Downregulated Kcnd3 in the PSTh is vital for CSDS-induced anxiety-like behavior

Anxiety disorders seriously damage our mental health, with chronic stress identified as a major etiologic factor. However, the precise neural mechanisms underlying the transition from chronic stress to anxiety remain unclear. In this study, with the chronic social defeat stress (CSDS) paradigm in mice, we verified a critical role of the parasubthalamic nucleus (PSTh) in anxiety regulation and found that CSDS results in a lasting increase in PSTh neuronal activity. Here, we explored the molecular substrates responsible for the increased intrinsic excitability of PSTh neurons following CSDS by RNA-sequence experiments. We found that CSDS downregulated Kcnd3 in PSTh neurons. Kcnd3 knockdown enhanced PSTh neuronal activity and produced anxiogenic effects in unstressed naïve mice, whereas overexpression of Kcnd3 in PSTh neurons dampened neuronal over-excitability and alleviated anxiety-like behavior in CSDS animals. Taken together, our results provide a cellular mechanism that the downregulated Kcnd3 induced by CSDS mediates intrinsic excitability of PSTh neurons, leading to anxiety-like behavior.