Dexmedetomidine Inhibits Paraventricular Corticotropin-releasing Hormone Neurons that Attenuate Acute Stress-induced Anxiety-like Behavior in Mice

Background:Dexmedetomidine has repeatedly shown to improve anxiety, but the precise neural mechanisms underlying this effect remain incompletely understood. This study aims to explore the role of corticotropin-releasing hormone-producing hypothalamic paraventricular nucleus (CRHPVN) neurons in mediating the anxiolytic effects of dexmedetomidine.Methods:A social defeat stress mouse model was used to evaluate the anxiolytic effects induced by dexmedetomidine through the elevated plus maze, open-field test, and measurement of serum stress hormone levels. In vivo Ca2+ signal fiber photometry and ex vivo patch-clamp recordings were used to determine the excitability of CRHPVN neurons and investigate the specific mechanism involved. CRHPVN neuron modulation was achieved through chemogenetic activation or inhibition.Results:Compared with saline, dexmedetomidine (40 mu g/kg) alleviated anxiety-like behaviors. Additionally, dexmedetomidine reduced CRHPVN neuronal excitability. Chemogenetic activation of CRHPVN neurons decreased the time spent in the open arms of the elevated plus maze and in the central area of the open-field test. Conversely, chemogenetic inhibition of CRHPVN neurons had the opposite effect. Moreover, the suppressive impact of dexmedetomidine on CRHPVN neurons was attenuated by the alpha 2-receptor antagonist yohimbine.Conclusions:The results indicate that the anxiety-like effects of dexmedetomidine are mediated via alpha 2-adrenergic receptor-triggered inhibition of CRHPVN neuronal excitability in the hypothalamus. In mice, dexmedetomidine attenuated anxiety-like behavior, and this was correlated with a decrease in the activity of corticotropin-releasing hormone-producing neurons in the hypothalamic paraventricular nucleus. A combination of chemogenetic, pharmacologic, and electrophysiologic experiments in mice demonstrated a central role of these neurons in mediating anxiety-like behaviors. Altogether, these results indicate that the anxiety-like effects of dexmedetomidine may be mediated via alpha 2 -adrenergic receptor-triggered inhibition of corticotropin-releasing hormone-producing neuronal activity in the hypothalamus.