Evaluating different models of maternal stress on stress-responsive systems in prepubertal mice.

Introduction: Maternal adversity during pregnancy influences neurodevelopment in human and model animal offspring. Adversity can result from stressors coming from many different directions ranging from environmental to nutritional and physiological to immune (e.g., infection). Most stressors result in fetal overexposure to glucocorticoids that have been directly linked to long- and short-term negative impacts on neurological health of offspring. Neuropsychiatric diseases postulated to have fetal origins are diverse and include such things cardiovascular disease, obesity, affective disorders, and metabolic and immune disorders. Methods: The experiments in the current study compare 3 stressors: prenatal exposure to dexamethasone (DEX), maternal high fat diet (HFD), and maternal caloric restriction (CR). Offspring of mothers with these treatments were examined prepubertally to evaluate stress responsiveness and stress-related behaviors in in male and female mice. Results: Prenatal exposure to synthetic glucocorticoid, DEX, resulted in decreased neonatal body weights, reduced social interaction behavior, and hypoactive stress response offspring exposed to maternal DEX. Maternal CR resulted in decreased body weights and social interaction behavior in males and females and increased anxiety-like behavior and acute stress response only in males. HFD resulted in altered body weight gain in both sex offspring with decreased anxiety-like behavior in a female-biased manner. Discussion: The idea that glucocorticoid responses to different stressors might serve as a common stimulus across stress paradigms is insufficient, given that different modes of prenatal stress produced differential effects. Opposite nutritional stressors produced similar outcomes for anxiety-like behavior in both sexes, social-like behavior in females, and a hyperactive adrenal stress response in males. One common theme among the three models of maternal stress (DEX, CR, and HFD) was consistent data showing their role in activating the maternal and fetal immune response. By tuning in on the more immediate immunological aspect on the developing fetus (e.g., hormones, cytokines), additional studies may tease out more direct outcomes of maternal stress in rodents and increase their translational value to human studies.

Glucocorticoid regulation of diurnal spine plasticity in the murine ventromedial prefrontal cortex.

The ventromedial prefrontal cortex (vmPFC) regulates fear acquisition, fear extinction, mood, and HPA axis function. Multiple brain regions exhibit time-of-day dependent variations in learning, long term potentiation (LTP), and dendritic morphology. Glucocorticoids have been implicated in the regulation of dendritic structure in the context of stress. Glucocorticoids are also known to regulate molecular clock entrainment via upregulation of Per1 transcription. In the present study, C57BL/6 N mice were sacrificed at three distinct times of day (ZT3, ZT12, and ZT16, lights off at ZT12) and Per1 mRNA expression was measured in the infralimbic and prelimbic vmPFC subregions using droplet digital (dd) PCR after recovering from adrenalectomy or sham surgery for 10 days. Sham mice showed Per1 rhythmicity in both infralimbic (IL) and prelimbic (PL) cortex, with peak expression occurring at ZT12. Adrenalectomized mice showed reductions in Per1 amplitude at ZT12 in both IL and PL, suggesting that the vmPFC molecular clock is entrained by diurnal glucocorticoid oscillations. Thy1-eGFP mice were used to visualize and quantify dendritic spine density on deep layer pyramidal dendrites at ZT 3, 12, and 16. Spine density in both PL and IL exhibited changes between the light (inactive) and dark (active) phases, with peak spine density observed at ZT16 and trough spine density observed at ZT3. These changes in spine density were restricted to changes in long thin and stubby type spines. To determine if changes in spine density is regulated by glucocorticoid oscillations, the 11ß-hydroxylase inhibitor metyrapone was administered 2 h prior to the onset of the active phase (ZT10) daily for 7 days. Metyrapone administration blocked both the diurnal peak of plasma corticosterone and peak spine densities in the IL and PL at ZT16. These results suggest that vmPFC molecular clock gene and dendritic spine diurnal rhythms depend on intact diurnal glucocorticoid oscillations.

Sex differences in autonomic responses to stress: implications for cardiometabolic physiology.

