Review

Sex differences in HPA axis responses to stress: a review

Testosterone is a powerful steroid hormone that can impact the brain and behavior in various ways, including regulating behavioral and neuroendocrine (hypothalamic-pituitary-adrenal (HPA) axis) stress responses. Early in life androgens can act to alter development of brain regions associated with stress regulation, which ultimately impacts the display of stress responses later in life. Adult circulating androgens can also influence the expression of distinct genes and proteins that regulate stress responses. These changes in the brain are hypothesized to underlie the potent effects of androgens in regulating behaviors related to stress and stress-induced activation of the HPA axis. Androgens can induce alterations in these functions through direct binding to the androgen receptor (AR) or following conversion to estrogens and subsequent binding to estrogen receptors including estrogen receptor alpha (ERα), beta (ERβ), and G protein-coupled estrogen receptor 1 (GPER1). In this review, we focus on the role of androgens in regulating behavioral and neuroendocrine stress responses at different stages of the lifespan and the sex hormone receptors involved in regulating these effects. We also review the specific brain regions and cell phenotypes upon which androgens are proposed to act to regulate stress responses with an emphasis on hypothalamic and extended amygdala subregions. This knowledge of androgen effects on these neural systems is critical for understanding how sex hormones regulate stress responses.

Endometriosis (EM) is a gynecological inflammatory disease often accompanied by stress, chronic pelvic pain (CPP), anxiety, and depression, leading to a diminished quality of life. This review aims to discuss the relationship between systemic and local inflammatory responses in the central nervous system (CNS), focusing on glial dysfunctions (astrocytes and microglia) as in critical brain regions involved in emotion, cognition, pain processing, anxiety, and depression. The review presents that EM is connected to increased levels of pro-inflammatory cytokines in the circulation. Additionally, chronic stress and CPP as stressors may contribute to the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, depleting the production of inflammatory mediators in the circulatory system and the brain. The systemic cytokines cause blood–brain barrier (BBB) breakdown, activate microglia in the brain, and lead to neuroinflammation. Furthermore, CPP may induce neuronal morphological alterations in critical regions through central sensitization and the activation of glial cells. The activation of glial cells, particularly the polarization of microglia, leads to the activation of the NLRP3 inflammasome and the overproduction of inflammatory cytokines. These inflammatory cytokines interact with the signaling pathways involved in neural plasticity. Additionally, persistent inflammatory conditions in the brain lead to neuronal death, which is correlated with a reduced volume of key brain regions such as the hippocampus. This review highlights the involvement of glial cells in the pathogenesis of the mental comorbidities of EM (i.e., pain, anxiety, and depression) and to discuss potential therapeutic approaches for targeting the inflammation and activation of microglia in key brain regions.

In recent years, an increasing attention has given to the intricate and diverse connection of microorganisms residing in our gut and their impact on brain health and central nervous system disease. There has been a shift in mindset to understand that drug addiction is not merely a condition that affects the brain, it is now being recognized as a disorder that also involves external factors such as the intestinal microbiota, which could influence vulnerability and the development of addictive behaviors. Furthermore, stress and social interactions, which are closely linked to the intestinal microbiota, are powerful modulators of addiction. This review delves into the mechanisms through which the microbiota-stress-immune axis may shape drug addiction and social behaviors. This work integrates preclinical and clinical evidence that demonstrate the bidirectional communication between stress, social behaviors, substance use disorders and the gut microbiota, suggesting that gut microbes might modulate social stress having a significance in drug addiction.

Short-chain fatty acids (SCFAs) are produced in the colon following bacterial fermentation of dietary fiber and are important microbiota-gut-brain messengers. However, their mechanistic role in modulating psychobiological processes that underlie the development of stress- and anxiety-related disorders is scarcely studied in humans. We have previously shown that colonic administration of a SCFA mixture (acetate, propionate, butyrate) lowers the cortisol response to stress in healthy participants, but does not impact fear conditioning and extinction. To disentangle the effects of the three main SCFAs, we examined whether butyrate alone would similarly modulate these psychobiological responses in a randomized, triple-blind, placebo-controlled intervention study in 71 healthy male participants (M_{age =} 25.2, M_{BMI =} 22.7 [n = 35 butyrate group, n = 36 placebo group]). Colon-delivery capsules with pH-dependent coating were used to administer 5.28 g of butyrate or placebo daily for one week. Butyrate administration significantly increased serum butyrate concentrations without modulating serum acetate or propionate, nor fecal SCFAs. Butyrate administration also significantly modulated fear memory at the subjective but not physiological levels. Contrary to expectations, no changes in subjective nor neuroendocrine responses to acute stress were evident between the treatment groups from pre- to post-intervention. We conclude that colonic butyrate administration alone is not sufficient to modulate psychobiological stress responses, unlike administration of a SCFA mixture. The influence of colonic and systemic butyrate on fear memory and the persistence of fear extinction should be further systematically investigated in future studies.

The rotarod test, a sensorimotor assessment that allows for quantitative evaluation of motor coordination in rodents, has extensive application in many research fields. The test results exhibit extreme between-study variability, sometimes making it challenging to conclude the validity of certain disease models and related therapeutic effects. Although the variation in test paradigms may account for this disparity, some features of rotarod apparatus including rod diameter make differences. However, it is unknown whether the width of animal compartment has a role in rotarod performance. Here we comprehensively evaluated the active rotarod performance and adverse incidents in multiple strains of mice on an 11-cm- or a 5-cm-wide compartment apparatus. We found that mouse behaviors on these apparatuses were surprisingly different. It took a markedly longer time to train mice on the narrow- than wide-compartment rotarod. Further, non-transgenic B6129S and tau knockout mice aged 11 months and beyond showed different levels of improvement based on the compartment width. These mice had no overt improvements on accelerating rotarod over 4−5 training sessions on the narrow compartment, contrary to marked progress on the wide counterpart. The incidents of mice passively somersaulting round and fragmented running occurred significantly more on the wide than narrow compartment during accelerating rotarod sessions. Mice fell off rod more frequently on narrow than wide compartments upon attempt to turn around and when moving backward on rod. The pros and cons of narrow versus wide compartments are informative as to how to choose a rotarod apparatus that best fits the animal models used.

17β-Estradiol (E2) has been widely detected in natural water and treatment with E2 induces potential endocrine disrupting effects in fish. However, effects on fish fecundity and steroid system after treatment with environmentally relevant concentrations of E2 for the full sexual maturation cycle remain unclear. In this study, zebrafish were treatment with 0, 10 or 100 ng/L E2 from embryo to adult stage, and effects on gonadal development and differentiation, steroid hormone levels, transcription of genes associated with the hypothalamic-pituitary-gonadal-liver (HPG) axis in adults and fertilization rate of offspring were assessed. The results showed that treatment with E2 lead to increased number of feminization in zebrafish. In females, E2 decreased cumulative amount of spawning and inhibited the maturation of oocyte. In males, E2 inhibited the maturation and motility of sperm, as well as decreased the movement speed of sperm. These adverse effects on sperm might be responsible for the reduced fertilization observed in offspring. In addition, treatment with E2 changed the levels of steroid hormones in zebrafish gonad and altered the transcriptional levels of genes associated with HPG axis, which is responsible for the regulation of germ cells maturation and gonadal development in zebrafish. Overall, these results suggested that treatment with environmentally relevant concentrations of E2 for the full sexual maturity cycle resulted in adverse effects on reproduction in zebrafish.