Chronic adolescent stress alters GR-FKBP5 interactions in the hippocampus of adult female rats.

Chronic stress exposure during development can have lasting behavioral consequences that differ in males and females. More specifically, increased depressive behaviors in females, but not males, are observed in both humans and rodent models of chronic stress. Despite these known stress-induced outcomes, the molecular consequences of chronic adolescent stress in the adult brain are less clear. The stress hormone corticosterone activates the glucocorticoid receptor, and activity of the receptor is regulated through interactions with co-chaperones-such as the immunophilin FK506 binding proteins 5 (FKBP5). Previously, it has been reported that the adult stress response is modified by a history of chronic stress; therefore, the current study assessed the impact of chronic adolescent stress on the interactions of the glucocorticoid receptor (GR) with its regulatory co-chaperone FKBP5 in response to acute stress in adulthood. Although protein presence for FKBP5 did not differ by group, assessment of GR-FKBP5 interactions demonstrated that adult females with a history of chronic adolescent stress had elevated GR-FKBP5 interactions in the hippocampus following an acute stress challenge which could potentially contribute to a reduced translocation pattern given previous literature describing the impact of FKBP5 on GR activity. Interestingly, the altered co-chaperone interactions of the GR in the stressed female hippocampus were not coupled to an observable difference in transcription of GR-regulated genes. Together, these studies show that chronic adolescent stress causes lasting changes to co-chaperone interactions with the glucocorticoid receptor following stress exposure in adulthood and highlight the potential role that FKBP5 plays in these modifications. Understanding the long-term implications of adolescent stress exposure will provide a mechanistic framework to guide the development of interventions for adult disorders related to early life stress exposures.

HIV status affects PTSD symptom severity, psychophysiology, and heart rate variability in women with low but not high exposure to childhood maltreatment.

Objective: People living with HIV (PLWH) experience high rates of childhood trauma exposure, which is a significant risk factor for the development of posttraumatic stress disorder (PTSD). Because Black Americans living in urban environments are exposed to high levels of trauma, suffer from chronic PTSD, and are at increased risk for HIV infection, it is important to understand how HIV status interacts with childhood maltreatment to influence PTSD symptom severity and underlying psychophysiology. Methods: The current cross-sectional study assessed whether HIV status interacts with childhood maltreatment to influence PTSD symptom severity and heart rate variability during a dark-enhanced startle (DES) task in 88 Black women with (n=30) and without HIV (n=58). Results: HIV was associated with greater PTSD symptom severity only in women with low levels of childhood maltreatment (p=.024). Startle potentiation during DES was highest in women living without HIV and with high childhood maltreatment (p=.018). In women who had experienced low levels of childhood maltreatment, respiratory sinus arrhythmia (RSA) was lower during the dark phase of DES in women living without HIV than women living with HIV (WLWH), (p=.046). RSA during the light phase of DES was lower in WLWH than in women living without HIV (p=.042). Conclusion: In the current sample of Black women, HIV status was associated with PTSD symptom severity in a manner dependent on level of childhood maltreatment, suggesting that HIV status may be an important factor to consider for behavioral and pharmacological treatment strategies for PTSD. Additionally, HIV status is associated with lower percent potentiation to darkness and lower RSA during the light phase of DES, suggesting physiological mechanisms by which HIV may contribute to PTSD symptoms in individuals exposed to low levels of childhood maltreatment.

Associations between perinatal risk and physical health in pre-adolescence in the Adolescent Brain Cognitive Development (ABCD) Study®: the unexpected relationship with sleep disruption.

