Treatment Of Stress-related Psychiatric Disorders Research Articles

Sex Differences in Brain Region-Specific Activation of c-Fos following Kappa Opioid Receptor Stimulation or Acute Stress in Mice.

Kappa opioid receptors (KOPr) are involved in the response to stress. KOPr are also targets for the treatment of stress-related psychiatric disorders including depression, anxiety, and addiction although effects of KOPr are often sex-dependent. Here we investigated c-Fos expression in a range of brain regions in male and female mice following an acute stressor, and a single injection of KOPr agonist. Using adult C57BL/6 c-Fos-GFP transgenic mice and quantitative fluorescence microscopy, we identified brain regions activated in response to a challenge with the KOPr agonist U50,488 (20 mg/kg) or an acute stress (15 min forced swim stress, FSS). In male mice, U50,488 increased expression of c-Fos in the prelimbic area of the prefrontal cortex (PFCx), nucleus accumbens (NAcc), and basolateral nuclei of the amygdala (BLA). In contrast, in female mice U50,488 only activated the BLA but not the PFCx or the NAcc. FSS increased activation of PFCx, NAcc, and BLA in males while there was no activation of the PFCx in female mice. In both sexes, the KOPr antagonist norBNI significantly blocked U50,488-induced, but not stress-induced activation of brain regions. In separate experiments, activated cells were confirmed as non-GABAergic neurons in the PFCx and NAcc. Together these data demonstrate sex differences in activation of brain regions that are key components of the 'reward' circuitry. These differential responses may contribute to sex differences in stress-related psychiatric disorders and in the treatment of depression, anxiety, and addiction.

Sex- and age-dependent effects of chronic corticosterone exposure on depressive-like, anxiety-like, and fear-related behavior: Role of amygdala glutamate receptors in the rat.

Persistent glucocorticoid elevation consistent with chronic stress exposure can lead to psychopathology, including mood and anxiety disorders. Women and stress-exposed adolescents are more likely to be diagnosed with mood disorders, suggesting that sex and age are important factors in determining vulnerability, though much remains to be determined regarding the mechanisms underlying this risk. Thus, the aim of the present experiments was to use the chronic corticosterone (CORT) exposure paradigm, a model of depression-like behavior that has previously been established primarily in adult males, to determine the mood-related effects of CORT in female and adolescent rats. Depression- and anxiety-like effects in adulthood were determined using the sucrose preference (SPT), the forced swim test (FST), the elevated plus maze, and fear conditioning. Basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) glutamate receptor subunit levels were then measured. In a subsequent experiment, adult male and female rats were tested for the effects of pharmacological activation (via AMPA) or inhibition (via NBQX) of AMPA receptors in the BLA on behavior in the FST. Overall, females showed reduced anxiety- and depressive-like behaviors relative to males. However, females treated with CORT in adolescence, but not adulthood, had increased immobility in the FST, indicative of depression-like behavior. In contrast, CORT did not alter behavior in adolescent-treated males, though the previously reported depression-like effect of adult CORT exposure was observed. Control females had higher expression of the AMPA receptor subunits GluA1 and GluA2/3 selectively in the BLA relative to males. Adolescent CORT treatment, however, decreased BLA GluA1 and GluA2/3 expression in females, but increased expression in males, consistent with the direction of depression-like behavioral effects. Male and female rats also demonstrated opposing patterns of response to BLA AMPA receptor modulation in the FST, with AMPA infusion magnifying the sex difference of decreased immobility in females. Overall, these experiments show that increased glutamate receptor function in the BLA may decrease the risk of developing depressive-like behavior, further supporting efforts to target glutamatergic receptors for the treatment of stress-related psychiatric disorders. These findings also support further focus on sex as a biological variable in neuropsychiatric research.

Evolutionary Aspects of Diverse Microbial Exposures and Mental Health: Focus on "Old Friends" and Stress Resilience.

