Role of neuroestrogens in the regulation of social behaviors - From social recognition to mating.

In this mini-review, we summarize the brain distribution of aromatase, the enzyme catalyzing the synthesis of estrogens from androgens, and the mechanisms responsible for regulating estrogen production within the brain. Understanding this local synthesis of estrogens by neurons is pivotal as it profoundly influences various facets of social behavior. Neuroestrogen action spans from the initial processing of socially pertinent sensory cues to integrating this information with an individual's internal state, ultimately resulting in the manifestation of either pro-affiliative or - aggressive behaviors. We focus here in particular on aggressive and sexual behavior as the result of correct individual recognition of intruders and potential mates. The data summarized in this review clearly point out the crucial role of locally synthesized estrogens in facilitating rapid adaptation to the social environment in rodents and birds of both sexes. These observations not only shed light on the evolutionary significance but also indicate the potential implications of these findings in the realm of human health, suggesting a compelling avenue for further investigation.

The Role of Androgens and Estrogens in Social Interactions and Social Cognition.

Gonadal hormones are becoming increasingly recognized for their effects on cognition. Estrogens, in particular, have received attention for their effects on learning and memory that rely upon the functioning of various brain regions. However, the impacts of androgens on cognition are relatively under investigated. Testosterone, as well as estrogens, have been shown to play a role in the modulation of different aspects of social cognition. This review explores the impact of testosterone and other androgens on various facets of social cognition including social recognition, social learning, social approach/avoidance, and aggression. We highlight the relevance of considering not only the actions of the most commonly studied steroids (i.e., testosterone, 17ß-estradiol, and dihydrotestosterone), but also that of their metabolites and precursors, which interact with a plethora of different receptors and signalling molecules, ultimately modulating behaviour. We point out that it is also essential to investigate the effects of androgens, their precursors and metabolites in females, as prior studies have mostly focused on males. Overall, a comprehensive analysis of the impact of steroids such as androgens on behaviour is fundamental for a full understanding of the neural mechanisms underlying social cognition, including that of humans.

Sex Differences in Social Cognition.

In this review we explore the sex differences underlying various types of social cognition. Particular focus will be placed on the behaviors of social recognition, social learning, and aggression. Known similarities and differences between sexes in the expressions of these behaviors and the known brain regions where these behaviors are mediated are discussed. The role that the sex hormones (estrogens and androgens) have as well as possible interactions with other neurochemicals, such as oxytocin, vasopressin, and serotonin is reviewed as well. Finally, implications about these findings on the mediation of social cognition are mediated and the sex differences related to humans are considered.

Neuroendocrine underpinning of social recognition in males and females.

Social recognition is an essential skill for the expression of appropriate behaviors towards conspecifics in most social species. Several studies point to oxytocin (OT) and arginine vasopressin (AVP) as key mediators of social recognition in males and females. However, sex differences in social cognitive behaviors highlight an important interplay between OT, AVP and the sex steroids. Estrogens facilitate social recognition by regulating OT action in the hypothalamus and that of OT receptor in the medial amygdala. The role of OT in these brain regions appears to be essential for social recognition in both males and females. Conversely, social recognition in male rats and mice is more dependent on AVP release in the lateral septum than in females. The AVP system comprises a series of highly sexually dimorphic brain nuclei, including the bed nucleus of the stria terminalis, the amygdala and the lateral septum. Various studies suggest that testosterone and its metabolites, including estradiol, influence social recognition in males by modulating the activity of the AVP at V1a receptor. Intriguingly, both estrogens and androgens can affect social recognition very rapidly, through non-genomic mechanisms. In addition, the androgen metabolites, namely 3α-diol and 3ß-diol, may also have an impact on social behaviors either by interacting with the estrogen receptors or through other mechanisms. Overall, the regulation of OT and AVP by sex steroids fine tunes social recognition and the behaviors that depend upon it (e.g., social bond, hierarchical organization, aggression) in a sex-dependent manner. Elucidating the sex-dependent interaction between sex steroids and neuroendocrine systems is essential for understanding sex differences in the normal and abnormal expression of social behaviors.

Maternal separation alters the reward system of activity-based anorexia rats.