Chronic stress is a significant risk factor for negative health outcomes. Furthermore, imbalance of autonomic nervous system control leads to dysregulation of physiological responses to stress and contributes to the pathogenesis of cardiometabolic and psychiatric disorders. However, research on autonomic stress responses has historically focused on males, despite evidence that females are disproportionality affected by stress-related disorders. Accordingly, this mini-review focuses on the influence of biological sex on autonomic responses to stress in humans and rodent models. The reviewed literature points to sex differences in the consequences of chronic stress, including cardiovascular and metabolic disease. We also explore basic rodent studies of sex-specific autonomic responses to stress with a focus on sex hormones and hypothalamic-pituitary-adrenal axis regulation of cardiovascular and metabolic physiology. Ultimately, emerging evidence of sex differences in autonomic-endocrine integration highlights the importance of sex-specific studies to understand and treat cardiometabolic dysfunction.

Sex Differences in Acute Neuroendocrine Responses to Stressors in Rodents and Humans.

Sex differences in the neuroendocrine response to acute stress occur in both animals and humans. In rodents, stressors such as restraint and novelty induce a greater activation of the hypothalamic-pituitary-adrenal axis (HPA) in females compared to males. The nature of this difference arises from steroid actions during development (organizational effects) and adulthood (activational effects). Androgens decrease HPA stress responsivity to acute stress, while estradiol increases it. Androgenic down-regulation of HPA responsiveness is mediated by the binding of testosterone (T) and dihydrotestosterone (DHT) to the androgen receptor, as well as the binding of the DHT metabolite, 3ß-diol, to the ß form of the estrogen receptor (ERß). Estradiol binding to the α form of the estrogen receptor (ERα) increases HPA responsivity. Studies of human sex differences are relatively few and generally employ a psychosocial paradigm to measure stress-related HPA activation. Men consistently show greater HPA reactivity than women when being evaluated for achievement. Some studies have found greater reactivity in women when being evaluated for social performance. The pattern is inconsistent with rodent studies but may involve the differential nature of the stressors employed. Psychosocial stress is nonphysical and invokes a significant degree of top-down processing that is not easily comparable to the types of stressors employed in rodents. Gender identity may also be a factor based on recent work showing that it influences the neural processing of positive and negative emotional stimuli independent of genetic sex. Comparing different types of stressors and how they interact with gender identity and genetic sex will provide a better understanding of sex steroid influences on stress-related HPA reactivity.

The Effects of Chronic Variable Stress and Photoperiod Alteration on the Hypothalamic-Pituitary-Adrenal Axis Response and Behavior of Mice.

The hypothalamic-pituitary-adrenal (HPA) axis mediates the physiological response to stressors and also synchronizes different physiological systems to environmental cues. Changes in day length (i.e., photoperiod) as well as chronic exposure to stressors are known to impact the HPA axis activity regulating the levels of glucocorticoid hormones. Over-exposure to inappropriate levels of glucocorticoids has been implicated in increased disease risk. In the present study, we examined the impact of chronic stress, using a chronic variable stress (CVS) paradigm, in combination with changes in photoperiod on physiological and behavioral measures, as well as on the reactivity and regulation of the HPA axis, in male and female mice. Six weeks of CVS, regardless of the photoperiod condition, decreased the body weight and attenuated the HPA axis reactivity to an acute stressor in both sexes. The attenuated HPA axis reactivity observed in stressed animals was related to reduced Pro-opiomelanocortin (POMC) mRNA levels in the pituitary of females. The gene expression analyses of key regulators of the HPA axis also indicated a sex-dependent effect with opposite patterns in the pituitary and adrenal glands. CVS effects on behavior were limited and related to an anxiety-like phenotype in both sexes, regardless of photoperiod condition. Our findings highlight sex-specific differences in the HPA axis and also sex-dependent effects of CVS on physiological parameters.

Gut microbiota and metabolic marker alteration following dietary isoflavone-photoperiod interaction.