BACKGROUND: To investigate relationships among different physical health problems in a large, sociodemographically diverse sample of 9-to-10-year-old children and determine the extent to which perinatal health factors are associated with childhood physical health problems. METHODS: A cross-sectional study was conducted utilizing the Adolescent Brain Cognitive Development℠ (ABCD) Study (n = 7613, ages 9-to-10-years-old) to determine the associations among multiple physical health factors (e.g., prenatal complications, current physical health problems). Logistic regression models controlling for age, sex, pubertal development, household income, caregiver education, race, and ethnicity evaluated relationships between perinatal factors and childhood physical health problems. RESULTS: There were significant associations between perinatal and current physical health measures. Specifically, those who had experienced perinatal complications were more likely to have medical problems by 9-to-10 years old. Importantly, sleep disturbance co-occurred with several physical health problems across domains and developmental periods. CONCLUSION: Several perinatal health factors were associated with childhood health outcomes, highlighting the importance of understanding and potentially improving physical health in youth. Understanding the clustering of physical health problems in youth is essential to better identify which physical health problems may share underlying mechanisms. IMPACT: Using a multivariable approach, we investigated the associations between various perinatal and current health problems amongst youth. Our study highlights current health problems, such as sleep problems at 9-to-10 years old, that are associated with a cluster of factors occurring across development (e.g., low birth weight, prenatal substance exposure, pregnancy complications, current weight status, lifetime head injury). Perinatal health problems are at large, non-modifiable (in this retrospective context), however, by identifying which are associated with current health problems, we can identify potential targets for intervention and prevention efforts.

Post-traumatic stress disorder symptomatology is associated with insomnia among women engaged in opioid use disorder treatment with buprenorphine.

This study aimed to explore the association between the degree of PTSD symptomatology and severity of insomnia symptoms in a clinical sample of women receiving buprenorphine for OUD. PTSD symptomatology was assessed via the PCL-5, and insomnia symptoms were determined via the Insomnia Severity Index. Analyses indicated that more participants experiencing clinically significant PTSD symptomatology also reported insomnia symptoms than their counterparts. Future work should investigate how holistic care (e.g., trauma-informed approaches) that addresses the overlap between trauma and sleep disturbance could inform gender-specific OUD treatment strategies in the overdose crisis.

Glucocorticoid Receptor Function and Cognitive Performance in Women With HIV.

OBJECTIVE: Alterations in glucocorticoid receptor (GCR) function may be a risk factor for cognitive complications among older people with human immunodeficiency virus (HIV). We evaluated whether HIV serostatus and age modify the GCR function-cognition association among women. METHODS: Eighty women with HIV ( n = 40, <40 years of age [younger]; n = 40, >50 years of age [older]) and 80 HIV-uninfected women ( n = 40 older, n = 40 younger) enrolled in the Women's Interagency HIV Study completed a comprehensive neuropsychological test battery. Peripheral blood mononuclear cells collected concurrent with neuropsychological testing were assessed for GCR function. Multivariable linear regression analyses were conducted to examine whether a) HIV serostatus and age were associated with GCR function, and b) GCR function-cognition associations are moderated by HIV serostatus and age adjusting for relevant covariates. RESULTS: Among older women, higher baseline FKBP5 expression level was associated with lower attention/working memory performance among women with HIV ( B = 6.4, standard error = 1.7, p = .0003) but not in women without HIV infection ( B = -1.7, standard error = 1.9, p = .37). There were no significant HIV serostatus by age interactions on dexamethasone (DEX)-stimulated expression of the genes regulated by the GCR or lipopolysaccharide-stimulated tumor necrosis factor α levels (with or without DEX stimulation; p values > .13). HIV serostatus was associated with GC target genes PER1 ( p = .006) and DUSP1 ( p = .02), but not TSC22D3 ( p = .32), after DEX stimulation. CONCLUSIONS: Collectively, these data suggest that HIV serostatus and age may modify the influence of the GCR, such that the receptor is likely engaged to a similar extent, but the downstream influence of the receptor is altered, potentially through epigenetic modification of target genes.

Neuroendocrine drivers of risk and resilience: The influence of metabolism & mitochondria.

The manifestation of risk versus resilience has been considered from varying perspectives including genetics, epigenetics, early life experiences, and type and intensity of the challenge with which the organism is faced. Although all of these factors are central to determining risk and resilience, the current review focuses on what may be a final common pathway: metabolism. When an organism is faced with a perturbation to the environment, whether internal or external, appropriate energy allocation is essential to resolving the divergence from equilibrium. This review examines the potential role of metabolism in the manifestation of stress-induced neural compromise. In addition, this review details the current state of knowledge on neuroendocrine factors which are poised to set the tone of the metabolic response to a systemic challenge. The goal is to provide an essential framework for understanding stress in a metabolic context and appreciation for key neuroendocrine signals.

Traumatic stress history interacts with sex and chronic peripheral inflammation to alter mitochondrial function of synaptosomes.

