Stress-related Psychiatric Disorders Research Articles

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.

From Matrices to Knowledge: Using Semantic Networks to Annotate the Connectome.

The connectome is regarded as the key to brain function in health and disease. Structural and functional neuroimaging enables us to measure brain connectivity in the living human brain. The field of connectomics describes the connectome as a mathematical graph with its connection strengths being represented by connectivity matrices. Graph theory algorithms are used to assess the integrity of the graph as a whole and to reveal brain network biomarkers for brain diseases; however, the faulty wiring of single connections or subnetworks as the structural correlate for neurological or mental diseases remains elusive. We describe a novel approach to represent the knowledge of human brain connectivity by a semantic network – a formalism frequently used in knowledge management to describe the semantic relations between objects. In our novel approach, objects are brain areas and connectivity is modeled as semantic relations among them. The semantic network turns the graph of the connectome into an explicit knowledge base about which brain areas are interconnected. Moreover, this approach can semantically enrich the measured connectivity of an individual subject by the semantic context from ontologies, brain atlases and molecular biological databases. Integrating all measurements and facts into one unified feature space enables cross-modal comparisons and analyses. We used a query mechanism for semantic networks to extract functional, structural and transcriptome networks. We found that in general higher structural and functional connectivity go along with a lower differential gene expression among connected brain areas; however, subcortical motor areas and limbic structures turned out to have a localized high differential gene expression while being strongly connected. In an additional explorative use case, we could show a localized high availability of fkbp5, gmeb1, and gmeb2 genes at a connection hub of temporo-limbic brain networks. Fkbp5 is known for having a role in stress-related psychiatric disorders, while gmeb1 and gmeb2 encode for modulator proteins of the glucocorticoid receptor, a key receptor in the hormonal stress system. Semantic networks tremendously ease working with multimodal neuroimaging and neurogenetics data and may reveal relevant coincidences between transcriptome and connectome networks.

Paternal Preconception Chronic Variable Stress Confers Attenuated Ethanol Drinking Behavior Selectively to Male Offspring in a Pre-Stress Environment Dependent Manner.

Stress-related psychiatric disorders such as major depression are strongly associated with alcohol abuse and alcohol use disorder. Recently, many epidemiological and preclinical studies suggest that chronic stress prior to conception has cross-generational effects on the behavior and physiological response to stress in subsequent generations. Thus, we hypothesized that chronic stress may also affect ethanol drinking behaviors in the next generation. In the first cohort of mice, we found that paternal preconception chronic variable stress significantly reduced both two-bottle choice and binge-like ethanol drinking selectively in male offspring. However, these results were not replicated in a second cohort that were tested under experimental conditions that were nearly identical, except for one notable difference. Cohort 1 offspring were derived from in-house C57BL/6J sires that were born in the animal vivarium at the University of Pittsburgh whereas cohort 2 offspring were derived from C57BL/6J sires shipped directly from the vendor. Therefore, a third cohort that included both in-house and vendor born sires was analyzed. Consistent with the first two cohorts, we observed a significant interaction between chronic stress and sire-source with only stressed sires that were born in-house able to impart reduced ethanol drinking behaviors to male offspring. Overall, these results demonstrate that paternal preconception stress can impact ethanol drinking behavior in males of the next generation. These studies provide additional support for a recently recognized role of the paternal preconception environment in shaping ethanol drinking behavior.

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.

Depression-like behaviors induced by chronic corticosterone exposure via drinking water: Time-course analysis