Maternal separation (MS) is a known chronic stressor in the postnatal period and when associated with another paradigm like the activity-based anorexia (ABA) rat model, causes different effects in the two sexes. In ABA females, the separation leads to increased hyperactivity and anxiety reduction, whereas, in males, the separation induces decreased locomotor activity without similar reduction of anxiety-like behaviors as observed in females. To understand the mechanisms altered by MS in synergy with the induction of the anorexic-like phenotype, we considered the reward system, which involves neurons synthesizing dopamine (DA) in the ventral tegmental area (VTA), substantia nigra pars compacta, and serotoninergic neurons in the dorsal raphe nucleus. Moreover, we analyzed the orexin circuit in the lateral hypothalamic area (LHA), which affects DA synthesis in the VTA and is also known to regulate food consumption and locomotor activity. Rats of both sexes were exposed to the two paradigms (MS and ABA), leading to four experimental groups for each sex: non-separated control (CON), non-separated ABA groups (ABA), MS control (MSCON), and MS plus ABA groups (MSABA). Immunohistochemistry analysis was performed to determine quantitative differences in the number of cells expressing DA, orexin, and serotonin (5-HT) among the experimental groups. The results showed that, in the DA system, the effect of MS was more evident in females than in males, with a substantial increase in DA cells in the VTA of MSABA. However, the analysis of the orexin system revealed a similar cellular increment in the LHA in the non-separated ABA groups of both sexes. Regarding 5-HT, there was an opposite effect in males and females of the MSABA groups, with only females showing a greater density of 5-HT cells. The changes in the reward system could partially explain the behavioral data: the hyperactivity, weight loss, and decreased anxiety levels of the MSABA females could be linked to an increase in DA and 5-HT cells, whereas in males, MS could mitigate the behavioral effects of the ABA protocol affecting the anxiety levels and locomotor activity through a lack of increased activation of the reward system.

Epigenetic Regulation of GABAergic Neurotransmission and Neurosteroid Biosynthesis in Alcohol Use Disorder.

BACKGROUND: Alcohol use disorder (AUD) is a chronic relapsing brain disorder. GABAA receptor (GABAAR) subunits are a target for the pharmacological effects of alcohol. Neurosteroids play an important role in the fine-tuning of GABAAR function in the brain. Recently, we have shown that AUD is associated with changes in DNA methylation mechanisms. However, the role of DNA methylation in the regulation of neurosteroid biosynthesis and GABAergic neurotransmission in AUD patients remains under-investigated. METHODS: In a cohort of postmortem brains from 20 male controls and AUD patients, we investigated the expression of GABAAR subunits and neurosteroid biosynthetic enzymes and their regulation by DNA methylation mechanisms. Neurosteroid levels were quantified by gas chromatography-mass spectrometry. RESULTS: The α 2 subunit expression was reduced due to increased DNA methylation at the gene promoter region in the cerebellum of AUD patients, a brain area particularly sensitive to the effects of alcohol. Alcohol-induced alteration in GABAAR subunits was also observed in the prefrontal cortex. Neurosteroid biosynthesis was also affected with reduced cerebellar expression of the 18kDa translocator protein and 3α-hydroxysteroid dehydrogenase mRNAs. Notably, increased DNA methylation levels were observed at the promoter region of 3α-hydroxysteroid dehydrogenase. These changes were associated with markedly reduced levels of allopregnanolone and pregnanolone in the cerebellum. CONCLUSION: Given the key role of neurosteroids in modulating the strength of GABAAR-mediated inhibition, our data suggest that alcohol-induced impairments in GABAergic neurotransmission might be profoundly impacted by reduced neurosteroid biosynthesis most likely via DNA hypermethylation.

Maternal Separation in ABA Rats Promotes Cell Proliferation in the Dentate Gyrus of the Hippocampus.

Anorexia nervosa (AN) is a serious eating disorder characterized by self-starvation and excessive weight loss. Several studies support the idea that life stressors during the postnatal period could play a pivotal role in the pathogenesis of AN, underlying the multifactorial etiology of this disease. The activity-based anorexia (ABA) animal model mimics core features of the mental disorder, including severe food restriction, weight loss, and hyperactivity. Previous results obtained in our lab showed that maternal separation (MS) induces behavioral changes in anorexic-like ABA rats in a sexually dimorphic way: in females, the MS promoted hyperactivity and a less anxious-like phenotype in ABA animals; in males, instead, the MS attenuated the anxiolytic effect of the ABA protocol. These results led us to investigate the effect of the MS on brain areas involved in the control of the anxiety-like behavior. We focused our attention on the adult hippocampal neurogenesis, a process involved in the response to environmental stimuli and stressful condition. We analyzed the volume of the whole hippocampus and the proliferation rate in the dentate gyrus (DG) by quantifying Ki67-cells density and characterizing neuronal phenotype (DCX) and glial cells (GFAP) with double-fluorescence technique. The results obtained showed that only in maternally separated anorexic rats there is an increase of proliferation in DG, underlying the presence of a synergic effect of MS and ABA that boost the proliferation of new neurons and glia progenitors in a more evident way in females in comparison to males.