BACKGROUND: Repeated exposures to chronic stress can lead to long lasting negative behavioral and metabolic outcomes. Here, we aim to determine the impact of chronic stress and chronic low-level inflammation on behavior and synaptosomal metabolism. METHODS: Male (n = 31) and female (n = 32) C57Bl/6 mice underwent chronic repeated predation stress or daily handling for two rounds of 15 consecutive days of exposure during the adolescent and early adult timeframes. Subsequently, mice were exposed to repeated lipopolysaccharide (LPS; 7.5 × 105 EU/kg) or saline injections every third day for eight weeks. Exploratory and social behaviors were assessed in the open field and social interaction tests prior to examination of learning and memory with the Barnes Maze. Mitochondrial function and morphology were assessed in synaptosomes post-mortem using the Cell Mito Stress test and Seahorse XFe24 analyzer, TEM, and western analysis, respectively. In addition, expression of TNF-α, IL-1ß, and ROMO1 were examined in the hippocampus and prefrontal cortex with Taqman qPCR. Circulating pro- and anti-inflammatory cytokines in the periphery were assessed using the MSD V-plex Proinflammatory Panel 1 following the first and last LPS injection as well as at the time of tissue collection. Circulating ROMO1 was assessed in terminal samples via ELISA. RESULTS: Exposure to repeated predatory stress increased time spent in the corners of the open field, suggestive of anxiety-like behavior, in both males and females. There were no significant group differences in the social interaction test and minimal effects were evident in the Barnes maze. A history of chronic stress interacted with chronic LPS in male mice to lead to a deficit in synaptosomal respiration. Female mice were more sensitive to both chronic stress and chronic LPS such that either a history of chronic stress or chronic LPS exposure was sufficient to disrupt synaptosomal respiration in females. Both stress and chronic LPS were sufficient to increase inflammation and reactive oxygen in males centrally and peripherally. Females had increased markers of peripheral inflammation following acute LPS but no evidence of peripheral or central increases in inflammatory factors or reactive oxygen following chronic exposures. CONCLUSION: Collectively, these data suggest that while metrics of inflammation and reactive oxygen are disrupted in males following chronic stress and chronic LPS, only the combined condition is sufficient to alter synaptosomal respiration. Conversely, although evidence of chronic inflammation or chronic elevation in reactive oxygen is absent, females demonstrate profound shifts in synaptosomal mitochondrial function with either a history of chronic stress or a history of chronic inflammation. These data highlight that different mechanisms are likely in play between the sexes and that sex differences in neural outcomes may be precipitated by sex-specific effects of life experiences on mitochondrial function in the synapse.

Progesterone Attenuates Stress-Induced NLRP3 Inflammasome Activation and Enhances Autophagy following Ischemic Brain Injury.

NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome inhibition and autophagy induction attenuate inflammation and improve outcome in rodent models of cerebral ischemia. However, the impact of chronic stress on NLRP3 inflammasome and autophagic response to ischemia remains unknown. Progesterone (PROG), a neuroprotective steroid, shows promise in reducing excessive inflammation associated with poor outcome in ischemic brain injury patients with comorbid conditions, including elevated stress. Stress primes microglia, mainly by the release of alarmins such as high-mobility group box-1 (HMGB1). HMGB1 activates the NLRP3 inflammasome, resulting in pro-inflammatory interleukin (IL)-1ß production. In experiment 1, adult male Sprague-Dawley rats were exposed to social defeat stress for 8 days and then subjected to global ischemia by the 4-vessel occlusion model, a clinically relevant brain injury associated with cardiac arrest. PROG was administered 2 and 6 h after occlusion and then daily for 7 days. Animals were killed at 7 or 14 days post-ischemia. Here, we show that stress and global ischemia exert a synergistic effect in HMGB1 release, resulting in exacerbation of NLRP3 inflammasome activation and autophagy impairment in the hippocampus of ischemic animals. In experiment 2, an in vitro inflammasome assay, primary microglia isolated from neonatal brain tissue, were primed with lipopolysaccharide (LPS) and stimulated with adenosine triphosphate (ATP), displaying impaired autophagy and increased IL-1ß production. In experiment 3, hippocampal microglia isolated from stressed and unstressed animals, were stimulated ex vivo with LPS, exhibiting similar changes than primary microglia. Treatment with PROG reduced HMGB1 release and NLRP3 inflammasome activation, and enhanced autophagy in stressed and unstressed ischemic animals. Pre-treatment with an autophagy inhibitor blocked Progesterone's (PROG's) beneficial effects in microglia. Our data suggest that modulation of microglial priming is one of the molecular mechanisms by which PROG ameliorates ischemic brain injury under stressful conditions.