Hypothalamic-pituitary-adrenal (HPA) axis activity is commonly dysregulated in stress-related psychiatric disorders. The corticosterone rat model was developed to understand the influence of stress on depression-like symptomatology. To further understand the effects of corticosterone on the development of depression-like behavior, rats were continuously exposed to corticosterone (200 μg/ml) or vehicle via drinking water daily for 21 days. The rats underwent a series of behavioral tests, and electroencephalographical recordings were performed after 7, 14, and 21 days of treatment. The measurements included immobility time (i.e., despair) in the forced swim test, locomotor activity in the open field test, sucrose consumption (i.e., anhedonia) in the sucrose preference test, and sleep-wake parameters. The rats in the 7-day corticosterone exposure group exhibited depression-like behavior, including increases in despair, anhedonia, anxiety, and sleep impairments. The rats in the 14-day corticosterone exposure group exhibited normal patterns of behavior and sleep structure. When corticosterone exposure was extended to 21 days, depression-like symptoms recurred, including despair, anhedonia, anxiety, and sleep disturbances. Overall, the present study observed U-shaped depression-like effects across 3 weeks of corticosterone exposure via drinking water.

Effects of Epigallocatechin Gallate on Behavioral and Cognitive Impairments, Hypothalamic-Pituitary-Adrenal Axis Dysfunction, and Alternations in Hippocampal BDNF Expression Under Single Prolonged Stress.

Post-traumatic stress disorder (PTSD) is a traumatic stress-related psychiatric disorder stimulated by experience. Green tea has potent antioxidative properties, due, in part, to the catechin (-) epigallocatechin-3-gallate (EGCG). EGCG is an important polyphenol with advantageous effects on anxiety and depression. Nevertheless, the mechanism about the inhibition of PTSD-like symptoms of EGCG is still unidentified. We examined whether EGCG improved learning and memory deficit stimulated in rats after single prolonged stress (SPS). Rats were administrated intraperitoneally (i.p.) with EGCG for 14 successive days after the SPS process. The SPS procedure stimulated cognitive deficit in the Morris water maze test and the object recognition task, and this impairment was improved by EGCG (25 mg/kg, i.p.). Daily EGCG administration significantly decreased the freezing response to contextual fear conditioning. The administration of EGCG also significantly moderated memory-related decreases in the alternation of cAMP-response element-binding protein and brain-derived neurotrophic factor in the hippocampus. Our results suggest that EGCG alleviated SPS-stimulated learning and memory deficit by inhibiting the increase of neuroinflammation in the rat brain. In addition, EGCG reversed the alternation of allopregnanolone and progesterone in the brain, and diminished simultaneously the hypothalamic-pituitary-adrenal axis dysfunction. Thus, EGCG reversed learning and memory-related behavioral dysfunction and molecular alternation accelerated by traumatic stress and may be a useful therapeutic material for PTSD.

Ketamine Corrects a Deficit in Reversal Learning Caused by Chronic Intermittent Cold Stress in Female Rats.

BackgroundIndividuals with stress-related psychiatric disorders exhibit deficits in cognitive flexibility. We have shown that chronic intermittent cold stress induces deficits in reversal learning, a form of cognitive flexibility mediated in the orbitofrontal cortex, that was reversed by ketamine in male rats. Such effects have not been tested in females. In this study, we examined effects of chronic intermittent cold stress and ketamine on reversal learning in females.MethodsFemale Sprague-Dawley rats underwent 14 days of chronic intermittent cold and 3 days later received an injection of ketamine (10 mg/kg, i.p.). They were tested on reversal learning 24 hours post-injection. A separate cohort of female rats underwent 14 days of chronic intermittent cold. Three days later they received ketamine and were killed 2 hours post-injection for measurement of the synaptic marker PSD95 in orbitofrontal cortex.ResultsChronic intermittent cold induced a reversal learning deficit in females comparable with that seen in males, which was corrected by ketamine. Moreover, chronic intermittent cold increased PSD95 expression in orbitofrontal cortex, but this increase was not seen in rats receiving ketamine.ConclusionsChronic intermittent cold stress and ketamine altered reversal learning in female rats similar to effects seen in males. Further, chronic intermittent cold increased PSD95 in orbitofrontal cortex of female rats, indicative of synaptic dysregulation. This effect was attenuated after ketamine administration.