The prevalence of inflammatory disease conditions, including allergies, asthma, and autoimmune disorders, increased during the latter half of the twentieth century, as societies transitioned from rural to urban lifestyles. A number of hypotheses have been put forward to explain the increasing prevalence of inflammatory disease in modern urban societies, including the hygiene hypothesis and the "Old Friends" hypothesis. In 2008, Rook and Lowry proposed, based on the evidence that increased inflammation was a risk factor for stress-related psychiatric disorders, that the hygiene hypothesis or "Old Friends" hypothesis may be relevant to psychiatric disorders. Since then, it has become more clear that chronic low-grade inflammation is a risk factor for stress-related psychiatric disorders, including anxiety disorders, mood disorders, and trauma- and stressor-related disorders, such as posttraumatic stress disorder (PTSD). Evidence now indicates that persons raised in modern urban environments without daily contact with pets, relative to persons raised in rural environments in proximity to farm animals, respond with greater systemic inflammation to psychosocial stress. Here we consider the possibility that increased inflammation in persons living in modern urban environments is due to a failure of immunoregulation, i.e., a balanced expression of regulatory and effector T cells, which is known to be dependent on microbial signals. We highlight evidence that microbial signals that can drive immunoregulation arise from phylogenetically diverse taxa but are strain specific. Finally, we highlight Mycobacterium vaccae NCTC 11659, a soil-derived bacterium with anti-inflammatory and immunoregulatory properties, as a case study of how single strains of bacteria might be used in a psychoneuroimmunologic approach for prevention and treatment of stress-related psychiatric disorders.

Rapidly Growing Mycobacterium Species: The Long and Winding Road from Tuberculosis Vaccines to Potent Stress-Resilience Agents

Inflammatory diseases and stressor-related psychiatric disorders, for which inflammation is a risk factor, are increasing in modern Western societies. Recent studies suggest that immunoregulatory approaches are a promising tool in reducing the risk of suffering from such disorders. Specifically, the environmental saprophyte Mycobacterium vaccae National Collection of Type Cultures (NCTC) 11659 has recently gained attention for the prevention and treatment of stress-related psychiatric disorders. However, effective use requires a sophisticated understanding of the effects of M. vaccae NCTC 11659 and related rapidly growing mycobacteria (RGMs) on microbiome–gut–immune–brain interactions. This historical narrative review is intended as a first step in exploring these mechanisms and provides an overview of preclinical and clinical studies on M. vaccae NCTC 11659 and related RGMs. The overall objective of this review article is to increase the comprehension of, and interest in, the mechanisms through which M. vaccae NCTC 11659 and related RGMs promote stress resilience, with the intention of fostering novel clinical strategies for the prevention and treatment of stressor-related disorders.

The contribution of orbitofrontal cortex to stress-related psychiatric disorders: stress induced synaptic change in the orbitofrontal-basolateral amygdala pathway

Exposure to stress induces alterations in synaptic functions, and increases the risk of stress-related psychiatric disorders, such as major depression and PTSD. To develop new treatments for stress-related psychiatric disorders, it is important to understand the effect of stress on the emotional circuits, such as prefrontal cortex (PFC), amygdala and other limbic regions. The orbitofrontal cortex (OFC, ventral subregion of the PFC) has important roles for processing of negative emotion and has recently been highlighted as a critical region in stress-related psychiatric disorders. However, mechanisms how stress affect OFC circuit and induce psychiatric symptoms were less understood. OFC sends dense projection to the amygdala, which is one of the key nodes for processing of negative emotion. Taken together, there is a possibility that stress affects the information processing in the OFC-amygdala pathway, and it underlies stress-induced emotional alteration. In this article, we introduce our research that examined effects of stress on the excitatory synaptic transmission from OFC to the basolateral nucleus of the amygdala (BLA) using optogenetic and whole-cell patch-clamp methods in mice.

Optogenetically-induced long term depression in the rat orbitofrontal cortex ameliorates stress-induced reversal learning impairment