Sex modifies the consequences of extended fructose consumption on liver health, motor function, and physiological damage in rats.

Sex differences are evident in the presentation of metabolic symptoms. A shift of sex hormones that signal the onset of puberty combined with a poor diet consumed in adolescence is likely to have sex-specific, long-term impacts on adult physiology. Here, we expanded on existing literature to elucidate the sex-specific mechanisms driving physiological deficits following high fructose consumption. Male and female Wistar rats were fed a high-fructose (55%) diet beginning immediately postweaning for 10 wk. Female rats fed the high-fructose diet displayed elevated weight gain and extensive liver pathology consistent with markers of nonalcoholic fatty liver disease (NAFLD). Male rats fed the high-fructose diet exhibited increased circulating glucose along with moderate hepatic steatosis. Levels of cytokines and gene expression of inflammatory targets were not altered by fructose consumption in either sex. However, circulating levels of markers for liver health, including alanine transaminase and uric acid, and markers for epithelial cell death were altered by fructose consumption. From the alterations in these markers for liver health, along with elevated circulating triglycerides, it was evident that liver health had deteriorated significantly and that a number of factors were at play. Both adult fructose-fed male and female rats displayed motor deficits that correlated with aberrant structural changes at the neuromuscular junction; however, these deficits were exacerbated in males. These data indicate that consumption of a high-fructose diet beginning in adolescence leads to adult pathology that is modified by sex. Identification of these sex-specific changes has implications for treatment of clinical presentation of metabolic syndrome and related disorders.

Chronic adolescent stress sex-specifically alters central and peripheral neuro-immune reactivity in rats.

Adversity during development is a reliable predictor of psychiatric disorders such as depression and anxiety which are increasingly recognized to have an immune component. We have previously demonstrated that chronic adolescent stress (CAS) in rats leads to depressive-like behavior in adulthood along with long-lasting changes to the hypothalamic-pituitary-adrenal axis and pro-inflammatory cytokine induction in the hippocampus. However, the mechanisms by which CAS promotes hippocampal inflammation are not yet defined. Here we tested the hypothesis that a history of CAS exaggerates induction of the pro-inflammatory NFκB pathway in the adult rat hippocampus without compromising the peripheral immune response. We also assessed potential sex differences because it is unclear whether females, who are twice as likely to suffer from mood disorders as males, are disproportionally affected by stress-primed inflammation. Male and female adolescent rats underwent a CAS paradigm or received no stress. Six weeks following the last stressor, all rats received a single systemic injection of either lipopolysaccharide or vehicle to unmask possible immune-priming effects of CAS. An NFκB signaling PCR array demonstrated that CAS exaggerated the expression of NFκB-related genes in the hippocampus of both males and females. Interestingly, targeted qPCR demonstrated that CAS potentiated the induction of hippocampal IL1B and REL mRNA in female rats only, suggesting that some immune effects of CAS are indeed sex-specific. In contrast to the hippocampal findings, indices of peripheral inflammation such as NFκB activity in the spleen, plasma IL-1ß, IL-6, TNF-α, and corticosterone were not impacted by CAS in female rats. Despite showing no pro-inflammatory changes to hippocampal mRNA, male CAS rats displayed lower plasma corticosterone response to LPS at 2 h after injection followed by an exaggerated plasma IL-1ß response at 4 h. This potentially blunted corticosterone response coupled with excessive innate immune signaling in the periphery is consistent with possible glucocorticoid resistance in males. In contrast, the effects of CAS manifested as excessive hippocampal immune reactivity in females. We conclude that while a history of exposure to chronic adolescent stress enhances adult immune reactivity in both males and females, the mechanism and manifestation of such alterations are sex-specific.

