The hypothalamic neuropeptide oxytocin (OT) is well known for its prosocial, anxiolytic, and ameliorating effects on various psychiatric conditions, including alcohol use disorder (AUD). In this chapter, we will first introduce the basic neurophysiology of the OT system and its interaction with other neuromodulatory and neurotransmitter systems in the brain. Next, we provide an overview over the current state of research examining the effects of acute and chronic alcohol exposure on the OT system as well as the effects of OT system manipulation on alcohol-related behaviors in rodents and humans. In rodent models of AUD, OT has been repeatedly shown to reduce ethanol consumption, particularly in models of acute alcohol exposure. In humans however, the results of OT administration on alcohol-related behaviors are promising but not yet conclusive. Therefore, we further discuss several physiological and methodological limitations to the effective application of OT in the clinic and how they may be mitigated by the application of synthetic OT receptor (OTR) agonists. Finally, we discuss the potential efficacy of cutting-edge pharmacology and gene therapies designed to specifically enhance endogenous OT release and thereby rescue deficient expression of OT in the brains of patients with severe forms of AUD and other incurable mental disorders.

Chronic stress has long been hypothesized to play a role in driving population cycles. Christian (1950) hypothesized that high population density results in chronic stress and mass \"die-offs\" in small mammal populations. Updated variations of this hypothesis propose that chronic stress at high population density may reduce fitness, reproduction, or program aspects of phenotype, driving population declines. We tested the effect of density on the stress axis in meadow voles (Microtus pennsylvanicus) by manipulating population density in field enclosures over three years. Using fecal corticosterone metabolites as a non-invasive measure of glucocorticoid (GC) concentrations, we found that density alone was not associated with GC differences. However, we found that the seasonal relationship of GC levels differed by density treatment, with high-density populations having elevated GC levels early in the breeding season and decreasing towards late summer. We additionally tested hippocampal glucocorticoid receptor and mineralocorticoid receptor gene expression in juvenile voles born at different densities, with the hypothesis that high density may reduce receptor expression, altering negative feedback of the stress axis. We found that females had marginally higher glucocorticoid receptor expression at high density, no effect in males, and no detectable effect of density on mineralocorticoid receptor expression in either sex. Hence, we found no evidence that high density directly impairs negative feedback in the hippocampus, but rather female offspring may be better equipped for negative feedback. We compare our findings with prior studies to attempt to disentangle the complicated relationship between density, seasonality, sex, reproduction and the stress axis.

In vertebrates, the hypothalamus-pituitary-adrenal gland (HPA) axis is the main endocrine pathway regulating the stress response, thus also called the stress axis. It has been well-accepted that the stress axis is tightly controlled by both hypothalamic stimulators and inhibitors [e.g. corticotropin (ACTH)-releasing inhibitory factor (CRIF)]. However, the identity of authentic CRIF remains unclear for decades. Recently, neuropeptide W (NPW) was proved to be the physiological CRIF in chickens. Together with its functional receptor (NPBWR2), they play critical roles in attenuating the activity of the chicken stress axis. Because increasing pieces of evidence suggested that sex steroids could regulate the stress axis, using chicken as a model, we investigated whether the newly identified CRIF and its receptor are under the control of sex steroids in this study. Our results showed that: (1) expression of NPW-NPBWR2 in the hypothalamus-pituitary axis was sexually dimorphic and developmental stage-dependent; (2) progesterone (P4), rather than 17β-estradiol (E2) and dihydrotestosterone (DHT), could dose- and time-dependently upregulate NPBWR2 expression, which was accompanied with the decrease of ACTH synthesis and secretion, in cultured pituitary cells; (3) intraperitoneal injection of P4 could elevate the mRNA level of pituitary NPBWR2; (4) P4-stimulated NPBWR2 expression was relevant to both nPR-mediated genomic action and mPRs-triggered nongenomic route associated with MEK/ERK, PI3K/AKT cascade, and calcium influx. To our knowledge, our results discover a novel route of sex steroids in modulating the stress axis of chickens, which lays a foundation to reveal the complicated interaction network between reproduction and stress axes in chickens.