Introduction: The interaction between isoflavones and the gut microbiota has been highlighted as a potential regulator of obesity and diabetes. In this study, we examined the interaction between isoflavones and a shortened activity photoperiod on the gut microbiome. Methods: Male mice were exposed to a diet containing no isoflavones (NIF) or a regular diet (RD) containing the usual isoflavones level found in a standard vivarium chow. These groups were further divided into regular (12L:12D) or short active (16L:8D) photoperiod, which mimics seasonal changes observed at high latitudes. White adipose tissue and genes involved in lipid metabolism and adipogenesis processes were analysed. Bacterial genomic DNA was isolated from fecal boli, and 16S ribosomal RNA sequencing was performed. Results: NIF diet increased body weight and adipocyte size when compared to mice on RD. The lack of isoflavones and photoperiod alteration also caused dysregulation of lipoprotein lipase (Lpl), glucose transporter type 4 (Glut-4) and peroxisome proliferator-activated receptor gamma (Pparg) genes. Using 16S ribosomal RNA sequencing, we found that mice fed the NIF diet had a greater proportion of Firmicutes than Bacteroidetes when compared to animals on the RD. These alterations were accompanied by changes in the endocrine profile, with lower thyroid-stimulating hormone levels in the NIF group compared to the RD. Interestingly, the NIF group displayed increased locomotion as compared to the RD group. Conclusion: Together, these data show an interaction between the gut bacterial communities, photoperiod length and isoflavone compounds, which may be essential for understanding and improving metabolic health.

Sex Differences in Hemoglobin A1c Levels Related to the Comorbidity of Obesity and Depression.

Background: Obesity (OB) and major depressive disorder (MDD) are chronic conditions associated with disease burden, and their comorbidity appears more common among women. Mechanisms linking these conditions may involve inflammatory and metabolic pathways. The goal of this study was to evaluate the impact of MDD on relationships between OB and cardiometabolic function, and sex differences therein. Materials and Methods: Adult offspring from the New England Family Studies (NEFS) were assessed at ages 39-50, including anthropometry, cardiometabolic profile assays, and metabolic syndrome. Individuals were grouped by body mass index (BMI) and MDD status: healthy weight with (n = 50) or without MDD (n = 95) and obese with (n = 79) or without MDD (n = 131). The interaction of (recurrent) MDD and BMI on cardiometabolic markers was tested using quantile regression models. Results: Participants with MDD exhibited significantly higher hemoglobin A1c (HbA1c) than those without MDD (5.60% vs. 5.35%, p < 0.05). Women with comorbid recurrent MDD and OB had higher HbA1c levels compared to obese women without MDD (5.75% vs. 5.44%, p < 0.05); an interaction between MDD and BMI status was not observed among men. Conclusions: We demonstrated sex differences in the interaction between BMI and recurrent MDD status on a primary biomarker for diabetes risk, suggesting a common metabolic pathway predisposing women to these comorbid conditions. Further investigation is needed to identify mechanisms that may lead to more effective, sex-dependent screening and therapies.

Knockout of the circadian gene, Per2, disrupts corticosterone secretion and results in depressive-like behaviors and deficits in startle responses.