Sex Differences in Neurocognitive Function in Adults with HIV: Patterns, Predictors, and Mechanisms.

PURPOSE OF REVIEW: Sex differences in cognitive function are well documented yet few studies had adequate numbers of women and men living with HIV (WLWH; MLWH) to identify sex differences in neurocognitive impairment (NCI) and the factors contributing to NCI. Here, we review evidence that WLWH may be at greater risk for NCI. RECENT FINDINGS: We conducted a systematic review of recent studies of NCI in WLWH versus MLWH. A power analysis showed that few HIV studies have sufficient power to address male/female differences in NCI but studies with adequate power find evidence of greater NCI in WLWH, particularly in the domains of memory, speed of information processing, and motor function. Sex is an important determinant of NCI in HIV, and may relate to male/female differences in cognitive reserve, comorbidities (mental health and substance use disorders), and biological factors (e.g., inflammation, hormonal, genetic).

Cumulative Burden of Depression and All-Cause Mortality in Women Living With Human Immunodeficiency Virus.

Background: Research linking depression to mortality among people living with human immunodeficiency virus (PLWH) has largely focused on binary "always vs never" characterizations of depression. However, depression is chronic and is likely to have cumulative effects on mortality over time. Quantifying depression as a cumulative exposure may provide a better indication of the clinical benefit of enhanced depression treatment protocols delivered in HIV care settings. Methods: Women living with HIV (WLWH), naive to antiretroviral therapy, from the Women's Interagency HIV Study were followed from their first visit in or after 1998 for up to 10 semiannual visits (5 years). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. An area-under-the-curve approach was used to translate CES-D scores into a time-updated measure of cumulative days with depression (CDWD). We estimated the effect of CDWD on all-cause mortality using marginal structural Cox proportional hazards models. Results: Overall, 818 women contributed 3292 woman-years over a median of 4.8 years of follow-up, during which the median (interquartile range) CDWD was 366 (97-853). Ninety-four women died during follow-up (2.9 deaths/100 woman-years). A dose-response relationship was observed between CDWD and mortality. Each additional 365 days spent with depression increased mortality risk by 72% (hazard ratio, 1.72; 95% confidence interval, 1.34-2.20). Conclusions: In this sample of WLWH, increased CDWD elevated mortality rates in a dose-response fashion. More frequent monitoring and enhanced depression treatment protocols designed to reduce CDWD may interrupt the accumulation of mortality risk among WLWH.

Checks and balances: The glucocorticoid receptor and NFĸB in good times and bad.

Mutual regulation and balance between the endocrine and immune systems facilitate an organism's stress response and are impaired following chronic stress or prolonged immune activation. Concurrent alterations in stress physiology and immunity are increasingly recognized as contributing factors to several stress-linked neuropsychiatric disorders including depression, anxiety, and post-traumatic stress disorder. Accumulating evidence suggests that impaired balance and crosstalk between the glucocorticoid receptor (GR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) - effectors of the stress and immune axes, respectively - may play a key role in mediating the harmful effects of chronic stress on mood and behavior. Here, we first review the molecular mechanisms of GR and NFκB interactions in health, then describe potential shifts in the GR-NFκB dynamics in chronic stress conditions within the context of brain circuitry relevant to neuropsychiatric diseases. Furthermore, we discuss developmental influences and sex differences in the regulation of these two transcription factors.

Sex differences in the neuro-immune consequences of stress: Focus on depression and anxiety.

Women appear to be more vulnerable to the depressogenic effects of inflammation than men. Chronic stress, one of the most pertinent risk factors of depression and anxiety, is known to induce behavioral and affective-like deficits via neuroimmune alterations including activation of the brain's immune cells, pro-inflammatory cytokine expression, and subsequent changes in neurotransmission and synaptic plasticity within stress-related neural circuitry. Despite well-established sexual dimorphisms in the stress response, immunity, and prevalence of stress-linked psychiatric illnesses, much of current research investigating the neuroimmune impact of stress remains exclusively focused on male subjects. We summarize and evaluate here the available data regarding sex differences in the neuro-immune consequences of stress, and some of the physiological factors contributing to these differences. Furthermore, we discuss the extent to which sex differences in stress-related neuroinflammation can account for the overall female bias in stress-linked psychiatric disorders including major depressive disorder and anxiety disorders. The currently available evidence from rodent studies does not unequivocally support the peripheral inflammatory changes seen in women following stress. Replication of many recent findings in stress-related neuroinflammation in female subjects is necessary in order to build a framework in which we can assess the extent to which sex differences in stress-related inflammation contribute to the overall female bias in stress-related affective disorders.