Protective effects of elevated anandamide on stress and fear-related behaviors: translational evidence from humans and mice

Post-traumatic stress disorder (PTSD) is a common, debilitating condition with limited treatment options. Extinction of fear memories through prolonged exposure therapy, the primary evidence-based behavioral treatment for PTSD, has only partial efficacy. In mice, pharmacological inhibition of fatty acid amide hydrolase (FAAH) produces elevated levels of anandamide (AEA) and promotes fear extinction, suggesting that FAAH inhibitors may aid fear extinction-based treatments. A human FAAH 385C->A substitution encodes an FAAH enzyme with reduced catabolic efficacy. Individuals homozygous for the FAAH 385A allele may therefore offer a genetic model to evaluate the impact of elevations in AEA signaling in humans, helping to inform whether FAAH inhibitors have the potential to facilitate fear extinction therapy for PTSD. To overcome the challenge posed by low frequency of the AA genotype (appr. 5%), we prospectively genotyped 423 individuals to examine the balanced groups of CC, AC, and AA individuals (n = 25/group). Consistent with its loss-of-function nature, the A allele was dose dependently associated with elevated basal AEA levels, facilitated fear extinction, and enhanced the extinction recall. Moreover, the A-allele homozygotes were protected against stress-induced decreases in AEA and negative emotional consequences of stress. In a humanized mouse model, AA homozygous mice were similarly protected against stress-induced decreases in AEA, both in the periphery, and also in the amygdala and prefrontal cortex, brain structures critically involved in fear extinction and regulation of stress responses. Collectively, these data suggest that AEA signaling can temper aspects of thestress response and that FAAH inhibition may aid the treatment for stress-related psychiatric disorders, such as PTSD.

The Role of m6A/m-RNA Methylation in Stress Response Regulation

SummaryN6-methyladenosine (m6A) and N6,2′-O-dimethyladenosine (m6Am) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed m6A/m, in the stress response in the adult brain in vivo is currently unknown. Here, we provide a detailed analysis of the stress epitranscriptome using m6A/m-seq, global and gene-specific m6A/m measurements. We show that stress exposure and glucocorticoids region and time specifically alter m6A/m and its regulatory network. We demonstrate that deletion of the methyltransferase Mettl3 or the demethylase Fto in adult neurons alters the m6A/m epitranscriptome, increases fear memory, and changes the transcriptome response to fear and synaptic plasticity. Moreover, we report that regulation of m6A/m is impaired in major depressive disorder patients following glucocorticoid stimulation. Our findings indicate that brain m6A/m represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A/m response may contribute to the pathophysiology of stress-related psychiatric disorders.

Maternal regulation of the infant's hypothalamic-pituitary-adrenal axis stress response: Seymour 'Gig' Levine's legacy to neuroendocrinology.

Thirty years ago, Seymour 'Gig' Levine published a serendipitous, yet, seminal finding with respect to the regulatory role of maternal presence on the corticosterone stress response of neonatal rats during the developmental period known as the stress hyporesponsive period. At the same time, his group of students also investigated the stress response of infant monkeys with respect to maternal separation, as a means of understanding the stress to the primary caregiver resulting from disruptions of attachment. Gig and his group of students and collaborators, mainly in the USA and the Netherlands, investigated how initial social relationships buffer the stress response of nonhuman primates and rodent infants. His work in rodents involved determining how prolonged deprivation of maternal care disinhibits the stress response of neonates and how maternal behaviours regulate specific aspects of the hypothalamic-pituitary-adrenal axis. Maternal deprivation for 24hours was useful for determining the importance of nutrition in suppressing the corticosterone stress response, whereas anogenital licking and grooming inhibited stress-induced adrenocortoctrophic hormone release, with the combination of both behaviours preventing the effects of maternal deprivation on the central hypothalamic stress response. Levine's group also studied the consequences of maternal deprivation on basal and stress-induced activity of the hypothalamic-pituitary-adrenal axis in juveniles and the persistent effects of the replacement of maternal behaviours on these parameters. Gig's legacy allowed many groups around the world to use the 24-hour maternal deprivation paradigm as an animal model of vulnerability and resilience to stress-related psychiatric disorders, as well as in studies of the neurobiological underpinnings of disruption of the mother-infant relationship and loss of parental care, a highly prevalent condition in humans. This review pays homage to a great scientist and mentor, whose discoveries paved the way for the understanding of how early social relationsships build resilience or lead to susceptibility to emotional disorders later in life.