BACKGROUND: The Period Circadian Regulator 2 (Per2) gene is important for the modulation of circadian rhythms that influence biological processes. Circadian control of the hypothalamus-pituitary-adrenal (HPA) axis is critical for regulation of hormones involved in the stress response. Dysregulation of the HPA axis is associated with neuropsychiatric disorders. Therefore, it is important to understand how disruption of the circadian rhythm alters the HPA axis. One way to address this question is to delete a gene involved in regulating a central circadian gene such as Per2 in an animal model and to determine how this deletion may affect the HPA axis and behaviors that are altered when the HPA axis is dysregulated. To study this, corticosterone (CORT) levels were measured through the transition from light (inactive phase) to dark (active phase). Additionally, CORT levels as well as pituitary and adrenal mRNA expression were measured following a mild restraint stress. Mice were tested for depressive-like behaviors (forced swim test (FST)), acoustic startle response (ASR), and pre-pulse inhibition (PPI). RESULTS: The present results showed that Per2 knockout impacted CORT levels, mRNA expression, depressive-like behaviors, ASR and PPI. Unlike wild-type (WT) mice, Per2 knockout (Per2) mice showed no diurnal rise in CORT levels at the onset of the dark cycle. Per2-/- mice had enhanced CORT levels and adrenal melanocortin receptor 2 (Mc2R) mRNA expression following restraint. There were no changes in expression of any other pituitary or adrenal gene. In the FST, Per2-/- mice spent more time floating (less time struggling) than WT mice, suggesting increased depressive-like behaviors. Per2-/- mice had deficits in ASR and PPI startle responses compared to WT mice. CONCLUSIONS: In summary, these findings showed that disruption of the circadian system via Per2 gene deletion dysregulated the HPA stress axis and is subsequently correlated with increased depressive-like behaviors and deficits in startle response.

Androgens and Their Role in Regulating Sex Differences in the Hypothalamic/Pituitary/Adrenal Axis Stress Response and Stress-Related Behaviors.

Androgens play a pivotal role during development. These gonadal hormones and their receptors exert organizational actions that shape brain morphology in regions controlling the stress regulatory systems in a male-specific manner. Specifically, androgens drive sex differences in the hypothalamic/pituitary/adrenal (HPA) axis and corresponding hypothalamic neuropeptides. While studies have examined the role of estradiol and its receptors in sex differences in the HPA axis and associated behaviors, the role of androgens remains far less studied. Androgens are generally thought to modulate the HPA axis through the activation of androgen receptors (ARs). They can also impact the HPA axis through reduction to estrogenic metabolites that can bind estrogen receptors in the brain and periphery. Such regulation of the HPA axis stress response by androgens can often result in sex-biased risk factors for stress-related disorders, such as anxiety and depression. This review focuses on the biosynthesis pathways and molecular actions of androgens and their nuclear receptors. The impact of androgens on hypothalamic neuropeptide systems (corticotropin-releasing hormone, arginine vasopressin, oxytocin, dopamine, and serotonin) that control the stress response and stress-related disorders is discussed. Finally, this review discusses potential therapeutics involving androgens (androgen replacement therapies, selective AR modulator therapies) and ongoing clinical trials.

Roles for androgens in mediating the sex differences of neuroendocrine and behavioral stress responses.

Estradiol and testosterone are powerful steroid hormones that impact brain function in numerous ways. During development, these hormones can act to program the adult brain in a male or female direction. During adulthood, gonadal steroid hormones can activate or inhibit brain regions to modulate adult functions. Sex differences in behavioral and neuroendocrine (i.e., hypothalamic pituitary adrenal (HPA) axis) responses to stress arise as a result of these organizational and activational actions. The sex differences that are present in the HPA and behavioral responses to stress are particularly important considering their role in maintaining homeostasis. Furthermore, dysregulation of these systems can underlie the sex biases in risk for complex, stress-related diseases that are found in humans. Although many studies have explored the role of estrogen and estrogen receptors in mediating sex differences in stress-related behaviors and HPA function, much less consideration has been given to the role of androgens. While circulating androgens can act by binding and activating androgen receptors, they can also act by metabolism to estrogenic molecules to impact estrogen signaling in the brain and periphery. This review focuses on androgens as an important hormone for modulating the HPA axis and behaviors throughout life and for setting up sex differences in key stress regulatory systems that could impact risk for disease in adulthood. In particular, impacts of androgens on neuropeptide systems known to play key roles in HPA and behavioral responses to stress (corticotropin-releasing factor, vasopressin, and oxytocin) are discussed. A greater knowledge of androgen action in the brain is key to understanding the neurobiology of stress in both sexes.

Social isolation alters hypothalamic pituitary adrenal axis activity after chronic variable stress in male C57BL/6 mice.

