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

早期乙醇对睡眠期间网络活动的长期影响

• 批准号: 8744623
• 负责人: Mariko Saito
• 金额: $ 32.24万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-10 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8744623
• 关键词: Acute; Adult; Affect; Age; Alcohol abuse; Amygdaloid structure; Animals; Attention; Behavioral; Binding; Biological Models; Biological Neural Networks; Brain; Brain region; Cell Survival; Cells; Circadian Rhythm Sleep Disorders; Cognition; Cognitive; Cognitive deficits; Complex; Data; Development; Dissection; Ethanol; Etiology; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; Hippocampal Formation; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; Impairment; Intellectual functioning disability; Interneurons; Learning; Link; Lithium; Memory; Modeling; Modification; Moods; Mus; Neocortex; Neonatal; Nervous System Physiology; Nervous system structure; Neuroprotective Agents; Nose; Odors; Outcome; Parvalbumins; Pathway interactions; Pattern; Perception; Play; Prevention; Process; Psychological Transfer; Regulation; Research Personnel; Rest; Role; Shapes; Sleep; Sleep Fragmentations; Sleep disturbances; Slow-Wave Sleep; Stimulus; Structure; Synapses; System; Techniques; Testing; Time; TimeLine; Training; Transgenic Model; Work; alcohol effect; alcohol exposure; base; conditioning; experience; neural circuit; neurobehavioral; neuroregulation; novel; piriform cortex; prevent; public health relevance; relating to nervous system; repaired

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).

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，具有神经行为的标志，例如学习，记忆和情绪中的缺陷。众所周知，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过程中神经活动模式的长期破坏，这对于记忆巩固和突触稳态很重要。如果是这样，这将造成一种情况，即神经系统在睡眠期间修复和重新调整的正常能力会受到损害，从而导致每天对乙醇暴露结束很长时间的神经系统功能。具体而言，在该提案（PA-12-177：酗酒，睡眠障碍和昼夜节律[R01]）中，我们计划探索暴饮暴食的影响 - 如产前或新生儿小鼠对长期乙醇暴露对Olfacto-Hippocampalpal Pathway的睡眠相关活性的长期变化的影响，以探索Gabaegron的角色。虽然长时间的暴露范例可能与FASD的常见病因更紧密地保持一致，但暴饮暴食模型允许对机制进行更精确的解剖，从而可以进行治疗的潜在途径。目的1是测试以下假设：早期乙醇暴露会诱导慢波睡眠期间Olfacto-Hampocampal途径内的局部（区域）和全局（区域之间）的长期修改。我们将探讨早期乙醇暴露对单单位活动中与睡眠相关的变化的持久影响 和区域连贯性，并预测睡眠结构，尖峰训练时间结构以及在睡眠过程中静止状态功能连接的特定破坏，这可能导致认知和行为缺陷。目的2是检验以下假设：早期乙醇暴露会诱导海马和梨状皮质中GABA能中神经元结构和功能的长期修饰。我们将探索早期乙醇暴露对GABA能细胞存活的持久影响，并使用新型的转基因模型测试特定的GABA能细胞类别中的干扰是否对控制神经同步模拟发育乙醇对醒来和睡眠中神经电路功能的影响很重要。最后，AIM 3将探讨以下假设：早期乙醇暴露时递送的神经保护剂，成年人中的GABA能或慢波睡眠操纵可以防止或修复睡眠破坏及其对认知的影响。如果成功，数据可能会为早期乙醇引起的神经和认知障碍的理解和修复开辟一个新窗口。此外，该协作提案将另一个领域的知名研究人员带入乙醇领域（Wilson）。