Stress primes microglial polarization after global ischemia: Therapeutic potential of progesterone.

Despite the fact that stress is associated with increased risk of stroke and worsened outcome, most preclinical studies have ignored this comorbid factor, especially in the context of testing neuroprotective treatments. Preclinical research suggests that stress primes microglia, resulting in an enhanced reactivity to a subsequent insult and potentially increasing vulnerability to stroke. Ischemia-induced activated microglia can be polarized into a harmful phenotype, M1, which produces pro-inflammatory cytokines, or a protective phenotype, M2, which releases anti-inflammatory cytokines and neurotrophic factors. Selective modulation of microglial polarization by inhibiting M1 or stimulating M2 may be a potential therapeutic strategy for treating cerebral ischemia. Our laboratory and others have shown progesterone to be neuroprotective against ischemic stroke in rodents, but it is not known whether it will be as effective under a comorbid condition of chronic stress. Here we evaluated the neuroprotective effect of progesterone on the inflammatory response in the hippocampus after exposure to stress followed by global ischemia. We focused on the effects of microglial M1/M2 polarization and pro- and anti-inflammatory mediators in stressed ischemic animals. Male Sprague-Dawley rats were exposed to 8 consecutive days of social defeat stress and then subjected to global ischemia or sham surgery. The rats received intraperitoneal injections of progesterone (8mg/kg) or vehicle at 2h post-ischemia followed by subcutaneous injections at 6h and once every 24h post-injury for 7days. The animals were killed at 7 and 14days post-ischemia, and brains were removed and processed to assess outcome measures using histological, immunohistochemical and molecular biology techniques. Pre-ischemic stress (1) exacerbated neuronal loss and neurodegeneration as well as microglial activation in the selectively vulnerable CA1 hippocampal region, (2) dysregulated microglial polarization, leading to upregulation of both M1 and M2 phenotype markers, (3) increased pro-inflammatory cytokine expression, and (4) reduced anti-inflammatory cytokine and neurotrophic factor expression in the ischemic hippocampus. Treatment with progesterone significantly attenuated stress-induced microglia priming by modulating polarized microglia and the inflammatory environment in the hippocampus, the area most vulnerable to ischemic injury. Our findings can be taken to suggest that progesterone holds potential as a candidate for clinical testing in ischemic stroke where high stress may be a contributing factor.

PTSD co-morbid with HIV: Separate but equal, or two parts of a whole?

Approximately 30 million people currently live with HIV worldwide and the incidence of stress-related disorders, such as post-traumatic stress disorder (PTSD), is elevated among people living with HIV as compared to those living without the virus. PTSD is a severely debilitating, stress-related psychiatric illness associated with trauma exposure. Patients with PTSD experience intrusive and fearful memories as well as flashbacks and nightmares of the traumatic event(s) for much of their lives, may avoid other people, and may be constantly on guard for new negative experiences. This review will delineate the information available to date regarding the comorbidity of PTSD and HIV and discuss the biological mechanisms which may contribute to the co-existence, and potential interaction of, these two disorders. Both HIV and PTSD are linked to altered neurobiology within areas of the brain involved in the startle response and altered function of the hypothalamic-pituitary-adrenal axis. Collectively, the data highlighted suggest that PTSD and HIV are more likely to actively interact than to simply co-exist within the same individual. Multi-faceted interactions between PTSD and HIV have the potential to alter response to treatment for either independent disorder. Therefore, it is of great importance to advance the understanding of the neurobiological substrates that are altered in comorbid PTSD and HIV such that the most efficacious treatments can be administered to improve both mental and physical health and reduce the spread of HIV.

Development of the HPA axis: where and when do sex differences manifest?