The chronic variable stress (CVS) paradigm is frequently used to model the changes in hypothalamic pituitary adrenal (HPA) axis function characteristic of many stress-related diseases. However, male C57BL/6 mice are typically resistant to CVS's effects, making it difficult to determine how chronic stress exposure may alter acute HPA function and regulation in these mice. As social support in rodents can profoundly influence physiological and behavioral processes, including the HPA axis, we sought to characterize the effects of CVS exposure on basal and acute stress-induced HPA axis function in pair- and single-housed adult male mice. Despite all subjects exhibiting decreased body weight gain after six weeks of CVS, the corticosterone response to a novel, acute restraint stressor was enhanced by CVS exclusively in single-housed males. CVS also significantly increased arginine vasopressin (AVP) mRNA in the hypothalamic paraventricular nucleus (PVN) in single-housed males only. Moreover, in single-, but not pair-housed mice, CVS attenuated decreases in circulating OT found following acute restraint. Only the effect of CVS to elevate PVN corticotropin releasing hormone (CRH) mRNA levels after an acute stressor was restricted to pair-housed mice. Collectively, our findings suggest that social isolation reveals effects of CVS on the HPA axis in male C57BL/6 mice.

The Hypothalamic-Pituitary-Adrenal Axis: Development, Programming Actions of Hormones, and Maternal-Fetal Interactions.

The hypothalamic-pituitary-adrenal axis is a complex system of neuroendocrine pathways and feedback loops that function to maintain physiological homeostasis. Abnormal development of the hypothalamic-pituitary-adrenal (HPA) axis can further result in long-term alterations in neuropeptide and neurotransmitter synthesis in the central nervous system, as well as glucocorticoid hormone synthesis in the periphery. Together, these changes can potentially lead to a disruption in neuroendocrine, behavioral, autonomic, and metabolic functions in adulthood. In this review, we will discuss the regulation of the HPA axis and its development. We will also examine the maternal-fetal hypothalamic-pituitary-adrenal axis and disruption of the normal fetal environment which becomes a major risk factor for many neurodevelopmental pathologies in adulthood, such as major depressive disorder, anxiety, schizophrenia, and others.

Sex-Dependent Mechanisms of Glucocorticoid Regulation of the Mouse Hypothalamic Corticotropin-Releasing Hormone Gene.

To limit excessive glucocorticoid secretion following hypothalamic-pituitary-adrenal (HPA) axis stimulation, circulating glucocorticoids inhibit corticotropin-releasing hormone (CRH) expression in paraventricular nucleus (PVN) neurons. As HPA function differs between sexes and depends on circulating estradiol (E2) levels in females, we investigated sex/estrous stage-dependent glucocorticoid regulation of PVN Crh. Using NanoString nCounter technology, we first demonstrated that adrenalectomized (ADX'd) diestrous female (low E2), but not male or proestrous female (high E2), mice exhibited a robust decrease in PVN CRH mRNA following 2-day treatment with the glucocorticoid receptor (GR) agonist RU28362. Immunohistochemical analysis of PVN CRH neurons in Crh-IRES-Cre;Ai14 mice, where TdTomato fluorescence permanently tags CRH-expressing neurons, showed similarly abundant co-expression of GR-immunoreactivity in males, diestrous females, and proestrous females. However, we identified sex/estrous stage-related glucocorticoid regulation or expression of GR transcriptional coregulators. Out of 17 coregulator genes examined using nCounter multiplex analysis, mRNAs that were decreased by RU28362 in ADX'd mice in a sex/estrous stage-dependent fashion included: GR (males = diestrous females > proestrous females), signal transducer and activator of transcription 3 (STAT3) (males < diestrous = proestrous), and HDAC1 (males < diestrous > proestrous). Steroid receptor coactivator 3 (SRC-3), nuclear corepressor 1 (NCoR1), heterogeneous nuclear ribonucleoprotein U (hnrnpu), CREB binding protein (CBP) and CREB-regulated transcription coactivator 2 (CRTC2) mRNAs were lower in ADX'd diestrous and proestrous females versus males. Additionally, most PVN CRH neurons co-expressed methylated CpG binding protein 2 (MeCP2)-immunoreactivity in diestrous female and male Crh-IRES-Cre;Ai14 mice. Our findings collectively suggest that GR's sex-dependent regulation of PVN Crh may depend upon differences in the GR transcriptional machinery and an underlying influence of E2 levels in females.

