally, we identified circulating vascular biomarkers, such as sE-selectin and matrix metallopeptidase 9 (MMP-9), altered following NOR exposure supporting that recognition memory formation has an impact on the neurovasculature. Although deemed as a neutral valence test, NOR experimental conditions can shift it toward a negative valence, impacting performance and highlighting the need to minimize anxiety when performing this commonly used test in mice.

Neurovascular adaptations modulating cognition, mood, and stress responses.

The neurovascular unit (NVU) is a dynamic center for substance exchange between the blood and the brain, making it an essential gatekeeper for central nervous system (CNS) homeostasis. Recent evidence supports a role for the NVU in modulating brain function and cognition. In addition, alterations in NVU processes are observed in response to stress, although the mechanisms via which they can affect mood and cognitive functions remain elusive. Here, we summarize recent studies of neurovascular regulation of emotional processes and cognitive function, including under stressful conditions. We also highlight relevant RNA-sequencing (RNA-seq) databases aiming to profile the NVU along with innovative tools to study and manipulate NVU function that can be exploited in the context of cognition and stress research throughout development, aging, or brain disorders.

The Use of Computer-Driven Technologies in the Treatment of Borderline Personality Disorder: A Systematic Review.

The objective of this study was to perform a systematic review of the effectiveness of computer-driven technologies for treatment of patients suffering from BPD. A systematic literature review was conducted using the Pubmed, EMBASE, PsycNET (PsycINFO), CINAHL and Google Scholar electronic databases for the period from their inception dates until 2022. Thirty studies were selected for abstract screening. Seven studies were excluded for not meeting inclusion criteria. The remaining 23 studies were fully assessed, and 12 were excluded. Therefore, 11 studies were included in the analysis of the effectiveness of computer-driven technologies, which encompassed mobile applications, telehealth interventions, internet-based interventions, virtual reality MBT and dialogue-based integrated interventions. Computer-driven interventions are showing signs of effectiveness in the treatment of BPD symptoms. The limited number of articles found on the subject demonstrates a need for further exploration of this subject.

Predict, prevent and manage moral injuries in Canadian frontline healthcare workers and leaders facing the COVID-19 pandemic: Protocol of a mixed methods study.

Moral injuries can occur when perpetrating, failing to prevent, or bearing witness to acts that transgress deeply held moral beliefs and expectations. The COVID-19 crisis highlighted the fact that psychosocial stressors at work, such as high emotional demands, are placing Canadian healthcare workers at risk of moral injuries. Evidence linking psychosocial stressors at work to moral injuries are needed to better predict, prevent and manage moral injuries, as these stressors are frequent and modifiable occupational risk factors. This protocol presents a study aiming to: 1) understand workplace events having the potential to either cause or reduce moral injuries, 2) predict the risk and severity of moral injuries using a disease prevention model, 3) identify biological signatures (biomarkers) associated with psychosocial stressors at work and moral injuries and 4) elaborate preliminary guidelines of organizational practices for frontline healthcare workers to reduce and manage moral injuries. This study is a mixed methods research with three components: qualitative, quantitative and biological. The data collection has been completed and because of the COVID-19 pandemic, it was adjusted to allow for gathering qualitative and quantitative data remotely. Frontline healthcare workers and leaders were included. Through focus groups and individual interviews, and an online questionnaire, events and psychosocial working conditions that may increase the risk of moral injuries will be documented. In addition, blood samples which were collected from a sub-sample of volunteer participants will measure an innovative set of biomarkers associated with vulnerability to stress and mental health. Data analyses are ongoing. We anticipate to identify workplace events that may trigger moral injuries. We expect that potential predictors of moral injury risk occurrence and severity will be identified from psychosocial stressors at work that can be improved by implementing organizational practices. We also expect to observe a different mental health state and biological inflammation signature across workers exposed compared to workers not exposed to psychosocial stressors at work. Based on these future findings, we intend to develop preliminary recommendations of organizational practices for managers. This research will contribute to expand our knowledge of the events in the workplace likely to generate or lessen the impact moral injuries, to build a model for predicting the risk of moral injuries at work, all in the specific context of the COVID-19 health crisis among healthcare workers.

Sex differences in the blood-brain barrier: Implications for mental health.

Prevalence of mental disorders, including major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ) are increasing at alarming rates in our societies. Growing evidence points toward major sex differences in these conditions, and high rates of treatment resistance support the need to consider novel biological mechanisms outside of neuronal function to gain mechanistic insights that could lead to innovative therapies. Blood-brain barrier alterations have been reported in MDD, BD and SZ. Here, we provide an overview of sex-specific immune, endocrine, vascular and transcriptional-mediated changes that could affect neurovascular integrity and possibly contribute to the pathogenesis of mental disorders. We also identify pitfalls in current literature and highlight promising vascular biomarkers. Better understanding of how these adaptations can contribute to mental health status is essential not only in the context of MDD, BD and SZ but also cardiovascular diseases and stroke which are associated with higher prevalence of these conditions.

Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue.

Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD.

Inflammation-driven brain and gut barrier dysfunction in stress and mood disorders.

