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、记忆和情绪障碍等神经行为特征。虽然已知发育性酒精暴露可以扰乱睡眠结构，但我们在这里提出，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中断，这对记忆巩固和突触动态平衡是重要的。如果是这样的话，这将造成一种情况，即神经系统在睡眠期间自我修复和重新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每天都会对神经系统功能造成侮辱。具体地说，在这项建议(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暴露对嗅觉-海马区通路中睡眠相关活动的长期变化的影响，并开始探索GABA能中间神经元在这一网络活动中的作用。虽然长期暴露的范例可能更接近于FASD的常见病因，但暴饮暴食模型允许更精确地剖析机制，从而实现潜在的治疗途径。第一个目的是验证这一假说，即在慢波睡眠期间，早期酒精暴露会导致嗅觉-海马区通路中局部(区域内)和全局(区域间)网络活动的长期改变。我们将探索早期酒精暴露对睡眠相关单位活动变化的长期影响 和区域一致性，并预测睡眠结构、脉冲训练时间结构和睡眠期间休息状态功能连接的特定中断，这可能会导致认知和行为缺陷。目的2验证早期酒精暴露导致海马和梨状皮质GABA能中间神经元结构和功能长期改变的假说。我们将探索早期酒精暴露对GABA能细胞存活的长期影响，并使用一种新的转基因模型，测试特定GABA能细胞类别中的干扰是否模仿发育中乙醇对清醒和睡眠中神经回路功能的影响。GABA能细胞类别是控制神经同步性的重要因素。最后，目标3将探索这样一种假设，即在酒精暴露的早期给予神经保护剂，或成人的GABA能或慢波睡眠操作可以防止或修复睡眠中断及其对认知的影响。如果成功，这些数据可能会为理解和修复早期乙醇引起的神经和认知损伤打开一扇新的窗口。此外，这一合作提议将另一个领域的知名研究人员带入乙醇领域(威尔逊)。

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).