Unraveling the Genetics of Major Depression and Stress-Related Psychiatric Disorders: Is It Time for a Paradigm Shift?

Unraveling the Genetics of Major Depression and Stress-Related Psychiatric Disorders: Is It Time for a Paradigm Shift?

Orexins and stress.

The neuropeptides orexins are important in regulating the neurobiological systems that respond to stressful stimuli. Furthermore, orexins are known to play a role many of the phenotypes associated with stress-related mental illness such as changes in cognition, sleep-wake states, and appetite. Interestingly, orexins are altered in stress-related psychiatric disorders such as Major Depressive Disorder and Anxiety Disorders. Thus, orexins may be a potential target for treatment of these disorders. In this review, we will focus on what is known about the role of orexins in acute and repeated stress, in stress-induced phenotypes relevant to psychiatric illness in preclinical models, and in stress-related psychiatric illness in humans. We will also briefly discuss how orexins may contribute to sex differences in the stress response and subsequent phenotypes relevant to mental health, as many stress-related psychiatric disorders are twice as prevalent in women.

The long-term effect of maternal dietary protein restriction on 5-HT1A receptor function and behavioral responses to stress in adulthood

Maternal nutrition impacts fetal development, and may play a role in determining resilience to stress and vulnerability to stress-precipitated psychiatric disorders, such as anxiety and depression. In this study, we examined the effect of a reduction in maternal dietary protein during pregnancy on the brain neurochemistry and behavior of offspring. We focused specifically on the serotonin system, the 5-HT1A receptor and the responsivity of offspring as adults to stress. Dams were fed either a low protein diet (10% protein by weight) or isocaloric control diet (20% protein by weight). The low protein diet did not alter maternal food intake and body weight, or litter size and the average birth weight of male or female littermates. 5-HT1A receptor function, as measured by quantitative autoradiography of 8-OH-DPAT (1 μM)-stimulated [35S]GTPγS binding, was markedly reduced in hippocampus of weanling female, but not male offspring (postnatal day, PND 21) of dams fed the low protein diet. The number of serotonergic cell bodies in the rostral raphe, and 5-HT metabolism in the limbic system of weanling offspring was not altered by maternal low protein diet. The deficit in hippocampal 5-HT1A receptor function observed in weanling female offspring persisted into adulthood (PND 112), and was accompanied by an increased sensitivity to stress, specifically increased immobility during a 15-minute forced swim challenge and increased anorexia following 30-minute restraint (PND 97-100). The present work begins to uncover important future directions for understanding the early developmental origins of resilience to stress, and factors that may put individuals at greater risk for stress-related psychiatric disorders.

Autonomic and Brain Morphological Predictors of Stress Resilience.

Stressful life events are an important cause of psychopathology. Humans exposed to aversive or stressful experiences show considerable inter-individual heterogeneity in their responses. However, the majority does not develop stress-related psychiatric disorders. The dynamic processes encompassing positive and functional adaptation in the face of significant adversity have been broadly defined as resilience. Traditionally, the assessment of resilience has been confined to self-report measures, both within the general community and putative high-risk populations. Although this approach has value, it is highly susceptible to subjective bias and may not capture the dynamic nature of resilience, as underlying construct. Recognizing the obvious benefits of more objective measures of resilience, research in the field has just started investigating the predictive value of several potential biological markers. This review provides an overview of theoretical views and empirical evidence suggesting that individual differences in heart rate variability (HRV), a surrogate index of resting cardiac vagal outflow, may underlie different levels of resilience toward the development of stress-related psychiatric disorders. Following this line of thought, recent studies describing associations between regional brain morphometric characteristics and resting state vagally-mediated HRV are summarized. Existing studies suggest that the structural morphology of the anterior cingulated cortex (ACC), particularly its cortical thickness, is implicated in the expression of individual differences in HRV. These findings are discussed in light of emerging structural neuroimaging research, linking morphological characteristics of the ACC to psychological traits ascribed to a high-resilient profile and abnormal structural integrity of the ACC to the psychophysiological expression of stress-related mental health consequences. We conclude that a multidisciplinary approach integrating brain structural imaging with HRV monitoring could offer novel perspectives about brain-body pathways in resilience and adaptation to psychological stress.