Regulation of emotions is generally associated exclusively with the brain. However, there is evidence that peripheral systems are also involved in mood, stress vulnerability vs. resilience, and emotion-related memory encoding. Prevalence of stress and mood disorders such as major depression, bipolar disorder, and post-traumatic stress disorder is increasing in our modern societies. Unfortunately, 30%-50% of individuals respond poorly to currently available treatments highlighting the need to further investigate emotion-related biology to gain mechanistic insights that could lead to innovative therapies. Here, we provide an overview of inflammation-related mechanisms involved in mood regulation and stress responses discovered using animal models. If clinical studies are available, we discuss translational value of these findings including limitations. Neuroimmune mechanisms of depression and maladaptive stress responses have been receiving increasing attention, and thus, the first part is centered on inflammation and dysregulation of brain and circulating cytokines in stress and mood disorders. Next, recent studies supporting a role for inflammation-driven leakiness of the blood-brain and gut barriers in emotion regulation and mood are highlighted. Stress-induced exacerbated inflammation fragilizes these barriers which become hyperpermeable through loss of integrity and altered biology. At the gut level, this could be associated with dysbiosis, an imbalance in microbial communities, and alteration of the gut-brain axis which is central to production of mood-related neurotransmitter serotonin. Novel therapeutic approaches such as anti-inflammatory drugs, the fast-acting antidepressant ketamine, and probiotics could directly act on the mechanisms described here improving mood disorder-associated symptomatology. Discovery of biomarkers has been a challenging quest in psychiatry, and we end by listing promising targets worth further investigation.

Neuromodulatory effect of interleukin 1ß in the dorsal raphe nucleus on individual differences in aggression.

Heightened aggressive behavior is considered as one of the central symptoms of many neuropsychiatric disorders including autism, schizophrenia, and dementia. The consequences of aggression pose a heavy burden on patients and their families and clinicians. Unfortunately, we have limited treatment options for aggression and lack mechanistic insight into the causes of aggression needed to inform new efforts in drug discovery and development. Levels of proinflammatory cytokines in the periphery or cerebrospinal fluid were previously reported to correlate with aggressive traits in humans. However, it is still unknown whether cytokines affect brain circuits to modulate aggression. Here, we examined the functional role of interleukin 1ß (IL-1ß) in mediating individual differences in aggression using a resident-intruder mouse model. We found that nonaggressive mice exhibit higher levels of IL-1ß in the dorsal raphe nucleus (DRN), the major source of forebrain serotonin (5-HT), compared to aggressive mice. We then examined the effect of pharmacological antagonism and viral-mediated gene knockdown of the receptors for IL-1 within the DRN and found that both treatments consistently increased aggressive behavior of male mice. Aggressive mice also exhibited higher c-Fos expression in 5-HT neurons in the DRN compared to nonaggressive mice. In line with these findings, deletion of IL-1 receptor in the DRN enhanced c-Fos expression in 5-HT neurons during aggressive encounters, suggesting that modulation of 5-HT neuronal activity by IL-1ß signaling in the DRN controls expression of aggressive behavior.

Neurobiology of resilience in depression: immune and vascular insights from human and animal studies.

Major depressive disorder (MDD) is a chronic and recurrent psychiatric condition characterized by depressed mood, social isolation and anhedonia. It will affect 20% of individuals with considerable economic impacts. Unfortunately, 30-50% of depressed individuals are resistant to current antidepressant treatments. MDD is twice as prevalent in women and associated symptoms are different. Depression's main environmental risk factor is chronic stress, and women report higher levels of stress in daily life. However, not every stressed individual becomes depressed, highlighting the need to identify biological determinants of stress vulnerability but also resilience. Based on a reverse translational approach, rodent models of depression were developed to study the mechanisms underlying susceptibility vs resilience. Indeed, a subpopulation of animals can display coping mechanisms and a set of biological alterations leading to stress resilience. The aetiology of MDD is multifactorial and involves several physiological systems. Exacerbation of endocrine and immune responses from both innate and adaptive systems are observed in depressed individuals and mice exhibiting depression-like behaviours. Increasing attention has been given to neurovascular health since higher prevalence of cardiovascular diseases is found in MDD patients and inflammatory conditions are associated with depression, treatment resistance and relapse. Here, we provide an overview of endocrine, immune and vascular changes associated with stress vulnerability vs. resilience in rodents and when available, in humans. Lack of treatment efficacy suggests that neuron-centric treatments do not address important causal biological factors and better understanding of stress-induced adaptations, including sex differences, could contribute to develop novel therapeutic strategies including personalized medicine approaches.

Central and peripheral stress-induced epigenetic mechanisms of resilience.

PURPOSE OF REVIEW: Resilience is an adaptation process presented by an individual despite facing adversities. Epigenetic changes, such as histone acetylation/methylation and DNA methylation, have been demonstrated to mediate stress response. In this review, we summarize recent findings on epigenetic mechanisms contributing to stress resilience. RECENT FINDINGS: Epigenetic modifications of genes involved in synaptic plasticity, endocrine, immune, and vascular systems are linked to resilience. For instance, increased DNA methylation of the nonneuronal growth factor Gdnf in specific brain regions promotes stress resilience. Additionally, high DNA methylation at the glucocorticoid receptor gene was associated with resilience in both rodents and humans. At the immune level, chronic stress induces increased DNA methylation at IL6 gene, a mediator of stress vulnerability. Moreover, epigenetic adaptations of the blood--brain barrier have been recently associated with stress resilience, which could lead to innovative therapeutic approaches to treat depression. SUMMARY: Identification of both central and peripheral epigenetic changes promoting stress resilience represent promising novel targets in the development of preventive and personalized medicine. Nevertheless, more research is needed to establish sex specific differences and to identify novel epigenetic mechanisms, such as serotonylation and dopaminylation, that hold great promises for the field of psychiatry.