Cognitive flexibility is a higher-order executive function that requires plasticity in neuronal circuits of the prefrontal cortex. Deficits in cognitive flexibility are prominent in a variety of psychiatric disorders, such as major depression, obsessive-compulsive disorder, and posttraumatic stress disorder. Chronic stress induces deficits in cognitive flexibility, perhaps through effects on plasticity, but the mechanism is not well understood. Previous work has demonstrated that stress reduces activity and dendritic elaboration in the medial prefrontal cortex (mPFC). In contrast, stress appears to increase dendritic elaboration in the orbitofrontal cortex (OFC). This suggests that there may be a differential effect of stress on plasticity in different prefrontal cortical areas. To test this hypothesis, we examined the effects of inducing plasticity optogenetically in the OFC on reversal learning, an OFC-mediated form of cognitive flexibility, in stressed and non-stressed rats. Inducing opto-LTD in the projection from mediodorsal thalamus to OFC ameliorated reversal learning deficits in rats exposed to chronic intermittent cold (CIC) stress. Additionally, we found that inducing opto-LTP in non-stressed rats produced deficits in reversal learning similar to those seen in rats after CIC stress. Finally, CIC stress produced complex subregion-specific changes in dendritic material and spine subtype composition in the OFC. These results indicate that the effects of stress on plasticity in the OFC are distinct from those in the mPFC, and that the PFC should therefore not be treated as a homogenous region in studying either stress effects or potential treatments for stress-related psychiatric disorders.

Application of Noninvasive Vagal Nerve Stimulation to Stress-Related Psychiatric Disorders.

Background: Vagal Nerve Stimulation (VNS) has been shown to be efficacious for the treatment of depression, but to date, VNS devices have required surgical implantation, which has limited widespread implementation. Methods: New noninvasive VNS (nVNS) devices have been developed which allow external stimulation of the vagus nerve, and their effects on physiology in patients with stress-related psychiatric disorders can be measured with brain imaging, blood biomarkers, and wearable sensing devices. Advantages in terms of cost and convenience may lead to more widespread implementation in psychiatry, as well as facilitate research of the physiology of the vagus nerve in humans. nVNS has effects on autonomic tone, cardiovascular function, inflammatory responses, and central brain areas involved in modulation of emotion, all of which make it particularly applicable to patients with stress-related psychiatric disorders, including posttraumatic stress disorder (PTSD) and depression, since dysregulation of these circuits and systems underlies the symptomatology of these disorders. Results: This paper reviewed the physiology of the vagus nerve and its relevance to modulating the stress response in the context of application of nVNS to stress-related psychiatric disorders. Conclusions: nVNS has a favorable effect on stress physiology that is measurable using brain imaging, blood biomarkers of inflammation, and wearable sensing devices, and shows promise in the prevention and treatment of stress-related psychiatric disorders.

Cyclooxygenase-2 inhibition reduces anxiety-like behavior and normalizes enhanced amygdala glutamatergic transmission following chronic oral corticosterone treatment

Chronic stress increases the probability of receiving an anxiety, depression, or chronic illness diagnosis. Pharmacological interventions that reduce the behavioral and physiological effects of chronic stress in animal models may represent novel approaches for the treatment of stress-related psychiatric disorders. Here, we examined the effects of cyclooxygenase-2 (COX-2) inhibition on anxiety-like behaviors and amygdala glutamatergic signaling after chronic non-invasive oral corticosterone (CORT) administration in mice. Treatment with the highly selective COX-2 inhibitor Lumiracoxib (LMX) reversed anxiety-like behavior induced by chronic CORT. Specifically, acute and repeated administration of LMX 5 mg kg−1 reduced chronic CORT-induced anxiety-like behavior measured using the elevated-plus maze, elevated-zero maze, and light-dark box tests. In contrast, LMX did not affect anxiety-like behaviors in naïve mice. Ex vivo electrophysiology studies revealed that repeated LMX treatment normalized chronic CORT-induced increases in spontaneous excitatory glutamatergic currents recorded from anterior, but not posterior, basolateral amygdala neurons. These data indicate COX-2 inhibition can reverse chronic CORT-induced increases in anxiety-like behaviors and amygdala glutamatergic signaling, and support further clinical investigation of selective COX-2 inhibitors for the treatment of affective and stress-related psychiatric disorders.

Acute prazosin administration does not reduce stressor reactivity in healthy adults.

