Oubraim Saida, Hausknecht Kathryn, Micov Veronika, Shen Roh-Yu, Haj-Dahmane Samir
Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, USA.
University at Buffalo Neuroscience Program, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, 1021 Main Street, Buffalo, NY, 14203, USA.
Sci Rep. 2025 Apr 24;15(1):14397. doi: 10.1038/s41598-025-99181-8.
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.
产前乙醇暴露（PE）会导致胎儿酒精谱系障碍（FASD），其特征为认知、行为和情感缺陷，包括焦虑和抑郁。PE引起的中缝背核（DRN）5-羟色胺（5-HT）能神经元功能改变被认为是焦虑增加的主要因素。然而，其中涉及的确切神经回路尚不清楚。通过电生理学、光遗传学、化学遗传学和行为学方法，我们发现，PE优先增强投射到内侧前额叶皮质（mPFC）的DRN 5-HT能神经元的内侧前额叶皮质（mPFC）谷氨酸能输入，但不增强外侧缰核（LHb）的输入。此外，PE还增强了投射到中央杏仁核（Ce）的DRN 5-HT能神经元的外侧缰核（LHb）而非内侧前额叶皮质（mPFC）的兴奋性输入。PE的这种输入和靶点选择性效应是由一氧化氮（NO）信号通路在特定回路中的增加介导的。重要的是，化学遗传学抑制mPFC-DRN神经回路可减轻PE大鼠的焦虑样行为。因此，我们的研究结果揭示了受PE影响的DRN神经回路，这些神经回路控制着FASD诱导的焦虑样行为。