Sex differences in the response to stress contribute to sex differences in somatic, neurological, and psychiatric diseases. Despite a growing literature on the mechanisms that mediate sex differences in the stress response, the ontogeny of these differences has not been comprehensively reviewed. This review focuses on the development of the hypothalamic-pituitary-adrenal (HPA) axis, a key component of the body's response to stress, and examines the critical points of divergence during development between males and females. Insight gained from animal models and clinical studies are presented to fully illustrate the current state of knowledge regarding sex differences in response to stress over development. An appreciation for the developmental timelines of the components of the HPA axis will provide a foundation for future areas of study by highlighting both what is known and calling attention to areas in which sex differences in the development of the HPA axis have been understudied.

Microglial activation occurs in the absence of anxiety-like behavior following microembolic stroke in female, but not male, rats.

BACKGROUND: The incidence of depression and anxiety disorders is twice as high in women than men; however, females exhibit less neuronal damage following an equivalent ischemic event. Microembolic stroke increases anxiety- and depressive-like behaviors in male rats but the behavioral repercussions in females are unknown. FINDINGS: Given the relative neuronal protection from stroke in ovary-intact females, female rats exposed to microembolic stroke may be behaviorally protected as compared to males. The data presented demonstrate that anxiety-like behavior is increased in males despite a comparable increase in microglial activation following microembolic stroke in both males and females. CONCLUSIONS: These data suggest that males may be more behaviorally susceptible to the effects of microembolic stroke and further illustrate a dissociation between neuroinflammation and behavior in females.

Heartsick: psychiatric and inflammatory implications of cerebromicrovascular disease.

BACKGROUND: Cerebromicrovascular disease (CMVD) strikes 87% of the population older than 65 years and is linked to an increased risk of ischemic stroke, depression, cognitive impairment, and Alzheimer's disease. Despite the wealth of knowledge on the consequences to the body stemming from poor vascular health, little focus has been placed on the consequences to the brain. DESIGN: In this review, we present the preclinical and clinical evidence that supports the role of CMVD in behavioral dysfunction, argues for a clinical need for better recognition of the vascular depression phenotype, and calls for a more integrative translational approach to CMVD. RESULTS AND CONCLUSIONS: Although the concept of cerebrovascular-induced behavioral change has existed for over 100 years, the difficulty of diagnosis, the slow progression of CMVD, and the lack of causative data have led to an underestimation of the patient population and poor treatment strategies. Preclinical studies have focused on the use of microsphere embolic models and vascular inflammation models to assess the mechanisms of, and treatment options for, CMVD. Though preclinical models provide support for correlative data collected in the clinic, translational reciprocity has not been established. The lack of clinical appreciation for the role of cerebrovascular health in brain function may result in missed diagnoses and inadequate treatment of underlying cardiovascular disease. Enhanced recognition of symptoms and disease presentation will allow for earlier prevention, detection, and identification of novel targets for drug development and other intervention strategies.

Chronic corticosterone administration alters synaptic mitochondrial function within the hippocampus of C57Bl/6NTac mice.

Chronic activation of the hypothalamic-pituitary-adrenal axis increases circulating corticosterone levels, causing a host of downstream behavioral, molecular, and metabolic changes. Here, we assess the effects of chronic exogenous CORT administration on changes in behavior and mitochondrial respiration in hippocampal synaptosomes of male and female mice. Adult male (n = 15) and female (n = 17) C57Bl/6NTac mice were given 35ug/mL CORT or vehicle dissolved in their drinking water for 21 consecutive days. Chronic CORT increased piloerection in males only. Although volume of CORT-containing water consumed was similar between males and females, circulating plasma and fecal corticosterone levels were only elevated in CORT-exposed males. Behavioral effects of CORT were evident in the Y-maze such that CORT caused a decrease in direct revisits in both sexes. There was no observed presentation of anxiety-like behavior following chronic CORT administration. Functional hippocampal synaptosomes were analyzed for mitochondrial respiration using Agilent's Cell Mito Stress test. Chronic CORT caused a decrease in synaptic mitochondria basal respiration, maximal respiration, proton leak, and ATP production in both sexes. Despite only observing an effect of chronic CORT on corticosterone concentrations in fecal and blood samples of males, chronic CORT induced marked changes in hippocampal synaptic mitochondrial function of both sexes. These data highlight the importance of considering effects of stress hormone exposure on neural function even in the absence of measurable peripheral elevations in females.