Low testosterone promotes anxiety through astrocytic mitochondrial remodelling at the nucleus accumbens blood-brain barrier

Here, using outbred male rats stratified by natural variation in anxiety-like behaviour, we establish its causal endocrine contribution and uncover an astrocytic mitochondrial mechanism at the nucleus accumbens (NAc) blood-brain barrier (BBB). High-anxiety rats showed a NAc-selective increase in BBB permeability, alongside reduced astrocytic endfoot coverage, disrupted endfoot mitochondrial organisation and mitochondria-endoplasmic reticulum contacts, and lower mitofusin 2 (Mfn2).

Testosterone suppression increased anxiety in low-anxiety rats, whereas physiological testosterone restoration reduced anxiety, reconfigured astrocytic mitochondrial and BBB-related transcriptional programmes, increased perivascular AQP4 coverage and endfoot-associated Mfn2, and reduced BBB permeability, with related effects in aged low-testosterone rats. NAc androgen receptor (AR) knockdown blunted behavioural and neurovascular responses, whereas NAc astrocyte-specific Mfn2 overexpression reduced anxiety.