Gestational ethanol exposure impairs motor skills in female mice through dysregulated striatal dopamine and acetylcholine function.
Gestational ethanol exposure impairs motor skills in female mice through dysregulated striatal dopamine and acetylcholine function.
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DOI：
10.1038/s41386-023-01594-4
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发表时间：
2023-11
影响因子：
7.6
通讯作者：
Lovinger, David M.
中科院分区：
文献类型：
--
作者：
Bariselli, Sebastiano;Mateo, Yolanda;Reuveni, Noa;Lovinger, David M.
胎儿酒精暴露对胎儿酒精谱系障碍（FASD）患者以及妊娠期乙醇暴露（GEE）的临床前模型的运动技能有有害影响。纹状体胆碱能中间神经元（CINs）和多巴胺功能的缺陷会损害动作学习和执行，但GEE对乙酰胆碱（ACh）和纹状体多巴胺释放的影响仍未被探究。在此，我们报告在出生后的前十天进行酒精暴露（GEEP0 - P10），这模拟了人类妊娠晚期的乙醇摄入，会在成年雌性小鼠中诱导出性别特异性的解剖结构和运动技能缺陷。与这些行为损伤一致，我们观察到GEEP0 - P10雌性小鼠（而非雄性小鼠）的背外侧纹状体（DLS）中刺激诱发的多巴胺水平升高。进一步的实验揭示了含β2的烟碱型乙酰胆碱受体（nAChR）对电刺激诱发的多巴胺释放的调节存在性别特异性缺陷。此外，我们发现GEEP0 - P10雌性小鼠的DLS中乙酰胆碱瞬变的衰减减少以及纹状体CINs的兴奋性降低，表明纹状体CIN功能失调。最后，给予伐尼克兰（一种含β2的nAChR部分激动剂）以及通过化学遗传学方法增加CIN活性，可改善成年GEEP0 - P10雌性小鼠的运动表现。总之，这些数据为GEE诱导的纹状体缺陷提供了新的见解，并确立了潜在的药理学和特定回路干预措施以改善FASD的运动症状。
Fetal alcohol exposure has deleterious consequences on the motor skills of patients affected by Fetal Alcohol Spectrum Disorder (FASD) and in pre-clinical models of gestational ethanol exposure (GEE). Deficits in striatal cholinergic interneurons (CINs) and dopamine function impair action learning and execution, yet the effects of GEE on acetylcholine (ACh) and striatal dopamine release remain unexplored. Here, we report that alcohol exposure during the first ten postnatal days (GEEP0-P10), which mimics ethanol consumption during the last gestational trimester in humans, induces sex-specific anatomical and motor skill deficits in female mice during adulthood. Consistent with these behavioral impairments, we observed increased stimulus evoked-dopamine levels in the dorsolateral striatum (DLS) of GEEP0-P10 female, but not male, mice. Further experiments revealed sex-specific deficits in β2-containing nicotinic ACh receptor (nAChR)-modulation of electrically evoked dopamine release. Moreover, we found a reduced decay of ACh transients and a decreased excitability of striatal CINs in DLS of GEEP0-P10 females, indicating striatal CIN dysfunctions. Finally, the administration of varenicline, a β2-containing nAChR partial agonist, and chemogenetic-mediated increase in CIN activity improved motor performance in adult GEEP0-P10 females. Altogether, these data shed new light on GEE-induced striatal deficits and establish potential pharmacological and circuit-specific interventions to ameliorate motor symptoms of FASD.
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影响因子：
64.8
作者：
Cui, Guohong;Jun, Sang Beom;Jin, Xin;Pham, Michael D.;Vogel, Steven S.;Lovinger, David M.;Costa, Rui M.
通讯作者：
Costa, Rui M.
影响因子：
3.8
作者：
BLOMQVIST, O;SODERPALM, B;ENGEL, JA
通讯作者：
ENGEL, JA
影响因子：
3.7
作者：
Allan, Andrea M.;Goggin, Samantha L.;Caldwell, Kevin K.
通讯作者：
Caldwell, Kevin K.
影响因子：
16.6
作者：
Carlson, Verginia C. Cuzon;Gremel, Christina M.;Lovinger, David M.
通讯作者：
Lovinger, David M.
影响因子：
4.7
作者：
Barbier, Estelle;Pierrefiche, Olivier;Naassila, Mickael
通讯作者：
Naassila, Mickael