Chronic variable stress alters hypothalamic-pituitary-adrenal axis function in the female mouse.

Chronic stress is often associated with a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which can greatly increase risk for a number of stress-related diseases, including neuropsychiatric disorders. Despite a striking sex-bias in the prevalence of many of these disorders, few preclinical studies have examined female subjects. Hence, the present study aimed to explore the effects of chronic stress on the basal and acute stress-induced activity of the HPA axis in the female C57BL/6 mouse. We used a chronic variable stress (CVS) paradigm in these studies, which successfully induces physiological and behavioral changes that are similar to those reported for some patients with mood disorders. Using this model, we found pronounced, time-dependent effects of chronic stress on the HPA axis. CVS-treated females exhibited adrenal hypertrophy, yet their pattern of glucocorticoid secretion in the morning resembled that of controls. CVS-treated and control females had similar morning basal corticosterone (CORT) levels, which were both significantly elevated following a restraint stressor. Although morning basal gene expression of the key HPA-controlling neuropeptides corticotropin releasing hormone (CRH), arginine vasopressin (AVP) and oxytocin (OT) was unaltered within the paraventricular nucleus (PVN) by CVS, CVS altered the PVN OT and AVP mRNA responses to acute restraint. In control females, acute stress decreased AVP, but not OT mRNA; whereas, in CVS females, it decreased OT, but not, AVP mRNA. Unlike the morning pattern of HPA activity, in the evening, CVS-treated females showed increased basal CORT with hypoactive responses of CORT and PVN c-Fos immunoreactivity to restraint stress. Furthermore, CVS elevated evening PVN CRH and OT mRNAs in the PVN, but it did not influence anxiety- or depressive-like behavior after a light/dark box or tail suspension test. Taken together, these findings indicate that CVS is an effective model for HPA axis dysregulation in the female mouse and may be relevant for stress-related diseases.

Androgens Drive Sex Biases in Hypothalamic Corticotropin-Releasing Hormone Gene Expression After Adrenalectomy of Mice.

Although prominent sex differences exist in the hypothalamic-pituitary-adrenal axis's response to stressors, few studies of its regulation in the hypothalamic paraventricular nucleus (PVN) have compared both male and female subjects. In this study, we sought to explore sex differences in the acute regulation of PVN neuropeptide expression following glucocorticoid (GC) removal and the underlying role of gonadal hormones. We first examined the effects of short-term adrenalectomy (ADX) on PVN Crh and arginine vasopressin (Avp) expression in mice using in situ hybridization. ADX increased PVN AVP mRNA levels in both sexes. In contrast, PVN CRH mRNA was increased by 2 days after ADX in males only. Both sexes showed increases in CRH mRNA after 4 days. To determine if gonadal hormones contributed to this sex bias, we examined adrenalectomized (ADX'd) and gonadectomized (GDX'd) mice with or without gonadal hormone replacement. Unlike the pattern in intact animals, 2 days following ADX/gonadectomy, CRH mRNA levels did not increase in either sex. When males were given DHT propionate, CRH mRNA levels increased in ADX'd/GDX'd males similar to those observed following ADX alone. To determine a potential mechanism, we examined the coexpression of androgen receptor (AR) immunoreactivity and CRH neurons. Abundant colocalization was found in the anteroventral bed nucleus of the stria terminalis but not the PVN. Thus, our findings reveal a sex difference in PVN Crh expression following the removal of GC-negative feedback that may depend on indirect AR actions in males.