Sexually dimorphic behavioral effects of maternal separation in anorexic rats.

Exposure to negative events during the neonatal period is one of the leading factors contributing to the development of psychiatric disorders, including anorexia nervosa. In this study, we investigated the effects of maternal separation (MS) on the development of anorexia in rodents using the mild-stress form of the activity-based anorexia (ABA) model (2 hr of free access to a running wheel and a 1-hr feeding test) in both male and female rats. We assessed anxiety-like and locomotor behavior and hyperactivity with the open field and elevated plus maze tests. Our results showed that ABA rats of both sexes displayed hyperactive behavior associated with reduced anxiety-like behavior when compared to controls. However, a sexually dimorphic effect of MS emerged in anorexic rats: while the females exposed to MS + ABA were hyperactive with diminished anxiety-related behaviors compared to females of the ABA group, MS in males attenuated or did not alter the effects of the ABA protocol. In conclusion, our data reveal that the synergistic effects of MS and ABA on physical activity and anxiety-like behavior act in opposite directions in the two sexes.

Animal models of post-traumatic stress disorder and novel treatment targets.

Understanding the neurobiological basis of post-traumatic stress disorder (PTSD) is fundamental to accurately diagnose this neuropathology and offer appropriate treatment options to patients. The lack of pharmacological effects, too often observed with the most currently used drugs, the selective serotonin reuptake inhibitors (SSRIs), makes even more urgent the discovery of new pharmacological approaches. Reliable animal models of PTSD are difficult to establish because of the present limited understanding of the PTSD heterogeneity and of the influence of various environmental factors that trigger the disorder in humans. We summarize knowledge on the most frequently investigated animal models of PTSD, focusing on both their behavioral and neurobiological features. Most of them can reproduce not only behavioral endophenotypes, including anxiety-like behaviors or fear-related avoidance, but also neurobiological alterations, such as glucocorticoid receptor hypersensitivity or amygdala hyperactivity. Among the various models analyzed, we focus on the social isolation mouse model, which reproduces some deficits observed in humans with PTSD, such as abnormal neurosteroid biosynthesis, changes in GABAA receptor subunit expression and lack of pharmacological response to benzodiazepines. Neurosteroid biosynthesis and its interaction with the endocannabinoid system are altered in PTSD and are promising neuronal targets to discover novel PTSD agents. In this regard, we discuss pharmacological interventions and we highlight exciting new developments in the fields of research for novel reliable PTSD biomarkers that may enable precise diagnosis of the disorder and more successful pharmacological treatments for PTSD patients.

Could a blood test for PTSD and depression be on the horizon?

INTRODUCTION: Depression and posttraumatic stress disorder (PTSD) are two complex and debilitating psychiatric disorders that result in poor life and destructive behaviors against self and others. Currently, diagnosis is based on subjective rather than objective determinations leading to misdiagnose and ineffective treatments. Advances in novel neurobiological methods have allowed assessment of promising biomarkers to diagnose depression and PTSD, which offers a new means of appropriately treating patients. Areas covered: Biomarkers discovery in blood represents a fundamental tool to predict, diagnose, and monitor treatment efficacy in depression and PTSD. The potential role of altered HPA axis, epigenetics, NPY, BDNF, neurosteroid biosynthesis, the endocannabinoid system, and their function as biomarkers for mood disorders is discussed. Insofar, we propose the identification of a biomarker axis to univocally identify and discriminate disorders with large comorbidity and symptoms overlap, so as to provide a base of support for development of targeted treatments. We also weigh in on the feasibility of a future blood test for early diagnosis. Expert commentary: Potential biomarkers have already been assessed in patients' blood and need to be further validated through multisite large clinical trial stratification. Another challenge is to assess the relation among several interdependent biomarkers to form an axis that identifies a specific disorder and secures the best-individualized treatment. The future of blood-based tests for PTSD and depression is not only on the horizon but, possibly, already around the corner.