Long-lasting consequences of early ethanol on network activity during sleep

描述（申请人提供）：胎儿酒精谱系障碍（FASD）是西方国家智力残疾的主要原因之一，具有学习、记忆和情绪缺陷等神经行为特征。虽然已知发育性乙醇暴露会破坏睡眠结构，但在这里，我们提出发育性乙醇暴露可能会导致睡眠期间神经活动模式的长期破坏，而这对于记忆巩固和突触稳态是重要的。如果是这样的话，这将造成一种情况，即神经系统在睡眠中自我修复和调整的正常能力将受到损害，导致在酒精暴露结束后很长一段时间内神经系统功能每天都受到损害。具体来说，在这个提案（PA- 12-177：酒精滥用，睡眠障碍和昼夜节律[R01]）中，我们计划探索产前或新生小鼠酗酒样乙醇暴露对嗅觉-海马通路中睡眠相关活动的长期变化的影响，并开始探索gaba能中间神经元在该网络活动中的作用。虽然长时间暴露模式可能更接近于FASD的常见病因，但暴食模型可以更精确地解剖机制，从而找到潜在的治疗途径。目的1是验证早期乙醇暴露在慢波睡眠期间引起局部（区域内）和整体（区域之间）嗅-海马通路网络活动的长期改变的假设。我们将探索早期乙醇暴露对单单位活动睡眠相关变化的长期影响

DESCRIPTION (provided by applicant): Fetal alcohol spectrum disorder (FASD) is one of the primary causes of intellectual disability in western nations, with neurobehavioral hallmarks such as deficits in learning, memory and mood. While it is known that developmental ethanol exposure can disrupt sleep structure, here we propose that developmental ethanol exposure may induce long-lasting disruption of neural activity patterns during sleep which are known to be important for memory consolidation and synaptic homeostasis. If so, this would create a situation wherein the normal ability of the nervous system to repair and readjust itself during sleep would be impaired, resulting in a daily insult to nervous system function long after the ethanol exposure ended. Specifically, in this proposal (PA- 12-177: Alcohol abuse, sleep disorders and circadian rhythms [R01]) we plan to explore the effects of binge- like ethanol exposure of prenatal or neonatal mice on long-term changes in sleep-associated activity in the olfacto-hippocampal pathway, and to begin to explore the role of GABAergic interneurons in this network activity. While prolonged exposure paradigms may align more closely to common etiologies of FASD, the binge model allows a more precise dissection of mechanisms, and thus potential avenues of treatment. Aim 1 is to test the hypothesis that early ethanol exposure induces long-term modification of both local (within region) and global (between regions) network activity within the olfacto-hippocampal pathway during slow-wave sleep. We will explore the long-lasting effects of early ethanol exposure on sleep related changes in single-unit activity and regional coherence, and predict specific disruptions in sleep structure, spike train temporal structure and in resting state functional connectivity during sleep that could result in cognitive and behavioral deficits. Aim 2 is to test the hypothesis that early ethanol exposure induces long-term modification of GABAergic interneuron structure and function in hippocampus and piriform cortex. We will explore the long-lasting effects of early ethanol exposure on GABAergic cell survival and, using a novel transgenic model, test whether disturbance in a specific GABAergic cell class known to be important for controlling neural synchrony mimics developmental ethanol's effects on neural circuit function in waking and sleep. Finally, Aim 3 will explore the hypothesis that neuroprotectants delivered at the time of the early ethanol exposure, or GABAergic or slow-wave sleep manipulations in adults can prevent or repair sleep disruption and its effects on cognition. If successful, the data could open a new window into both understanding and repair of early ethanol-induced neural and cognitive impairment. Furthermore, this collaborative proposal brings an established researcher in another field into the ethanol field (Wilson).