Norepinephrine plays a critical role in the stress response. Clarifying the psychopharmacological effects of norepinephrine manipulation on stress reactivity in humans has important implications for basic neuroscience and treatment of stress-related psychiatric disorders, such as posttraumatic stress disorder and alcohol use disorders. Preclinical research implicates the norepinephrine alpha-1 receptor in responses to stressors. The No Shock, Predictable Shock, Unpredictable Shock (NPU) task is a human laboratory paradigm that is well positioned to test cross-species neurobiological stress mechanisms and advance experimental therapeutic approaches to clinical trials testing novel treatments for psychiatric disorders. We hypothesized that acute administration of prazosin, a noradrenergic alpha-1 antagonist, would have a larger effect on reducing stress reactivity during unpredictable, compared to predictable, stressors in the NPU task. We conducted a double-blind, placebo-controlled, crossover randomized controlled trial in which 64 healthy adults (32 female) completed the NPU task at two visits (2mg prazosin vs. placebo). A single acute dose of 2mg prazosin did not reduce stress reactivity in a healthy adult sample. Neither NPU startle potentiation nor self-reported anxiety was reduced by prazosin (vs. placebo) during unpredictable (vs. predictable) stressors. Further research is needed to determine whether this failure to translate preclinical neuroscience to human laboratory models is due to methodological factors (e.g., acute vs. chronic drug administration, brain penetration, study population) and/or suggests limited clinical utility of noradrenergic alpha-1 antagonists for treating stress-related psychiatric disorders.

T33. Acute Prazosin Administration Does Not Reduce Stressor Reactivity in Healthy Adults

Norepinephrine plays a critical role in the stress response. Clarifying the psychopharmacological effects of norepinephrine manipulation on stress reactivity in humans has important implications for basic neuroscience and treatment of stress-related psychiatric disorders, such as posttraumatic stress disorder and alcohol use disorders. Preclinical research implicates the alpha-1 norepinephrine receptor in responses to stressors. The No Shock, Predictable Shock, Unpredictable Shock (NPU) task is a human laboratory paradigm that is well positioned to test cross-species neurobiological stress mechanisms and advance experimental therapeutic approaches to clinical trials testing novel treatments for psychiatric disorders. We hypothesized that acute administration of prazosin, an alpha-1 noradrenergic antagonist, would have a larger effect on reducing stress reactivity during unpredictable, compared to predictable, stressors in the NPU task.

Acetyl-L-carnitine as a putative candidate for the treatment of stress-related psychiatric disorders: Novel evidence from a zebrafish model

Stress-related psychiatric disorders are mental conditions that affect mood, cognition and behavior and arise because of the impact of prolonged stress on the central nervous system (CNS). Acetyl-L-carnitine (ALC) is an acetyl ester of L-carnitine that easily crosses the blood-brain barrier and was recently found to be decreased in patients with major depressive disorder. ALC plays a role in energy metabolism and is widely consumed as a nutritional supplement to improve physical performance. In this study, our objective was to evaluate the effects of ALC treatment (0.1 mg/L, 10 min) for 7 days on behavior and oxidative stress in zebrafish subjected to unpredictable chronic stress (UCS) protocol. Behavioral outcomes were assessed in the novel tank test, and parameters of oxidative status (lipid peroxidation and antioxidant defenses) were evaluated in the brain using colorimetric methods. According to our previous findings, UCS increased anxiety-like behavior and lipid peroxidation, while it decreased non-protein thiol levels and superoxide dismutase activity. However, ALC reversed the anxiety-like behavior and oxidative damage in stressed animals, while it was devoid of effect in control animals. Although our data reinforce the neuroprotective potential of ALC in the treatment of psychiatric disorders related to stress, further investigations are required to clarify its mechanisms of action and confirm its efficacy.

An Improved Model of Physical and Emotional Social Defeat: Different Effects on Social Behavior and Body Weight of Adolescent Mice by Interaction With Social Support.

Social stress is a prevalent etiological environmental factor that can affect health, especially during adolescence. Either experiencing or witnessing a traumatic event during adolescence can increase the risk of psychiatric disorders, such as PTSD. The present study attempted to establish an improved social stress model to better distinguish the effects of physical and emotional social stress on the behavior and physiology of adolescent mice. In addition, we investigated how social support affected these stress-induced changes in social behavior. On PND 28, male littermates were exposed to either physical stress (PS) or emotional stress (ES), afterwards, half of them were paired-housed and the others were singly housed. The PS exposed mice were directly confronted with a violent aggressor using the social defeat stress (SDS) paradigm for 15 min/trial (with the total of 10 trials randomly administered over a week), while the ES exposed mice were placed in a neighboring compartment to witness the PS procedure. Our results indicate that both stressors induced an effective stress response in adolescent mice, but PS and ES had differential influence in the context of relevant social anxiety/fear and social interaction with peers. Additionally, social support following stress exposure exerted beneficial effects on the social anxiety/fear in ES exposed mice, but not on PS exposed mice, suggesting that the type of stressor may affect the intervention efficacy of social support. These findings provide extensive evidence that physical and emotional stressors induce different effects. Moreover, ES exposed mice, rather than PS exposed mice, seemed to benefit from social support. In summary, the study suggests that this paradigm will be helpful in investigating the effects of psychological intervention for the treatment of stress-related psychiatric disorders.

