Chronic social isolation exerts opposing sex-specific consequences on serotonin neuronal excitability and behaviour.

Social isolation raises the risk for mood disorders associated with serotonergic disruption. Yet, the underlying mechanisms by which the stress of social isolation increases risk are not well understood. Men and women are differently vulnerable; however, this modulating role of sex is challenging to study in humans under carefully controlled conditions. Therefore, we investigated this question in mice of both sexes, asking how the long-term stress of social isolation (from weaning into adulthood) affects the excitability of serotonin neurons in the dorsal raphe nucleus as well as mouse behaviour. The electrophysiological experiments and the first set of behavioural tests were conducted in young adult mice, with additional behavioural assays completed as the mice matured to assess the stability of their behavioural phenotype. We found that social isolation exerted seemingly-opposite effects in male and female mice, relative to their respective group-housed littermate controls. This distinctive pattern was observed for the effect of social isolation on the control of serotonergic neuron excitability via the SK family of calcium-activated potassium channels. Furthermore, we observed a similar and consistent pattern on tests relevant to assessing the efficacy of anti-depressant medicines, including the forced swim test, the novelty-suppressed feeding test, and the sucrose preference test. These findings underscore the concept that stress-elicited illness manifests distinctly in males and females and that treatments aimed at restoring serotonergic function may require a sex-specific approach. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.