Conference Agenda

Early life adversity, such as early social isolation (ESI), and housing conditions, standard housing (SH) or communal nesting (CN), are associated with changes in neuronal development as well as cognitive, emotional and social domains. Given the pivotal role of the glutamatergic transmission in the brain development, our aim was to evaluate the presence and persistence of sexually dimorphic effects of different housing condition combined with early life stress on the homeostasis of the glutamatergic synapse in the medial prefrontal cortex (mPFC).

To this end, dams were standard housed or exposed to social enrichment through CN, i.e. housing together three pregnant rats that, upon delivery, will share care-giving till weaning. Pups were then socially deprived during the third postnatal week and tested in the social play behavior at post-natal day (P) 35. The analysis of the glutamatergic synapse in the mPFC was performed at P35 and P75.

At P35, only male rats exposed to the combination of CN and ESI showed increased number of pinning, suggesting a disinhibited social behavior. At molecular level in adolescent rats, even though ESI and CN per se reduced PSD95, an index of postsynaptic density integrity, and the combination of CN-ESI restored it in both sexes, SynCAM1, a protein that controls synaptic maturation, was increased in males while reduced in females. According to the sex-dependent structural reorganization of the synapse, CN-ESI condition reorganized NMDA receptor subunits composition potentiating the glutamate neurotransmission via increase in GluN2A levels in male rats, an effect blunted in females. At P75, the sex-dependent effects of ESI in CN rats were still present further contributing to a long-lasting effect on synaptic strength.

Taken together, CN sensitizes the male synapse to further stimuli thus inducing coping ability to ESI whereas the depotentiation of glutamate neurotransmission in females underlies their vulnerability to adverse events.

Early social experiences influence the neurodevelopment of individuals by affecting neurochemical substrates and behavior. Adequate social stimuli during the early stages of post-natal life are crucial for developing appropriate social-emotional and cognitive skills while adverse social experiences negatively affect neurobehavioral development. Although the exact molecular mechanisms by which environmental factors influence emotional development are not yet completely understood, alteration in endocannabinoid (eCB) and glucocorticoid systems, probably producing an imbalance of the excitatory and/or inhibitory tone in specific brain areas, could participate to the development of psychiatric disorders in adulthood. Given the relevance of these systems in mediating CNS functions, the aim of this study was to investigate the impact of different early social environment on emotional reactivity and molecular alterations of eCB and glucocorticoid systems in the PFC of juvenile or adult male and female rats. To this aim, a protocol of environmental manipulation based on early postnatal housing, in either social enriched or impoverished conditions, was applied. Social enrichment was realized through communal nesting (CN). Conversely, to mimic an adverse early social environment, an early social isolation (ESI) protocol was applied (post-natal days 14-21). Elevated plus maze test showed that CN males and females spent more time in open arms than animals housed in standard condition, thus indicating a less anxious phenotype. Molecular results indicated enriched/impoverished early social environmental conditions caused alterations of eCB and glucocorticoid systems’ expression, with sex and age-related differences. Indeed, the mRNA levels of CB1R, FAAH, and Nr3c1 were increased in adolescent females subjected to ESI protocol, thus suggesting the higher vulnerability of females to early social stress. Data suggest that different housing conditions and stress stimuli can induce alterations of specific genes involved in the modulation of reward mechanisms and in the development of neuropsychiatric disorders, in age- and sex-dependent fashion.

Stress experienced during the postnatal period represents one of the main negative environmental factors enhancing the risk to develop alcoholism. Maternal separation (MS) in rodent pups represents the most widely used stressor in the context of alcohol seeking. However, the majority of prior studies have used MS at very early time points and stressors experienced by rodents during this developmental period do not properly mimic similar stressors experienced by humans at comparatively developmental stages. Here, to enhance the translational value of our research to understand the long-term consequences of early life stress exposure on later vulnerability to develop alcoholism, we exposed preweaning male and female Marchigan Sardinian alcohol preferring (msP) and Wistar rats to mild repeated social deprivations during the third postnatal week. Operant responding for alcohol under fixed ratio 1 (FR1) and progressive ratio (PR) schedule of reinforcement were then determined starting from adolescence. The effect of the pharmacological stressor yohimbine in increasing alcohol self-administration (SA) as well as the vulnerability to relapse after yohimbine injection were also evaluated. Operant responding and motivation for alcohol were not altered by our environmental manipulation either in Wistars or in msP rats. Administration of the pharmacological stressor yohimbine (0.0, 0.312, 0.625 and 1.25mg/kg) increased alcohol SA in both rat lines independently from early social isolation (ESI). Following extinction, yohimbine (0.625 mg/kg) reinstated alcohol seeking in female rats only, where ESI resulted in a higher level of reinstatement in adult female msPs. Overall, results indicate that repeated mild social deprivations experienced during the third postnatal week did not affect later susceptibility to increase the motivation for alcohol in male and female msP and Wistar rats. However, in female msP rats, ESI increased alcohol seeking triggered by the pharmacological stressor yohimbine.

In recent years, eating disorders are starting to have an increasing incidence, above all younger people. Extremely complex is the clinical framework, not only in terms of symptoms and course, but also in terms of the factors that contribute to their onset.

In the present study, Anorexia Nervosa (AN), a psychiatric illness characterised by disturbed eating, is investigated when a chronic stressor such as maternal separation (MS) occurs in the postnatal period, before the onset of the disorder. Results from a previous study revealed a synergistic mechanism between early MS and a paradigm used to mimic anorectic conditions, the activity-based anorexia (ABA) rat model.

An important role is played by sex hormones in brain development and response to stressful events. For this reason, Gonadectomized (GDX) rats of both sexes were exposed to the two paradigms in order to investigate a possible sexual dimorphic effect of MS, ABA, and the combination of the two stressors. We evaluated anxiety-like behaviors, ABA-related parameters, the reward system, specifically dopamine (DA), serotonin (5-HT), and orexin (ORX) circuits, known to regulate food consumption and locomotor activity.

The results showed that GDX-ABA rats of both sexes displayed hyperactivity and a reduction in anxiety-like behavior compared to controls. Moreover, GDX rats with MS-ABA revealed sex-dependent alteration of the behavioral phenotype.

The immunohistochemical analysis of the circuits linked to the reward system and food consumption seems to show an alteration based on the nuclei considered. In particular 5-HT and DA system seem to be more affected by the stress event of early MS. On the contrary, the analysis suggests that ORX circuits could be more altered when the stressor is the ABA protocol.

The sexually distinct outcomes studied are probably linked to a different effect mediated by sex steroids on behaviour and reward systems.