Mechanisms underlying prelimbic prefrontal cortex mGlu3/mGlu5-dependent plasticity and reversal learning deficits following acute stress

Stress can precipitate or worsen symptoms of many psychiatric illnesses. Dysregulation of the prefrontal cortex (PFC) glutamate system may underlie these disruptions and restoring PFC glutamate signaling has emerged as a promising avenue for the treatment of stress disorders. Recently, we demonstrated that activation of metabotropic glutamate receptor subtype 3 (mGlu3) induces a postsynaptic form of long-term depression (LTD) that is dependent on the activity of another subtype, mGlu5. Stress exposure disrupted this plasticity, but the underlying signaling mechanisms and involvement in higher-order cognition have not yet been investigated. Acute stress was applied by 20-min restraint and early reversal learning was evaluated in an operant-based food-seeking task. We employed whole-cell patch-clamp recordings of layer 5 prelimbic (PL)-PFC pyramidal cells to examine mGlu3-LTD and several mechanistically distinct mGlu5-dependent functions. Acute stress impaired both mGlu3-LTD and early reversal learning. Interestingly, potentiating mGlu5 signaling with the mGlu5 positive allosteric modulator (PAM) VU0409551 rescued stress-induced deficits in both mGlu3-LTD and reversal learning. Other aspects of PL-PFC mGlu5 function were not disrupted following stress; however, signaling downstream of mGlu5-Homer interactions, phosphoinositide-3-kinase (PI3K), Akt, and glycogen synthase kinase 3β was implicated in these phenomena. These findings demonstrate that acute stress disrupts early reversal learning and PL-PFC-dependent synaptic plasticity and that potentiating mGlu5 function can restore these impairments. These findings provide a framework through which modulating coordinated mGlu3/mGlu5 signaling may confer benefits for the treatment of stress-related psychiatric disorders.

Sex differences in stress regulation of arousal and cognition

There are sex differences in the prevalence and presentation of many psychiatric disorders. For example, posttraumatic stress disorder (PTSD) and major depression are more common in women than men, and women with these disorders present with more hyperarousal symptoms than men. In contrast, attention deficit hyperactivity disorder (ADHD) and schizophrenia are more common in men than women, and men with these disorders have increased cognitive deficits compared to women. A shared feature of the aforementioned psychiatric disorders is the contribution of stressful events to their onset and/or severity. Here we propose that sex differences in stress responses bias females towards hyperarousal and males towards cognitive deficits. Evidence from clinical and preclinical studies is detailed. We also describe underlying neurobiological mechanisms. For example, sex differences in stress receptor signaling and trafficking in the locus coeruleus-arousal center are detailed. In learning circuits, evidence for sex differences in dendritic morphology is provided. Finally, we describe how evaluating sex-specific mechanisms for responding to stress in female and male rodents can lead to better treatments for stress-related psychiatric disorders.

P2X7 purinergic receptors participate in the expression and extinction processes of contextual fear conditioning memory in mice