We conducted a systematic review with meta-analytic elements using publicly available Gene Expression Omnibus (GEO) datasets to determine the role of epigenetic mechanisms in prenatal alcohol exposure (PAE)-induced hypothalamic-pituitary-adrenal (HPA) axis dysfunctions in offspring. Several studies have demonstrated that PAE has long-term consequences on HPA axis functions in offspring. Some studies determined that alcohol-induced epigenetic alterations during fetal development persist in adulthood. However, additional research is needed to understand the major epigenetic events leading to alcohol-induced teratogenesis of the HPA axis. Our network analysis of GEO datasets identified key pathways relevant to alcohol-mediated histone modifications, DNA methylation, and miRNA involvement associated with PAE-induced alterations of the HPA axis. Our analysis indicated that PAE perturbated the epigenetic machinery to activate corticotrophin-releasing hormone, while it suppressed opioid, glucocorticoid receptor, and circadian clock genes. These results help to further our understanding of the epigenetic basis of alcohol\'s effects on HPA axis development.

Primary polydipsia is characterized by excessive fluid intake which may suppress vasopressin levels. It is speculated that suppressed vasopressin levels lead to a dysregulated hypothalamic-pituitary-adrenal (HPA) axis as vasopressin co-modulates the HPA axis. However, data are contradictory. The aim of this study was to investigate markers of the HPA axis in patients with primary polydipsia compared to healthy controls.
Exploratory analysis combining data from two different prospective observational studies.
We included 34 patients with primary polydipsia (68% females, median aged 29.5 years (interquartile range, IQR: 26.0, 38.8) and 20 healthy controls (55% females, median age 24.0 years [IQR: 22.0, 27.2]).
The main outcome was difference in HPA axis activity assessed using circadian serum and salivary cortisol, 24-h urinary free cortisol and cortisol levels before and after adrenocorticotropic hormone (ACTH) stimulation; vasopressin suppression was assessed measuring fasting copeptin levels between patients with primary polydipsia and healthy controls using Wilcoxon rank-sum test.
No difference was seen in circadian serum cortisol levels (p = .9), urinary free cortisol levels (p = .17) and serum cortisol in response to ACTH stimulation (p = .77) between groups. Circadian salivary cortisol levels were significantly lower in patients with primary polydipsia compared to healthy controls with an estimated difference of -3.7 nmol/L (95% CI: -5.5, -1.8 nmol/L, p < .001). Fasting copeptin levels were significantly lower in patients with primary polydipsia compared to healthy volunteers (p < 0.01).
Our results suggest no difference in HPA axis activity between patients with primary polydipsia and healthy controls. The observed difference in salivary cortisol levels may be linked to a dilution effect in saliva rather than an altered stress axis considering the other findings.

Anticipation of stress induces physiological, behavioral and cognitive adjustments that are required for an appropriate response to the upcoming situation. Additional research examining the response of cardiopulmonary parameters and stress hormones during anticipation of stress in different chronic stress adaptive models is needed. As an addition to our previous research, a total of 57 subjects (16 elite male wrestlers, 21 water polo player and 20 sedentary subjects matched for age) were analyzed. Cardiopulmonary exercise testing (CPET) on a treadmill was used as the laboratory stress model; peak oxygen consumption (VO2) was obtained during CPET. Plasma levels of adrenocorticotropic hormone (ACTH), cortisol, alpha-melanocyte stimulating hormone (alpha-MSH) and N-terminal-pro-B type natriuretic peptide (NT-pro-BNP) were measured by radioimmunometric, radioimmunoassay and immunoassay sandwich technique, respectively, together with cardiopulmonary measurements, 10 minutes pre-CPET and at the initiation of CPET. The response of diastolic blood pressure and heart rate was different between groups during stress anticipation (p = 0.019, 0.049, respectively), while systolic blood pressure, peak VO2 and carbon-dioxide production responses were similar. ACTH and cortisol increased during the experimental condition, NT-pro-BNP decreased and alpha-MSH remained unchanged. All groups had similar hormonal responses during stress anticipation with the exception of the ACTH/cortisol ratio. In all three groups, ΔNT-pro-BNP during stress anticipation was the best independent predictor of peak VO2 (B = 36.01, r = 0.37, p = 0.001). In conclusion, the type of chronic stress exposure influences the hemodynamic response during anticipation of physical stress and the path of hormonal stress axis activation. Stress hormones released during stress anticipation may hold predictive value for overall cardiopulmonary performance during the stress condition.
LAY SUMMARYThe study revealed differences in hormonal and hemodynamic responses during anticipation of stress between athletes and sedentary participants. Stress hormones released during stress anticipation may hold predictive value for overall cardiopulmonary performance during the stress condition.

