Silent information regulator sirtuin 1-mediated neuronal excitation-inhibition imbalance in the central amygdala is involved in peripheral nerve injury-induced depression-related behavior in mice

Chronic pain often coexists with depression. We have found that histone deacetylase Silent information regulator sirtuin 1 (SIRT1) is involved in peripheral nerve injury-induced depression-related behavior in mice. However, the underlying mechanism is still unclear. In this study, using a mouse spared nerve injury (SNI) model, we found that SIRT1 was downregulated in both glutamatergic and GABAergic neurons in the central amygdala (CeA) of mice with peripheral nerve injury-induced depression-related behavior. SIRT1 overexpression in CeA glutamatergic or GABAergic neurons effectively alleviated peripheral nerve injury-induced depression-related behavior in mice. Moreover, peripheral nerve injury induced significant neuronal excitation-inhibition (E-I) imbalance in CeA, manifested by the increased glutamatergic neuronal excitability and decreased GABAergic neuronal excitability in SNI mice. SIRT1 overexpression in CeA glutamatergic neurons decreased glutamatergic neuronal activity without influence on GABAergic neuronal activity, while SIRT1 overexpression in CeA GABAergic neurons increased GABAergic neuronal activity and reduced glutamatergic neuronal activity in SNI mice. Moreover, optogenetic induction of neuronal E-I imbalance in CeA by activating glutamatergic neurons or inhibiting GABAergic neurons reversed the improvement of peripheral nerve injury-induced depression-related behavior by SIRT1 overexpression. These findings suggest that the dysfunction of SIRT1 is related to the development of peripheral nerve injury-induced depression-related behavior by decreasing GABAergic neuronal excitability and enhancing glutamatergic neuronal excitability, leading to the neuronal E-I imbalance in CeA. These results demonstrate that SIRT1 is a key regulator in peripheral nerve injury-induced depression-related behavior.