The purinergic system consists of two large receptor families – P2X and P2Y. Both are activated by adenosine triphosphate (ATP), although presenting different functions. These receptors are present in several brain regions, including those involved in emotion and stress-related behaviors. Hence, they seem to participate in fear- and anxiety-related responses. However, few studies have investigated the purinergic system in threatening situations, as observed in contextual fear conditioning (CFC). Therefore, this study investigated the involvement of purinergic receptors in the expression and extinction of aversive memories. C57Bl/6 background mice were submitted to the CFC protocol. Wildtype (WT) mice received i.p. injection of either a nonselective P2 receptor (P2R) antagonist, P178 (10 or 30 mg/kg); a selective P2X7 receptor (P2X7R) antagonist, A438079 (10 mg/kg); a selective P2Y1 receptor (P2Y1R) antagonist, MRS2179 (10 mg/kg); or vehicle 10 min prior to or immediately after the extinction session. Additionally, P2X7R KO mice were tested in the CFC protocol. After P2R antagonist treatment, contextual fear recall increased, while acquisition of extinction was impaired. Similar results were observed with the selective P2X7R antagonist, but not with the selective P2Y1R antagonist. Interestingly, P2X7R KO mice showed increased contextual fear recall, associated with impaired acquisition of extinction, in accordance with pharmacologic P2X7R antagonism. Our results suggest that specific pharmacological or genetic blockade of P2X7R promotes anxiogenic-like effects, along with deficits in extinction learning. Thus, these receptors could present an alternative treatment of stress-related psychiatric disorders.

Epigenetic programming of the neuroendocrine stress response by adult life stress.

The hypothalamic-pituitary-adrenal (HPA) axis is critically involved in the neuroendocrine regulation of stress adaptation, and the restoration of homeostasis following stress exposure. Dysregulation of this axis is associated with stress-related pathologies like major depressive disorder, post-traumatic stress disorder, panic disorder and chronic anxiety. It has long been understood that stress during early life can have a significant lasting influence on the development of the neuroendocrine system and its neural regulators, partially by modifying epigenetic regulation of gene expression, with implications for health and well-being in later life. Evidence is accumulating that epigenetic plasticity also extends to adulthood, proposing it as a mechanism by which psychological trauma later in life can long-lastingly affect HPA axis function, brain plasticity, neuronal function and behavioural adaptation to neuropsychological stress. Further corroborating this claim is the phenomenon that these epigenetic changes correlate with the behavioural consequences of trauma exposure. Thereby, epigenetic modifications provide a putative molecular mechanism by which the behavioural phenotype and transcriptional/translational potential of genes involved in HPA axis regulation can change drastically in response to environmental challenges, and appear an important target for treatment of stress-related disorders. However, improved insight is required to increase their therapeutic (drug) potential. Here, we provide an overview of the growing body of literature describing the epigenetic modulation of the (primarily neuroendocrine) stress response as a consequence of adult life stress and interpret the implications for, and the challenges involved in applying this knowledge to, the identification and treatment of stress-related psychiatric disorders.

Therapeutic Effects of Extinction Learning as a Model of Exposure Therapy in Rats.

Current treatments for stress-related psychiatric disorders, such as depression and posttraumatic stress disorder (PTSD), are inadequate. Cognitive behavioral psychotherapies, including exposure therapy, are an alternative to pharmacotherapy, but the neurobiological mechanisms are unknown. Preclinical models demonstrating therapeutic effects of behavioral interventions are required to investigate such mechanisms. Exposure therapy bears similarity to extinction learning. Thus, we investigated the therapeutic effects of extinction learning as a behavioral intervention to model exposure therapy in rats, testing its effectiveness in reversing chronic stress-induced deficits in cognitive flexibility and coping behavior that resemble dimensions of depression and PTSD. Rats were fear-conditioned by pairing a tone with footshock, and then exposed to chronic unpredictable stress (CUS) that induces deficits in cognitive set-shifting and active coping behavior. They then received an extinction learning session as a therapeutic intervention by repeated exposure to the tone with no shock. Effects on cognitive flexibility and coping behavior were assessed 24 h later on the attentional set-shifting test or shock-probe defensive burying test, respectively. Extinction reversed the CUS-induced deficits in cognitive flexibility and coping behavior, and increased phosphorylation of ribosomal protein S6 in the medial prefrontal cortex (mPFC) of stress-compromised rats, suggesting a role for activity-dependent protein synthesis in the therapeutic effect. Inhibiting protein synthesis by microinjecting anisomycin into mPFC blocked the therapeutic effect of extinction on cognitive flexibility. These results demonstrate the utility of extinction as a model by which to study mechanisms underlying exposure therapy, and suggest these mechanisms involve protein synthesis in the mPFC, the further study of which may identify novel therapeutic targets.

