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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.

2024-12-16 neuroscience
10.1101/2024.12.13.628438 bioRxiv
Show 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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