Subregion-specific transcriptomic profiling of rat brain reveals sex-distinct gene expression impacted by adolescent stress.

Stress during adolescence clearly impacts brain development and function. Sex differences in adolescent stress-induced or exacerbated emotional and metabolic vulnerabilities could be due to sex-distinct gene expression in hypothalamic, limbic, and prefrontal brain regions. However, adolescent stress-induced whole-genome expression changes in key subregions of these brain regions were unclear. In this study, female and male adolescent Sprague Dawley rats received one-hour restraint stress daily from postnatal day (PD) 32 to PD44. Corticosterone levels, body weights, food intake, body composition, and circulating adiposity and sex hormones were measured. On PD44, brain and blood samples were collected. Using RNA-sequencing, sex-specific differences in stress-induced differentially expressed (DE) genes were identified in subregions of the hypothalamus, limbic system, and prefrontal cortex. Canonical pathways reflected well-known sex-distinct maladies and diseases, substantiating the therapeutic potential of the DE genes found in the current study. Thus, we proposed specific sex distinct, adolescent stress-induced transcriptional changes found in the current study as examples of the molecular bases for sex differences witnessed in stress induced or exacerbated emotional and metabolic disorders. Future behavioral studies and single-cell studies are warranted to test the implications of the DE genes identified in this study in sex-distinct stress-induced susceptibilities.

Current Evidence for Biological Biomarkers and Mechanisms Underlying Acute to Chronic Pain Transition across the Pediatric Age Spectrum.

Chronic pain is highly prevalent in the pediatric population. Many factors are involved in the transition from acute to chronic pain. Currently, there are conceptual models proposed, but they lack a mechanistically sound integrated theory considering the stages of child development. Objective biomarkers are critically needed for the diagnosis, risk stratification, and prognosis of the pathological stages of pain chronification. In this article, we summarize the current evidence on mechanisms and biomarkers of acute to chronic pain transitions in infants and children through the developmental lens. The goal is to identify gaps and outline future directions for basic and clinical research toward a developmentally informed theory of pain chronification in the pediatric population. At the outset, the importance of objective biomarkers for chronification of pain in children is outlined, followed by a summary of the current evidence on the mechanisms of acute to chronic pain transition in adults, in order to contrast with the developmental mechanisms of pain chronification in the pediatric population. Evidence is presented to show that chronic pain may have its origin from insults early in life, which prime the child for the development of chronic pain in later life. Furthermore, available genetic, epigenetic, psychophysical, electrophysiological, neuroimaging, neuroimmune, and sex mechanisms are described in infants and older children. In conclusion, future directions are discussed with a focus on research gaps, translational and clinical implications. Utilization of developmental mechanisms framework to inform clinical decision-making and strategies for prevention and management of acute to chronic pain transitions in children, is highlighted.

Estrogenic Action in Stress-Induced Neuroendocrine Regulation of Energy Homeostasis.

Estrogens are among important contributing factors to many sex differences in neuroendocrine regulation of energy homeostasis induced by stress. Research in this field is warranted since chronic stress-related psychiatric and metabolic disturbances continue to be top health concerns, and sex differences are witnessed in these aspects. For example, chronic stress disrupts energy homeostasis, leading to negative consequences in the regulation of emotion and metabolism. Females are known to be more vulnerable to the psychological consequences of stress, such as depression and anxiety, whereas males are more vulnerable to the metabolic consequences of stress. Sex differences that exist in the susceptibility to various stress-induced disorders have led researchers to hypothesize that gonadal hormones are regulatory factors that should be considered in stress studies. Further, estrogens are heavily recognized for their protective effects on metabolic dysregulation, such as anti-obesogenic and glucose-sensing effects. Perturbations to energy homeostasis using laboratory rodents, such as physiological stress or over-/under- feeding dietary regimen prevalent in today's society, offer hints to the underlying mechanisms of estrogenic actions. Metabolic effects of estrogens primarily work through estrogen receptor α (ERα), which is differentially expressed between the sexes in hypothalamic nuclei regulating energy metabolism and in extrahypothalamic limbic regions that are not typically associated with energy homeostasis. In this review, we discuss estrogenic actions implicated in stress-induced sex-distinct metabolic disorders.

Difference in post-stress recovery of the gut microbiome and its altered metabolism after chronic adolescent stress in rats.

