Low testosterone promotes anxiety through astrocytic mitochondrial remodelling at the nucleus accumbens blood-brain barrier
- 1Ecole Polytechnique Federale de Lausanne, Brain Mind Institute, Lausanne, Switzerland
Abstract
Low testosterone is linked to anxiety in men, but its causal role and underlying brain mechanisms remain unknown. 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 astrocytic endfoot coverage and Mfn2, recovering 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. Thus, testosterone-AR signalling engages an astrocytic mitochondrial programme at the NAc neurovascular interface linking low testosterone to anxiety vulnerability.
Related
- C3a receptor signalling in ObRb-expressing neurons promotes leptin resistance and obesity-associated cardiac remodelling
- Astrocyte molecular rhythm disruption in nucleus accumbens promotes increased binge-like drinking in mice
- A stress-adapted fiber state promotes clonal expansion of deleted mitochondrial DNA
- Targeting Mitochondrial Redox Signaling Promotes Neuroregeneration and Functional Recovery in a Multiple Sclerosis Model.
- From Reward to Cue: Developmental Changes in Nucleus Accumbens and Dopamine Signaling from Adolescence to Adulthood
BibTeX
@misc{abrantes2026testosterone,
title = {{Low testosterone promotes anxiety through astrocytic mitochondrial remodelling at the nucleus accumbens blood-brain barrier}},
author = {H. de Castro Abrantes and L. R. Depaauw-Holt and D. H. Ulgen and C. Di Giulio and M. Barbetti and E. Gebara and F. Hollis and J. L. Solano and L. Schlotterose and C. Menard and M. Salman and S. Astori and C. Sandi},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.749088},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.749088v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Low testosterone promotes anxiety through astrocytic mitochondrial remodelling at the nucleus accumbens blood-brain barrier
AU - H. de Castro Abrantes
AU - L. R. Depaauw-Holt
AU - D. H. Ulgen
AU - C. Di Giulio
AU - M. Barbetti
AU - E. Gebara
AU - F. Hollis
AU - J. L. Solano
AU - L. Schlotterose
AU - C. Menard
AU - M. Salman
AU - S. Astori
AU - C. Sandi
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.749088
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.749088v1
AB - Low testosterone is linked to anxiety in men, but its causal role and underlying brain mechanisms remain unknown. 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 astrocytic endfoot coverage and Mfn2, recovering 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. Thus, testosterone-AR signalling engages an astrocytic mitochondrial programme at the NAc neurovascular interface linking low testosterone to anxiety vulnerability.
ER -