Social isolation during adolescence alters novel object recognition memory, brain and gut gene expression, and microbiota composition in a sex-specific manner.

Adolescent social isolation is a known risk factor for anxiety and depression related disorders, yet its effects on brain-gut communication and potential sex differences remain unclear. We hypothesised that isolation would heighten anxiety- and depression-related behaviors and consequently impair memory in both sexes. To investigate this we exposed male (M) and female (F) rats to four weeks of social isolation beginning at 3 weeks of age and assessed behavior, brain and gut gene expression and microbiota, in single- (S) or pair-housed (P) animals. Contrary to our hypothesis, the results showed higher novel object recognition memory in socially-isolated females (FS vs FP). No isolation-induced changes in anxiety-related behaviours were detected in either sex. Social isolation in females (FS vs FP) increased expression of hippocampal Grik5 (glutamate receptor/memory/learning), and decreased expression of prefrontal cortex genes: Mbp, Mobp, Plp1 (neuroplasticity), Cnp (neuroprotection) and Tph2 (serotonin synthesis). There was a trend toward lower microbial diversity in socially-isolated females (FS vs FP). Although no behaviour change was detected in isolated males, amygdala c-Fos (neuronal activity) and prefrontal cortex Gabbr1 (inhibitory) expression were decreased. Il6r, Tgfb1, Tlr9 (immune-related) were increased in the colon (MS vs MP). In both sexes, social isolation increased Tph1 expression in the colon (FS vs FP; MS vs MP). These findings indicate sex-specific responses to adolescent social isolation, with females showing enhanced novel object recognition memory performance alongside changes in genes linked to neuroplasticity and memory, while males showed altered brain and gut gene expression linked to brain neuro-activity and gut-immune function.