The neuroactive steroid allopregnanolone ((3α,5α)-3-hydroxypregnan-20-one or 3α,5α-THP) plays a key role in the response to stress, by normalizing hypothalamic-pituitary-adrenal (HPA) axis function to restore homeostasis. Most studies have been conducted on male rats, and little is known about the allopregnanolone response to stress in females, despite that women are more susceptible than men to develop emotional and stress-related disorders. Here, we provide an overview of animal and human studies examining the allopregnanolone responses to acute stress in females in the context of stress-related neuropsychiatric diseases and under the different conditions that characterize the female lifespan associated with the reproductive function. The blunted allopregnanolone response to acute stress, often observed in female rats and women, may represent one of the mechanisms that contribute to the increased vulnerability to stress and affective disorders in women under the different hormonal fluctuations that occur throughout their lifespan. These studies highlight the importance of targeting neuroactive steroids as a therapeutic approach for stress-related disorders in women.

Previous work from our laboratory demonstrated that parental stress, induced by social isolation starting at puberty, leads to behavioral, endocrine, and biochemical changes in the male, but not female, offspring (ISO-O) of Sprague-Dawley rats. Here, we report alterations in the gut microbiota composition of ISO-O vs. grouped-housed offspring (GH-O), although all animals received the same diet and were housed in the same conditions. Analysis of bacterial communities by next-generation sequencing (NGS) of 16S rRNA gene revealed alterations at family and order levels within the main phyla of Bacteroides, Proteobacteria, and Firmicutes, including an almost total deficit in Limosilactobacillus reuteri (formerly Lactobacillus reuteri) and a significant increase in Ligilactobacillus murinus (formerly Lactobacillus murinus). In addition, we found an increase in the relative abundance of Rhodospirillales and Clostridiales in the families of Lachnospiraceae and Ruminococcaceae, and Bacteroidales in the family of Prevotellaceae. Furthermore, we examined plasma levels of the proinflammatory cytokines interleukin-1-beta and tumor necrosis factor-alpha, which did not differ between the two groups, while corticosterone concentrations were significantly increased in ISO-O rats. Our findings suggest that adverse environmental conditions experienced by parents may have an impact on the likelihood of disease development in the subsequent generations.

Maternal immune activation (MIA) during pregnancy may increase the risk for neurodevelopmental disorders such as schizophrenia and autism in offspring. Preclinical and human evidence support a potential role for MIA in the development of depressive symptoms in offspring. Among animal models of MIA, prenatal treatment with the synthetic viral mimetic polyinosinic-polycytidylic acid [poly (I:C)] is well established in studying psychotic-like and autism-like phenotypes, while its validity for modeling depressive-like behaviors remains underexplored. In this study, we assessed whether MIA, induced in rats with an injection of high molecular weight (HMW) poly (I:C), at gestational day 15, leads to a depressive-like phenotype in the offspring. In male and female offspring during adolescence and adulthood, we evaluated i) behavioral despair and anhedonia using the forced swim test (FST) and sucrose preference test (SPT); ii) the electrophysiological properties of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons in vivo; iii) serum cytokine profile. We found that MIA offspring exhibited increased immobility and reduced climbing and swimming in the FST, with more pronounced effects in males, while sucrose preference remained unaltered. In vivo recordings revealed a significant increase in 5-HT neuron firing rate in MIA adult males. Peripheral cytokine analysis showed elevated IL-1α in MIA males and decreased GRO/KC levels in MIA females. In conclusion, these findings indicate that prenatal exposure to HMW poly (I:C) selectively affects stress-coping mechanisms without inducing anhedonia, modulates serotonergic signaling in a sex- dependent manner in the absence of widespread inflammatory alterations.

Cannabis remains by far the most consumed illicit drug in Europe. The availability of more potent cannabis has raised concerns regarding the enhanced health risks associated with its use, particularly among pregnant women. Growing evidence shows that cannabis use during pregnancy increases the risks of child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ ⁹ -tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), display a hyperdopaminergic phenotype associated with a differential susceptibility to acute THC- and stress-mediated effects on sensorimotor gating functions. Here, we explore the contribution of the hypothalamic-pituitary-adrenal (HPA) axis, key regulator of body adaptive stress responses, to the detrimental effects of acute stress on ventral tegmental area (VTA) dopamine neurons and sensorimotor gating function of PCE rats. We report a sex-dependent compromised balance in mRNA levels of genes encoding mineralocorticoid and glucocorticoid receptors in the VTA, alongside with stress-induced pre-pulse inhibition (PPI) deficits. Notably, VTA dopamine neuronal activity is required for the manifestation of stress-dependent deterioration of PPI. Finally, pharmacological manipulations targeting glycogen-synthase-kinase-3-β signaling during postnatal development correct these stress-induced, sex-specific and dopamine-dependent deficits of PPI. Collectively, these results highlight the critical sex-dependent interplay between HPA axis and dopamine system in the regulation of sensorimotor gating functions in rats.