Chemogenetic inhibition of prefrontal cortex inputs to dorsal raphe reduces anxiety behaviors in male rat model of fetal alcohol spectrum disorder.

Abstract

Prenatal ethanol exposure (PE) causes Fetal Alcohol Spectrum Disorders (FASD), characterized by cognitive, behavioral, and emotional deficits, including anxiety and depression. PE-induced alteration in the function of dorsal raphe nucleus (DRN) serotonin (5-HT) neurons is thought to be major contributing factor for increased anxiety. However, the precise neuronal circuits involved are unknown. Using electrophysiology, optogenetics, chemogenetics, and behavioral approaches, we find that PE preferentially potentiates medial prefrontal cortex (mPFC) glutamatergic inputs, but not lateral habenula (LHb), to DRN 5-HT neurons projecting to mPFC. Additionally, PE also increases the strength of LHb but not mPFC excitatory inputs to DRN 5-HT neurons projecting to central amygdala (Ce). This input and target selective effect of PE was mediated by a circuit-specific increase in nitric oxide (NO) signaling. Importantly, chemogenetic inhibition of mPFC-DRN neuronal circuit blunted anxiety-like behaviors in PE rats. As such, our results unraveled the DRN neuronal circuitries affected by PE, which gate FASD-induced anxiety-like behaviors.