Isoflavones Alter Hypothalamic-Pituitary-Adrenal Axis Response Following Photoperiod Alteration.

Photoperiod and diet are factors known to modulate the hypothalamic-pituitary-adrenal (HPA) axis. Specifically, shifts in photoperiod have been previously linked with affective and anxiety disorders. Furthermore, isoflavones have been shown to mediate behavioral outcome in response to the environment of the animal. Here, we investigated the effect of photoperiod alteration on the HPA axis and how the addition of isoflavones might modulate the response to stress. Male C57BL/6J mice were maintained on either a 12:12 or a 16:8 light-dark (LD) cycle for 10 days, and fed a diet of either standard rodent chow or an isoflavone free (IF) chow beginning 3 weeks prior to light alteration. Consistent with previous work, mice in the shorter active period (16:8 LD cycle) showed increased basal corticosterone (CORT) secretion. In the absence of isoflavones, this response was attenuated. Increases in mineralcorticoid (MR) and glucocorticoid (GR) receptor mRNA expression were seen in the pituitary following photoperiod alteration. However, animals fed the standard isoflavone rich chow showed increases in the ratio of MR:GR mRNA in the anterior bed nucleus of the stria terminalis following photoperiod alteration. Decreases in corticotrophin-releasing factor receptor 1 (CRFR1) mRNA expression were seen in animals fed the IF chow in the amygdala, prefrontal cortex and ventral hippocampus. These data suggest that alterations in CORT secretion following photoperiod alteration may be mediated through differences in CRFR1 gene expression or changes in MR:GR mRNA ratios. These findings provide insight into the potential mechanisms by which the HPA axis adapts to photoperiod and diet.

Sex related biases for attending to object color versus object position are reflected in reaction time and accuracy.

Processing of visual features related to objects and space relations occurs within separate cortical streams that interact with selective attention. Such separation has implications for cognitive development because the perception of 'what' and 'where' provide a neural foundation for the development of aspects of higher cognition. Thus, a small attentional bias in early development for attending to one aspect over the other might influence subsequent higher cognitive processing in tasks involving object recognition and space relations. We examined 134 men and women for evidence of an inherent sex-related bias for attending to basic perceptual features related to object discrimination versus object position. Each stimulus consisted of a circle located in one of 9 positions within a surrounding frame. Circles were one of three shades of blue or red. These stimuli were used in a match-to-sample paradigm where participants were required to match circles on the basis of color or spatial position. The first stimulus appeared in the center of the screen for 400 msec and the matching stimulus subsequently appeared for 400 msec oriented 5 degrees to the right or left of center. The same stimuli were used to test the perception of color and position, with order of testing counterbalanced across participants. Results showed significantly longer reaction times in females compared with males, with better accuracy to discriminate color when that color was tested before position. Males showed better accuracy when object position was tested before color discrimination. A second experiment employed the same procedure, but enhanced selective attention by adding an endogenous cue that predicted the right or left location for the appearance of the matching stimulus. This manipulation greatly attenuated the sex differences in reaction time and accuracy compared to Experiment 1, suggesting that the sex-related attentional biases are strongly coupled to bottom-up processing. Overall, the sex related attentional biases toward processing object characteristics versus object position location suggest a differential manifestation of biased competition between the weighted systems of dorsal and ventral stream processing. Results are discussed with how a developmental bias in the processing objects versus space relations may contribute to adult cognitive sex differences in humans and animals.

Sex differences in the hypothalamic-pituitary-adrenal axis' response to stress: an important role for gonadal hormones.

The hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrine network that controls hormonal responses to internal and external challenges in an organism's environment, exhibits strikingly sex-biased activity. In adult female rodents, acute HPA function following a stressor is markedly greater than it is in males, and this difference has largely been attributed to modulation by the gonadal hormones testosterone and estradiol. These gonadal hormones are produced by the hypothalamic-pituitary-gonadal (HPG) axis and have been shown to determine sex differences in adult HPA function after acute stress via their activational and organizational effects. Although these actions of gonadal hormones are well supported, the possibility that sex chromosomes similarly influence HPA activity is unexplored. Moreover, questions remain regarding sex differences in the activity of the HPA axis following chronic stress and the underlying contributions of gonadal hormones and sex chromosomes. The present review examines what is currently known about sex differences in the neuroendocrine response to stress, as well as outstanding questions regarding this sex bias. Although it primarily focuses on the rodent literature, a brief discussion of sex differences in the human HPA axis is also included.