Stress response is essential for the organism to quickly restore physiological homeostasis disturbed by various environmental insults. In addition to well-established physiological cascades, stress also evokes various brain and behavioral responses. Aquatic animal models, including the zebrafish (Danio rerio), have been extensively used to probe pathobiological mechanisms of stress and stress-related brain disorders. Here, we critically discuss the use of zebrafish models for studying mechanisms of stress and modeling its disorders experimentally, with a particular cross-taxon focus on the potential evolution of stress responses from zebrafish to rodents and humans, as well as its translational implications.

Dogs (Canis lupus familiaris) descend from wolves (Canis lupus) sharing the same ecological niche of cooperative hunters, as humans. Initially, humans and wolves were competitors starting interspecific communication in order to avoid risk of injury. The evolutionary continuity of mammalian brains enabled interspecific prosocial contacts between both of them, which reduced stress, and enabled behavioral cultures leading to genetic isolation of those wolves. Dogs are the first domesticated animal living together with humans for about 25,000 years. Domestication means decreased aggression and flight distance toward humans, thus changes in the stress axis are crucial. The hypothesis of Active Social Domestication considers genetic selection as a necessary prediction but not a sufficient explanation of dog domestication. In addition, dog domestication is suggested to be an epigenetic disclosure. Due to changed stress activity, epigenetic mechanisms affect cerebral receptor activity and regulate transposon expressions, thus shaping brain function and behavior. Interspecific prosocial contacts initiated via serotonin release an enzymatic cascade enhancing, epigeneti-cally, the glucocorticoid negative feedback loop. Reduced chronic stress improved social learning capability and inhibitory control. Over time, those wolves could integrate themselves into human social structures, thus becoming dogs. In analogy, human mental skills, such as creating art and culture, might have also improved during the Upper Paleolithic.

Developmental plasticity can allow the exploitation of alternative diets. While such flexibility during early life is often adaptive, it can leave a legacy in later life that alters the overall health and fitness of an individual. Species of the spadefoot toad genus Spea are uniquely poised to address such carryover effects because their larvae can consume drastically different diets: their ancestral diet of detritus or a derived shrimp diet. Here, we use Spea bombifrons to assess the effects of developmental plasticity in response to larval diet type and nutritional stress on juvenile behaviors and stress axis reactivity. We find that, in an open-field assay, juveniles fed shrimp as larvae have longer latencies to move, avoid prey items more often, and have poorer prey-capture abilities. While juveniles fed shrimp as larvae are more exploratory, this effect disappears if they also experienced a temporary nutritional stressor during early life. The larval shrimp diet additionally impairs juvenile jumping performance. Finally, larvae that were fed shrimp under normal nutritional conditions produce juveniles with higher overall glucocorticoid levels, and larvae that were fed shrimp and experienced a temporary nutritional stressor produce juveniles with higher stress-induced glucocorticoid levels. Thus, while it has been demonstrated that consuming the novel, alternative diet can be adaptive for larvae in nature, doing so has marked effects on juvenile phenotypes that may recalibrate an individual\'s overall fitness. Given that organisms often utilize diverse diets in nature, our study underscores the importance of considering how diet type interacts with early-life nutritional adversity to influence subsequent life stages.

Environmental sex determination (ESD) is common among ectothermic vertebrates. The stress axis and production of stress hormones (corticosteroids) regulates ESD in fish, but evidence of a similar influence in reptiles is sparse and conflicting. The central bearded dragon (Pogona vitticeps) has a system of sex determination involving the interplay between sex chromosomes (ZZ/ZW female heterogamety) and the thermal environment. High egg incubation temperatures induce sex reversal of the ZZ genotype, feminizing chromosomally male individuals. Here we show that corticosterone elevation is not associated with sex reversal in the central bearded dragon, either during embryonic development or adulthood. We also demonstrate experimentally that sex determination is not affected by corticosterone injection into the yolk. This strongly suggests that stress axis upregulation by high temperature during incubation does not cause sex reversal in P. vitticeps. Our work is in general agreement with other research in reptiles, which suggests that the stress axis does not mediate sex in reptiles with ESD. Alternative biological systems may be responsible for capturing environmental conditions during reptile development, such as cellular calcium and redox regulation or the action of temperature-sensitive splicing factors.