TESTOSTERONE REMODELS ASTROCYTE ENDFEET IN THE NUCLEUS ACCUMBENS TO MODULATE ANXIETY BEHAVIOUR

High anxiety is a critical risk factor for various physical and mental disorders, notably depression, with which it shares considerable comorbidity. Despite significant advances in our understanding of the neurocircuitry underlying anxiety, whether peripheral hormonal signalling can shape these circuits to influence behaviour remains unclear. Testosterone, the major male sex hormone, is associated with social dominance and reward processing. Emerging evidence suggests that androgen signalling can also modulate anxiety with a notable link between low testosterone and anxiety in humans. However, the specific signalling mechanisms through which testosterone may influence anxiety‑related behaviour remains poorly defined. Here, we investigated how testosterone modulates cellular and circuit function within the nucleus accumbens (NAc) in a rodent model of anxiety in Wistar rats. We found that highly anxious (HA) rats display reduced levels of blood testosterone. HA rats displayed alterations in astrocyte endfeet coverage of endothelial cells and showed compromised blood-brain-barrier (BBB), including reduced expression of endothelial tight junction proteins, BBB leakage, and changes in astrocyte endfeet mitochondria. These structural changes were linked to reductions in medium spiny neuron (MSN) dendritic complexity and mEPSCs. By pharmacologically inhibiting testosterone production in low anxious rats, we could recapitulate the cellular and behavioural phenotypes observed in HA rats. Conversely, supplementing HA rats with exogenous testosterone ameliorated anxiety-like behaviours, increased astrocyte endfeet coverage at the BBB, and rescued the effects of anxiety on MSN excitatory synaptic inputs. Together, these findings identify the specific mechanisms at the NAc level through which testosterone can modulate anxiety behaviour.