Sex differences in major depression and comorbidity of cardiometabolic disorders: impact of prenatal stress and immune exposures.

Major depressive disorder topped ischemic heart disease as the number one cause of disability worldwide in 2012, and women have twice the risk of men. Further, the comorbidity of depression and cardiometabolic disorders will be one of the primary causes of disability worldwide by 2020, with women at twice the risk. Thus, understanding the sex-dependent comorbidities has public health consequences worldwide. We propose here that sex differences in MDD-cardiometabolic comorbidity originate, in part, from pathogenic processes initiated in fetal development that involve sex differences in shared pathophysiology between the brain, the vascular system, the CNS control of the heart and associated hormonal, immune, and metabolic physiology. Pathways implicate neurotrophic and angiogenic growth factors, gonadal hormone receptors, and neurotransmitters such as gamma amino butyric acid (GABA) on neuronal and vascular development of HPA axis regions, such as the paraventricular nucleus (PVN), in addition to blood pressure, in part through the renin-angiotensin system, and insulin and glucose metabolism. We show that the same prenatal exposures have consequences for sex differences across multiple organ systems that, in part, share common pathophysiology. Thus, we believe that applying a sex differences lens to understanding shared biologic substrates underlying these comorbidities will provide novel insights into the development of sex-dependent therapeutics. Further, taking a lifespan perspective beginning in fetal development provides the opportunity to target abnormalities early in the natural history of these disorders in a sex-dependent way.

Sex-Dependent Effects of Mild Blast-induced Traumatic Brain Injury on Corticotropin-releasing Factor Receptor Gene Expression: Potential Link to Anxiety-like Behaviors.

Traumatic brain injury (TBI) affects 1.7 million people in the United States every year, resulting in increased risk of death and disabilities. A significant portion of TBIs experienced by military personnel are induced by explosive blast devices. Active duty military personnel are especially vulnerable to mild blast-induced (mb)TBI and the associated long-term effects, such as anxiety disorders. Additionally, females are at an increased risk of being diagnosed with anxiety-related disorders. The mechanism by which mbTBI results in anxiety disorders in males and females is unknown. The sexually dimorphic corticotropin-releasing factor (CRF) is a brain signaling system linked to anxiety. CRF and its family of related peptides modulate anxiety-related behaviors by binding to CRF receptor subtypes 1 and 2 (CRFR1, CRFR2, respectively). These receptors are distributed throughout limbic structures that control behaviors related to emotion, memory, and arousal. Therefore, the aim of this study was to understand the link between mbTBI and anxiety by examining the impact of mbTBI on the CRFR system in male and female mice. mbTBI increased anxiety-like behaviors in both males and females (p < 0.05). In the present study, mbTBI did not alter CRFR1 gene expression in males or females. However, mbTBI disrupted CRFR2 gene expression in different limbic structures in males and females. In males, mbTBI increased baseline CRFR2 gene expression in the ventral hippocampus (p < 0.05) and decreased restraint-induced expression in the anterior bed nucleus of the stria terminalis (aBNST) and amygdala (p < 0.05). In females, mbTBI decreased restraint-induced CRFR2 gene expression in the dorsal hippocampus (p < 0.05). The inherent sex differences and the mbTBI-induced decrease in restraint-induced CRFR2 gene expression may contribute to anxiety-like behaviors. The results of the present study show that the response to mbTBI within the limbic structures modulates anxiety in a sex-dependent manner. The studies further suggest that CRFR2 may serve as a potential target to mitigate mbTBI effects.