High salt intake enhances swim stress-induced PVN vasopressin cell activation and active stress coping

PurposeStress contributes to many psychiatric disorders; however, responsivity to stressors can vary depending on previous or current stress exposure. Relatively innocuous heterotypic (differing in type) stressors can summate to result in exaggerated neuronal and behavioral responses. Here we investigated the ability of prior high dietary sodium chloride (salt) intake, a dehydrating osmotic stressor, to enhance neuronal and behavioral responses of mice to an acute psychogenic swim stress (SS). Further, we evaluated the contribution of the osmo-regulatory stress-related neuropeptide arginine vasopressin (VP) in the hypothalamic paraventricular nucleus (PVN), one of only a few brain regions that synthesize VP. The purpose of this study was to determine the impact of high dietary salt intake on responsivity to heterotypic stress and the potential contribution of VPergic-mediated neuronal activity on high salt-induced stress modulation, thereby providing insight into how dietary (homeostatic) and environmental (psychogenic) stressors might interact to facilitate psychiatric disorder vulnerability. ApproachSalt loading (SL) with 4% saline for 7 days was used to dehydrate and osmotically stress mice prior to exposure to an acute SS. Fluid intake and hematological measurements were taken to quantify osmotic dehydration, and serum corticosterone levels were measured to index stress axis activation. Immunohistochemistry (IHC) was used to stain for the immediate early gene product c-Fos to quantify effects of SL on SS-induced activation of neurons in the PVN and extended amygdala – brain regions that are synaptically connected and implicated in responding to osmotic stress and in modulation of SS behavior, respectively. Lastly, the role of VPergic PVN neurons and VP type 1 receptor (V1R) activity in the amygdala in mediating effects of SL on SS behavior was evaluated by quantifying c-Fos activation of VPergic PVN neurons and, in functional experiments, by nano-injecting the V1R selective antagonist dGly[Phaa1,d-tyr(et), Lys, Arg]-VP bilaterally into the amygdala prior to the SS. FindingsSL increased serum osmolality (P < 0.01), which positively correlated with time spent mobile during, and time spent grooming after a SS (P < 0.01, P < 0.01), and SL increased serum corticosterone levels (P < 0.01). SL alone increased c-Fos immunoreactivity among PVN neurons (P = .02), including VP positive neurons (P < 0.01). SL increased SS-induced c-Fos activation of PVN neurons as well (P < 0.01). In addition, SL and SS each increased the total number of PVN neurons that were immunoreactive for VP (P < 0.01). An enhancing effect of SL and SS was observed on c-Fos positive cell counts in the central (P = .02) and basolateral (P < 0.01) nuclei of the amygdala and bilateral nano-injections of V1R antagonist into the amygdala reduced time spent mobile both in salt loaded and control mice during SS (P < 0.05, P < 0.05). SummaryTaken together, these data indicate that neuronal and behavioral responsivity to an acute psychogenic stressor is potentiated by prior exposure to high salt intake. This synergistic effect was associated with activation of PVN VP neurons and depended, in part, on activity of V1 receptors in the amygdala. Findings provide novel insight into neural mechanisms whereby prior exposure to a homeostatic stressor such as osmotic dehydration by excessive salt intake increases responsivity to a perceived stress. These experiments show that high dietary salt can influence stress responsivity and raise the possibility that excessive salt intake could be a contributing factor in the development of stress-related psychiatric disorders.

