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

描述（由申请人提供）：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，具有神经行为特征，如学习，记忆和情绪方面的缺陷。虽然它是已知的，发育乙醇暴露可以破坏睡眠结构，在这里，我们提出，发育乙醇暴露可能会导致长期的睡眠过程中的神经活动模式的破坏，这是已知的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，其中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，导致在乙醇暴露结束后很长一段时间内对神经系统功能的日常损害。具体而言，在本提案（PA- 12-177：酒精滥用、睡眠障碍和昼夜节律[R 01]）中，我们计划探索产前或新生小鼠的酒精暴露对嗅觉-海马通路中睡眠相关活动长期变化的影响，并开始探索GABA能中间神经元在该网络活动中的作用。虽然长期暴露范式可能更接近FASD的常见病因，但狂欢模型允许更精确地解剖机制，从而提供潜在的治疗途径。目的1是测试这一假设，即早期乙醇暴露诱导长期修改的本地（区域内）和全球（区域之间）的网络活动在慢波睡眠的嗅觉海马通路。我们将探讨早期乙醇暴露对睡眠相关的单单位活动变化的长期影响 和区域一致性，并预测睡眠结构，尖峰序列时间结构和睡眠期间静息状态功能连接的特定中断，可能导致认知和行为缺陷。目的二是验证早期乙醇暴露诱导海马和梨状皮质GABA能中间神经元结构和功能长期改变的假说。我们将探讨长期持久的影响，早期乙醇暴露对GABA能细胞的生存，并使用一种新的转基因模型，测试是否在一个特定的GABA能细胞类的干扰已知是重要的控制神经同步模仿发育乙醇的影响，在清醒和睡眠的神经回路功能。最后，目标3将探讨在早期乙醇暴露时提供的神经保护剂，或成人GABA能或慢波睡眠操作可以预防或修复睡眠中断及其对认知的影响。如果成功的话，这些数据可以为理解和修复早期乙醇诱导的神经和认知障碍打开一扇新的窗户。此外，这一合作提案将另一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).