1/8 NADIA UO1 Adolescent Alcohol Effects on Learning and Hippocampal Function

1/8 NADIA UO1 青少年酒精对学习和海马功能的影响

基本信息

批准号：
9768939
负责人：
H SCOTT SWARTZWELDER
金额：
$ 35.78万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768939
关键词：
Acetylcholinesterase Inhibitors Acute Address Adolescence Adolescent Adolescent and Young Adult Adult Area Behavioral Brain Broca&apos s area Cells Chronic Cognitive Collaborations Data Dendritic Spines Dependence Development Diagonal Band of Broca Diffuse Emotional Ethanol Exposure to Funding Hippocampal Formation Hippocampus (Brain)Impairment Learning Lesion Limb structure Link Long-Term Potentiation Medial Mediating Mediation Memory Memory impairment Metaplastic Morphology N-Methyl-D-Aspartate Receptors Neurobiology Neurons Nuclear Antigens Outcome Phase Prevention Process Proteins Pyramidal Cells Rattus Reporting Slice Stains Structure Synapses Synaptic plasticity Testing Thrombospondins Time Up-Regulation Work adolescent alcohol effect adolescent alcohol exposure alcohol effect alcohol exposure cholinergic cholinergic neuron cognitive process critical period density design donepezil excitotoxicity experimental study gabapentin granule cell interest neural circuit neurogenesis neuron loss neuronal excitability prevent public health relevance receptor relating to nervous system social spatial memory synaptogenesis underage drinking

项目摘要

DESCRIPTION (provided by applicant): Component 1 of the Neurobiology of Adolescent Drinking in Adulthood (NADIA) consortium is focused on the enduring effects of adolescent intermittent ethanol (AIE) on learning and hippocampal function in adulthood, issues that are of keen scientific and social interest. The collaborative studies of the NADIA consortium have identified a large number of enduring behavioral and neural effects of AIE, and have begun to identify possible mechanisms underlying them. During the proposed funding period we will directly pursue those mechanisms that are most promising and work to identify translational treatments to prevent or reverse the long-term neural and behavioral effects of AIE. This Component has observed AIE-induced impairment of spatial memory, which is accompanied by changes in hippocampal structure and function that suggest hyperexcitability and aberrant synaptogenesis within hippocampal circuits. For example, we have observed an apparent lowering of the threshold for the induction of long-term potentiation (LTP), decreased tonic inhibition, up-regulation of GluN2A and GluN2B receptor subtypes, and up-regulation of thrombospondins that are known to promote excitatory synaptogenesis, after AIE. Importantly, we have preliminary data indicating an enduring decrease in the numbers of mature neurons in area CA1 after AIE. Together, these findings strongly support our hypothesis that AIE produces hyperexcitability and aberrant plasticity in the hippocampus, resulting in neuronal loss caused by altered synaptogenesis and excitatory drive. Specific Aims 1&2 will address this hypothesis in detail by assessing the receptor mechanisms underlying the effects of AIE on hippocampal excitatory function and synaptic plasticity, the propensity of hippocampal circuits toward aberrant saturation of synaptic plasticity, and AIE-induced neuronal loss. We and other NADIA Components have also observed an AIE-induced reduction in the density of ChAT positive neurons in the medial septum and vertical limb of the diagonal band of Broca (also known as areas Ch1-2). Cholinergic neurons in this region project diffusely to the hippocampal formation and regulate both memory-related synaptic plasticity and neurogenesis. Their reduction after (and perhaps during) AIE is likely to have profound long-term consequences for hippocampal function. Therefore, we also hypothesize that reduced cholinergic input from Ch1-2 during or after AIE compromises memory-related hippocampal function, and that treatment with agents that enhance cholinergic function will prevent or reverse those effects. Specific Aim 3 will determine the point at which cholinergic cell loss in Ch1-2 is initiated during AIE, how the loss o that input to the hippocampal formation alters memory, and memory- related synaptic plasticity in the hippocampal formation, and whether those effects of AIE can be prevented or reversed by agents that promote cholinergic function. These two hypotheses are linked together, addressing related forms of hippocampal dysregulation - one intrinsic and one extrinsic - and our Specific Aims target timely questions that emerge directly from them and are of mechanistic and translational significance. Importantly, each of the Specific Aims in this Component includes direct collaboration with at least one other NADIA Component. This markedly increases our capacity to orient the proposed experiments mechanistically and allows us to be nimble in our pursuit of new directions as they emerge.

描述（由申请人提供）：成年期青少年饮酒神经生物学 (NADIA) 联盟的第 1 部分重点关注青少年间歇性乙醇 (AIE) 对成年期学习和海马功能的持久影响，这些问题具有敏锐的科学性和社会性NADIA 联盟的合作研究已经确定了 AIE 的大量持久的行为和神经影响，并已开始在拟议的资助期内确定其背后的可能机制。我们将直接探索那些最有希望的机制，并努力确定转化疗法，以预防或逆转 AIE 的长期神经和行为影响。该组件观察到 AIE 引起的空间记忆损伤，并伴有海马的变化。例如，我们观察到诱导长时程增强 (LTP) 的阈值明显降低、强直抑制减少、神经元突触发生上调。 AIE 后，GluN2A 和 GluN2B 受体亚型以及已知可促进兴奋性突触发生的血小板反应蛋白强烈上调。重要的是，我们有初步数据表明 AIE 后 CA1 区成熟神经元数量持续减少。支持我们的假设，即 AIE 在海马体中产生过度兴奋性和异常可塑性，导致突触发生和兴奋性特异性改变引起的神经元损失。目标 1 和 2 将通过评估 AIE 对海马兴奋功能和突触可塑性影响的受体机制、海马回路突触可塑性异常饱和的倾向以及 AIE 诱导的神经元损失来详细阐述这一假设。还观察到 AIE 诱导的布罗卡对角带的内侧隔膜和垂直肢中 ChAT 阳性神经元密度的降低（也称为 Ch1-2 区域）。该区域的胆碱能神经元广泛投射到海马结构并调节与记忆相关的突触可塑性和神经发生，它们在 AIE 后（或许在 AIE 期间）的减少可能会产生深远的长期后果。因此，我们还认为 AIE 期间或之后 Ch1-2 的胆碱能输入减少会损害与记忆相关的海马功能，并且使用增强胆碱能功能的药物进行治疗会影响海马功能。具体目标 3 将确定 AIE 期间 Ch1-2 中胆碱能细胞丢失的起始点、海马结构输入的丢失如何改变记忆以及海马结构中与记忆相关的突触可塑性。，以及 AIE 的这些影响是否可以通过促进胆碱能功能的药物来预防或逆转。这两种假设是相互关联的，解决了海马失调的相关形式——一种是内在的，另一种是内在的。外在的 - 我们的具体目标针对直接出现的问题，具有机械和转化意义。重要的是，该组件中的每个具体目标都包括与至少一个其他 NADIA 组件的直接合作，这显着提高了我们的定位能力。所提出的实验是机械地进行的，使我们能够在新方向出现时灵活地追求它们。