Dysfunction of Serotonergic and Dopaminergic Neuronal Systems in the Antidepressant-Resistant Impairment of Social Behaviors Induced by Social Defeat Stress Exposure as Juveniles

BackgroundExtensive studies have been performed on the role of monoaminergic neuronal systems in rodents exposed to social defeat stress as adults. In the present study, we investigated the role of monoaminergic neuronal systems in the impairment of social behaviors induced by social defeat stress exposure as juveniles.MethodsJuvenile, male C57BL/6J mice were exposed to social defeat stress for 10 consecutive days. From 1 day after the last stress exposure, desipramine, sertraline, and aripiprazole were administered for 15 days. Social behaviors were assessed at 1 and 15 days after the last stress exposure. Monoamine turnover was determined in specific regions of the brain in the mice exposed to the stress.ResultsStress exposure as juveniles induced the impairment of social behaviors in adolescent mice. In mice that showed impairment of social behaviors, turnover of serotonin and dopamine, but not noradrenaline, was decreased in specific brain regions. Acute and repeated administration of desipramine, sertraline, and aripiprazole failed to attenuate the impairment of social behaviors, whereas repeated administration of a combination of sertraline and aripiprazole showed additive attenuating effects.ConclusionsThese findings suggest that social defeat stress exposure as juveniles induces the treatment-resistant impairment of social behaviors in adolescents through dysfunction in the serotonergic and dopaminergic neuronal systems. The combination of sertraline and aripiprazole may be used as a new treatment strategy for treatment-resistant stress-related psychiatric disorders in adolescents with adverse juvenile experiences.

Sexual dimorphism in the neural impact of stress and alcohol.

Alcohol use disorder is a widespread mental illness characterized by periods of abstinence followed by recidivism, and stress is the primary trigger of relapse. Despite the higher prevalence of alcohol use disorder in males, the relationship between stress and behavioral features of relapse, such as craving, is stronger in females. Given the greater susceptibility of females to stress-related psychiatric disorders, understanding sexual dimorphism in the relationship between stress and alcohol use is essential to identifying better treatments for both male and female alcoholics. This review addresses sex differences in the impact of stressors on alcohol drinking and seeking in rodents and humans. As these behavioral differences in alcohol use and relapse originate from sexual dimorphism in neuronal function, the impact of stressors and alcohol, and their interaction, on molecular adaptations and neural activity in males and females will also be discussed. Together, the data reviewed herein, arising from a symposium titled "Sex matters in stress-alcohol interactions" presented at the Fourth Volterra Conference on Stress and Alcohol, will highlight the importance of identifying sex differences to improve treatments for comorbid stress and alcohol use disorder in both sexes.

Behavioural and neural sequelae of stressor exposure are not modulated by controllability in females.

The degree of behavioural control that an organism has over a stressor is a potent modulator of the stressor's impact; controllable stressors produce none of the neurochemical and behavioural sequelae that occur if the stressor is uncontrollable. Research demonstrating the importance of control and the neural mechanisms responsible has been conducted almost entirely with male rats. It is unknown if behavioural control is stress blunting in females, and whether or not a similar resilience circuitry is engaged. Female rats were exposed to controllable, yoked uncontrollable or no tailshock. In separate experiments, behavioural (juvenile social exploration, fear and shuttle box escape) and neurochemical (activation of dorsal raphe serotonin and dorsal raphe-projecting prelimbic neurons) outcomes, which are sensitive to the dimension of control in males, were assessed. Despite successful acquisition of the controlling response, behavioural control did not mitigate dorsal raphe serotonergic activation and behavioural outcomes induced by tailshock, as it does in males. Moreover, behavioural control failed to selectively engage prelimbic cells that project to the dorsal raphe as in males. Pharmacological activation of the prelimbic cortex restored the stress-buffering effects of control. Collectively, the data demonstrate stressor controllability phenomena are absent in females and that the protective prelimbic circuitry is present but not engaged. Reduced benefit from coping responses may represent a novel approach for understanding differential sex prevalence in stress-related psychiatric disorders.