MicroRNAs as biomarkers of resilience or vulnerability to stress

Identifying novel biomarkers of resilience or vulnerability to stress could provide valuable information for the prevention and treatment of stress-related psychiatric disorders. To investigate the utility of blood microRNAs as biomarkers of resilience or vulnerability to stress, microRNAs were assessed before and after 7days of chronic social defeat in rats. Additionally, microRNA profiles of two important stress-regulatory brain regions, the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA), were assessed. Rats that displayed vulnerability to subsequent chronic stress exhibited reductions in circulating miR-24-2-5p, miR-27a-3p, miR-30e-5p, miR-3590-3p, miR-362-3p, and miR-532-5p levels. In contrast, rats that became resilient to stress displayed reduced levels of miR-139-5p, miR-28-3p, miR-326-3p, and miR-99b-5p compared to controls. In the mPFC, miR-126a-3p and miR-708-5p levels were higher in vulnerability compared to resilient rats. In the BLA, 77 microRNAs were significantly altered by stress but none were significantly different between resilient and vulnerable animals. These results provide proof-of-principle that assessment of circulating microRNAs is useful in identifying individuals who are vulnerable to the effects of future stress or individuals who have become resilient to the effects of stress. Furthermore, these data suggest that microRNAs in the mPFC but not in the BLA are regulators of resilience/vulnerability to stress.

Activation of presynaptic oxytocin receptors enhances glutamate release in the ventral hippocampus of prenatally restraint stressed rats

Oxytocin receptors are known to modulate synaptic transmission and network activity in the hippocampus, but their precise function has been only partially elucidated. Here, we have found that activation of presynaptic oxytocin receptor with the potent agonist, carbetocin, enhanced depolarization-evoked glutamate release in the ventral hippocampus with no effect on GABA release. This evidence paved the way for examining the effect of carbetocin treatment in “prenatally restraint stressed” (PRS) rats, i.e., the offspring of dams exposed to repeated episodes of restraint stress during pregnancy. Adult PRS rats exhibit an anxious/depressive-like phenotype associated with an abnormal glucocorticoid feedback regulation of the hypothalamus-pituitary-adrenal (HPA) axis, and, remarkably, with a reduced depolarization-evoked glutamate release in the ventral hippocampus. Chronic systemic treatment with carbetocin (1mg/kg, i.p., once a day for 2–3 weeks) in PRS rats corrected the defect in glutamate release, anxiety- and depressive-like behavior, and abnormalities in social behavior, in the HPA response to stress, and in the expression of stress-related genes in the hippocampus and amygdala. Of note, carbetocin treatment had no effect on these behavioral and neuroendocrine parameters in prenatally unstressed (control) rats, with the exception of a reduced expression of the oxytocin receptor gene in the amygdala. These findings disclose a novel function of oxytocin receptors in the hippocampus, and encourage the use of oxytocin receptor agonists in the treatment of stress-related psychiatric disorders in adult life.

GABAB(1) receptor subunit isoforms differentially regulate stress resilience.

Stressful life events increase the susceptibility to developing psychiatric disorders such as depression; however, many individuals are resilient to such negative effects of stress. Determining the neurobiology underlying this resilience is instrumental to the development of novel and more effective treatments for stress-related psychiatric disorders. GABAB receptors are emerging therapeutic targets for the treatment of stress-related disorders such as depression. These receptors are predominantly expressed as heterodimers of a GABAB(2) subunit with either a GABAB(1a) or a GABAB(1b) subunit. Here we show that mice lacking the GABAB(1b) receptor isoform are more resilient to both early-life stress and chronic psychosocial stress in adulthood, whereas mice lacking GABAB(1a) receptors are more susceptible to stress-induced anhedonia and social avoidance compared with wild-type mice. In addition, increased hippocampal expression of the GABAB(1b) receptor subunit is associated with a depression-like phenotype in the helpless H/Rouen genetic mouse model of depression. Stress resilience in GABAB(1b)(-/-) mice is coupled with increased proliferation and survival of newly born cells in the adult ventral hippocampus and increased stress-induced c-Fos activation in the hippocampus following early-life stress. Taken together, the data suggest that GABAB(1) receptor subunit isoforms differentially regulate the deleterious effects of stress and, thus, may be important therapeutic targets for the treatment of depression.