Regional Differences in BDNF Expression and Behavior as a Function of Sex and Enrichment Type: Oxytocin Matters.

The early environment is critical to brain development, but the relative contribution of physical versus social stimulation is unclear. Here, we investigated in male and female rats the response to early physical and social environmental enrichment in relation to oxytocin (OT) and brain-derived neurotrophic factor (BDNF) expression. The findings show that males and females respond differently to prolonged sensorimotor stimulation from postnatal days 21-110 in terms of functional, structural, and molecular changes in the hippocampus versus medial prefrontal cortex (mPFC). Physical enrichment promoted motor and cognitive functions and hippocampal BDNF mRNA and protein expression in both sexes. Combined physical and social enrichment, however, promoted functional and structural gain in females. These changes were accompanied by elevated plasma oxytocin (OT) levels and BDNF mRNA expression in the mPFC, while the hippocampus was not affected. Administration of an OT antagonist in females blocked the beneficial effects of enrichment and led to reduced cortical BDNF signaling. These findings suggest that an OT-based mechanism selectively stimulates a region-specific BDNF response which is dependent on the type of experience.

Oxytocin-mediated social enrichment promotes longer telomeres and novelty seeking.

The quality of social relationships is a powerful determinant of lifetime health. Here, we explored the impact of social experiences on circulating oxytocin (OT) concentration, telomere length (TL), and novelty-seeking behaviour in male and female rats. Prolonged social housing raised circulating OT levels in both sexes while elongating TL only in females. Novelty-seeking behaviour in females was more responsive to social housing and increased OT levels than males. The OT antagonist (OT ANT) L-366,509 blocked the benefits of social housing in all conditions along with female-specific TL erosion and novelty-seeking deficit. Thus, females seem more susceptible than males to genetic and behavioural changes when the secretion of endogenous OT in response to social life is interrupted. Social enrichment may, therefore, provide a therapeutic avenue to promote stress resiliency and chances of healthy aging across generations.

Intergenerational Sex-Specific Transmission of Maternal Social Experience.

The social environment is a major determinant of individual stress response and lifetime health. The present study shows that (1) social enrichment has a significant impact on neuroplasticity and behaviour particularly in females; and (2) social enrichment in females can be transmitted to their unexposed female descendants. Two generations (F0 and F1) of male and female rats raised in standard and social housing conditions were examined for neurohormonal and molecular alterations along with changes in four behavioural modalities. In addition to higher cortical neuronal density and cortical thickness, social experience in mothers reduced hypothalamic-pituitary-adrenal (HPA) axis activity in F0 rats and their F1 non-social housing offspring. Only F0 social mothers and their F1 non-social daughters displayed improved novelty-seeking exploratory behaviour and reduced anxiety-related behaviour whereas their motor and cognitive performance remained unchanged. Also, cortical and mRNA measurements in the F1 generation were affected by social experience intergenerationally via the female lineage (mother-to-daughter). These findings indicate that social experience promotes cortical neuroplasticity, neurohormonal and behavioural outcomes, and these changes can be transmitted to the F1 non-social offspring in a sexually dimorphic manner. Thus, a socially stimulating environment may form new biobehavioural phenotypes not only in exposed individuals, but also in their intergenerationally programmed descendants.

Lack of Social Support Raises Stress Vulnerability in Rats with a History of Ancestral Stress.

Stress is a primary risk factor for psychiatric disorders. However, it is not fully understood why some stressed individuals are more vulnerable to psychiatric disorders than others. Here, we investigated whether multigenerational ancestral stress produces phenotypes that are sensitive to depression-like symptoms in rats. We also examined whether social isolation reveals potentially latent sensitivity to depression-like behaviours. F4 female rats born to a lineage of stressed mothers (F0-F3) received stress in adulthood while housed in pairs or alone. Social isolation during stress induced cognitive and psychomotor retardation only in rats exposed to ancestral stress. Social isolation also hampered the resilience of the hypothalamic-pituitary-adrenal axis to chronic stress and reduced hippocampal volume and brain-derived neurotrophic factor (BDNF) expression. Thus, synergy between social isolation and stress may unmask a latent history of ancestral stress, and raises vulnerability to mental health conditions. The findings support the notion that social support critically promotes stress coping and resilience.

Topographical disorientation after ischemic mini infarct in the dorsal hippocampus: whispers in silence.

Silent focal ischemic mini infarcts in the brain are thought to cause no clinically overt symptoms. Some populations of hippocampal cells are particularly sensitive to ischemic events, however, rendering hippocampal functions especially vulnerable to ischemia-induced deficits. The present study investigated whether an otherwise silent ischemic mini infarct in the hippocampus (HPC) can produce impairments in spatial performance in rats. Spatial performance was assessed in the ziggurat task (ZT) using a 10-trial spatial learning protocol for 4 days prior to undergoing hippocampal ischemic lesion or sham surgery. Hippocampal silent ischemia was induced by infusion of endothelin-1 (ET-1), a potent vasoconstrictor, into either the dorsal or the ventral hippocampus (dHPC and vHPC). When tested postoperatively in the ZT using a standard testing protocol for 8 days, rats with hippocampal lesions exhibited no spatial deficit. Although spatial learning and memory in the ZT were not affected by the ET-1-induced silent ischemia, rats with dHPC stroke showed more returns when navigating the ZT as opposed to the vHPC rats. Comparison of region-specific HPC lesions in the present study indicated that dorsal hippocampal function is critically required for topographic orientation in a complex environment. Topographic disorientation as reflected by enhanced return behaviors may represent one of the earliest predictors of cognitive decline after silent ischemic insult that may be potentially traced with sensitive clinical examination in humans.