Early-life adversity mediates a thalamo-amgydalar circuit dysfunction underlying chronic pain and anxiety

Borruto, A. M.; Kohlund, T.; Renesse, M. v.; Rettig, L.; Leonhardt, N.; Calpe-Lopez, C.; Benn, L.; Friederich, H.-C.; Kuner, R.; Kuner, T.; Spanagel, R.; Wieland, S.

doi:10.1101/2024.12.13.628438

bioRxiv · 10.1101/2024.12.13.628438

Early-life adversity mediates a thalamo-amgydalar circuit dysfunction underlying chronic pain and anxiety

Borruto, A. M.·Kohlund, T.·Renesse, M. v.·Rettig, L.·Leonhardt, N.·Calpe-Lopez, C.·Benn, L.·Friederich, H.-C.·Kuner, R.·Kuner, T.·Spanagel, R.·Wieland, S.

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Abstract

Childhood adversity increases the risk of developing a vicious cycle of chronic pain and comorbid anxious avoidance, yet the underlying biological mechanisms remain unclear. Here, we investigated the role of a brain circuit from the paraventricular thalamus (PVT) to the central amygdala (CeA) in mediating hyperalgesia and comorbid anxiety following early life stress. Using a vulnerability-stress model, we exposed both male and female mice to early social isolation (vulnerability) followed by nerve injury (stress) and showed increased hyperalgesia and anxious avoidance behavior in nerve-injured female mice following early adversity. Chemogenetic, electrophysiological, and optophysiological analyses revealed a causal contribution of a hyperexcitable PVT-CeA circuit dysfunction to chronic hyperalgesia and anxiety in nerve-injured female mice after early life stress. Our findings reveal a neural mechanism linking childhood adversity to chronic pain and anxiety, and suggest that reprogramming this pathway may reverse the impact of childhood adversity.

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Borruto, A. M., Kohlund, T., Renesse, M. v., Rettig, L., Leonhardt, N., Calpe-Lopez, C., Benn, L., Friederich, H.-C., Kuner, R., Kuner, T., Spanagel, R., Wieland, S.. 2024-12-16. Early-life adversity mediates a thalamo-amgydalar circuit dysfunction underlying chronic pain and anxiety. https://doi.org/10.1101/2024.12.13.628438

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