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.

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 3β‐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.

No abstract

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 subjects remain under-investigated. METHODS In a cohort of postmortem brains from 20 male controls and AUD subjects, 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 α2 subunit expression was reduced due to increased DNA methylation at the gene promoter region in the cerebellum of AUD subjects, 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 (3α-HSD) mRNAs. Notably, increased DNA methylation levels were observed at the promoter region of 3α-HSD. 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.

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.