The human gut microbiome plays a central role in human health, and has been implicated in the development of a number of chronic gastrointestinal and systemic diseases. For example, microorganisms can serve as microbial endocrine mediators and can respond to stimuli and produce neurochemicals, ultimately influencing the brain-gut-microbiome axis of their host, a bidirectional communication system between the central nervous system and the gastrointestinal tract, especially during developmental stages. To begin to explore potential dynamic changes of the gut microbiome, we characterized gut microbiota in adolescent rats that underwent a fixed period of restraint stress, examined whether the gut microbial population and their metabolic functions were changed by stress, and if such changes during adolescence persist or recover in young adulthood. Integrated 16S ribosomal DNA sequencing and liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) based metabolic profiling were utilized to discover any significant differences in gut microbial genus and microbial metabolites immediately at the end of the chronic restraint stress and three weeks after the stress treatment, compared to control rats that did not receive stress treatment. Interestingly, while adolescent chronic stress-induced differences in relative microbial abundance (i.e., microbial species and distribution) disappeared three weeks after the stress treatment ended, the differences in microbial metabolic profiles persisted into adulthood. In addition, a number of significantly altered metabolites and their correlated gut microbes detected in our study facilitated a possible connection between gut microbiota and host stress response, which can be further investigated in the future to study the causal relationship between gut microbial metabolites and their impact on human health.

Differential Sympathetic Activation of Adipose Tissues by Brain-Derived Neurotrophic Factor.

Centrally administered brain-derived neurotrophic factor (BDNF) decreases body adiposity beyond what can be accounted for by decreased food intake, implying enhanced lipid metabolism by BDNF. Consistent with this notion, intracerebroventricular (icv) injection of BDNF in rats increased the expression of lipolytic enzymes in white adipose tissues (WAT) and increased circulating concentrations of lipolytic products without changing the levels of adrenal gland hormones. This suggests that central BDNF-induced lipid mobilization is likely due to sympathetic neural activation, rather than activation of the adrenocortical or adrenomedullary system. We hypothesized that BDNF activated sympathetic innervation of adipose tissues to regulate lipolysis. Rats with unilateral denervation of interscapular brown adipose tissue (BAT) and different WAT depots received icv injections of saline or BDNF. Both intact and denervated adipose tissues were exposed to the same circulating factors, but denervated adipose tissues did not receive neural signals. Norepinephrine (NE) turnover (NETO) of BAT and WAT was assessed as a measure of sympathetic activity. Findings revealed that central BDNF treatment induced a change in NETO in some but not all the adipose tissues tested. Specifically, greater NETO rates were found in BAT and gonadal epididymal WAT (EWAT), but not in inguinal WAT (IWAT) or retroperitoneal WAT (RWAT), of BDNF-treated rats compared to saline-treated rats. Furthermore, intact innervation was necessary for BDNF-induced NETO in BAT and EWAT. In addition, BDNF increased the expression of lipolytic enzymes in both intact and denervated EWAT and IWAT, suggesting that BDNF-induced WAT lipolysis was independent of intact innervation. To summarize, centrally administered BDNF selectively provoked sympathetic drives to BAT and EWAT that was dependent on intact innervation, while BDNF also increased lipolysis in a manner independent of intact innervation.

Effects of Estrogens on Central Nervous System Neurotransmission: Implications for Sex Differences in Mental Disorders.

Nearly one of every five US individuals aged 12 years old or older lives with certain types of mental disorders. Men are more likely to use various types of substances, while women tend to be more susceptible to mood disorders, addiction, and eating disorders, all of which are risks associated with suicidal attempts. Fundamental sex differences exist in multiple aspects of the functions and activities of neurotransmitter-mediated neural circuits in the central nervous system (CNS). Dysregulation of these neural circuits leads to various types of mental disorders. The potential mechanisms of sex differences in the CNS neural circuitry regulating mood, reward, and motivation are only beginning to be understood, although they have been largely attributed to the effects of sex hormones on CNS neurotransmission pathways. Understanding this topic is important for developing prevention and treatment of mental disorders that should be tailored differently for men and women. Studies using animal models have provided important insights into pathogenesis, mechanisms, and new therapeutic approaches of human diseases, but some concerns remain to be addressed. The purpose of this chapter is to integrate human and animal studies involving the effects of the sex hormones, estrogens, on CNS neurotransmission, reward processing, and associated mental disorders. We provide an overview of existing evidence for the physiological, behavioral, cellular, and molecular actions of estrogens in the context of controlling neurotransmission in the CNS circuits regulating mood, reward, and motivation and discuss related pathology that leads to mental disorders.