Activity in the Ventral Medial Prefrontal Cortex Is Necessary for the Therapeutic Effects of Extinction in Rats.

Poor response and high relapse rates remain problematic in the treatment of stress-related psychiatric disorders such as depression and post-traumatic stress disorder. Although mechanisms of pharmacotherapies are intensely studied, little is known about mechanisms of behavioral therapy that could inform improved treatments. We have previously demonstrated the therapeutic effects of extinction learning as a behavioral intervention modeling exposure therapy in rats. In the present study, we tested the hypothesis that activity in the ventral medial prefrontal cortex (vmPFC) during extinction is necessary for its therapeutic effects. The inhibitory Gi-coupled designer receptor exclusively activated by designer drug CaMKIIα-hM4Di was expressed in vmPFC before administering chronic unpredictable stress (CUS). vmPFC projection neurons were then inhibited during extinction treatment by administering clozapine-N-oxide. Coping behavior and cognitive flexibility were assessed 24 h later on the shock-probe defensive burying test and attentional set-shifting test, respectively. Replicating previous results, extinction reversed the CUS-induced deficits in coping behavior and cognitive flexibility. Inhibiting vmPFC during extinction blocked these therapeutic effects. Further, increasing vmPFC activity with the excitatory Gq-coupled designer receptor exclusively activated by designer drug hM3Dq 24 h before testing was sufficient to reverse the CUS-induced deficits. CUS reduced mPFC responsivity, assessed by measuring afferent-evoked field potentials in the mPFC, and this reduction was reversed by extinction treatment 24 h before testing. These results demonstrate the necessity of vmPFC activity in the therapeutic effects of extinction as a model of exposure therapy, and suggest that increased vmPFC activity induced by extinction is sufficient to produce lasting plastic changes that underlie its beneficial effects.SIGNIFICANCE STATEMENT Stress-related psychiatric disorders remain poorly treated. Psychotherapies can be effective, but their mechanisms remain unknown, hindering progress toward improved treatment. We used a rat model of behavioral therapy to identify potential targets for enhancing treatment. Fear extinction as a therapeutic behavioral intervention reversed stress-induced cognitive dysfunction and passive coping in rats, modeling components of stress-related psychiatric disease. Extinction also reversed stress-induced attenuation of mPFC responsivity. The therapeutic effects were prevented by blocking activity of glutamatergic neurons in the mPFC during extinction, and were mimicked by inducing activity in lieu of extinction. Thus, activity and plasticity in the mPFC underlie the beneficial effects of extinction on cognitive flexibility and coping behavior compromised by stress, and could be targets to enhance behavioral therapy.

Acupuncture on the Stress-Related Drug Relapse to Seeking.

Drug addiction is a chronic relapsing disease, which causes serious social and economic problems. The most important trial for the successful treatment of drug addiction is to prevent the high rate of relapse to drug-seeking behaviors. Opponent process as a motivational theory with excessive drug seeking in the negative reinforcement of drug dependence reflects both loss of brain reward system and recruitment of brain stress system. The negative emotional state produced by brain stress system during drug withdrawal might contribute to the intense drug craving and drive drug-seeking behaviors via negative reinforcement mechanisms. Decrease in dopamine neurotransmission in the nucleus accumbens and recruitment of corticotropin-releasing factor in the extended amygdala are hypothesized to be implicated in mediating this motivated behavior. Also, a brain stress response system is hypothesized to increase drug craving and contribute to relapse to drug-seeking behavior during the preoccupation and anticipation stage of dependence caused by the exposure to stress characterized as the nonspecific responses to any demands on the body. Acupuncture has proven to be effective for reducing drug addiction and stress-related psychiatric disorders, such as anxiety and depression. Furthermore, acupuncture has been shown to correct reversible brain malfunctions by regulating drug addiction and stress-related neurotransmitters. Accordingly, it seems reasonable to propose that acupuncture attenuates relapse to drug-seeking behavior through inhibition of stress response. In this review, a brief description of stress in relapse to drug-seeking behavior and the effects of acupuncture were presented.