1/8 NADIA U01 Effects of Adolescent Alcohol Exposure on Hippocampal Function in Adulthood

1/8 NADIA U01 青少年酒精暴露对成年后海马功能的影响

• 批准号: 10328618
• 负责人: H SCOTT SWARTZWELDER
• 金额: $ 16.08万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328618
• 关键词: Adolescence; Adolescent; Adolescent and Young Adult; Adult; Affective; Alcohols; Animals; Anxiety; Area; Aricept; Attenuated; Behavior; Behavioral; Brain; Brain region; CASP3 gene; Cell Death; Cell Survival; Cells; Child; Childhood; Choline; Cholinesterase Inhibitors; Cognition; Cognitive; Development; Diet; Dietary Supplementation; Diffuse; Ethanol; Exposure to; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Genes; Grant; Hippocampal Formation; Hippocampus (Brain); Human; Lead; Long-Term Effects; Longevity; Mediation; Memory; Memory impairment; Methylation; Neurologic; Neurons; Neurophysiology - biologic function; Parents; Perinatal; Prevention; Production; Public Health; Rattus; Regulation; Reporting; Risk; Rodent; Safety; Severities; Structure; Synapses; Testing; activity marker; adolescent alcohol effect; adolescent alcohol exposure; alcohol effect; alcohol exposure; anxiety-like behavior; basal forebrain; behavioral study; brain behavior; choline supplementation; cholinergic; cholinergic neuron; clinically significant; conditioned fear; critical period; dietary; dietary control; donepezil; excitotoxicity; immunoreactivity; inflammatory milieu; male; memory recognition; neurogenesis; neuroinflammation; neuron loss; neurotransmission; object recognition; parent grant; perinatal alcohol exposure; prevent; promoter; receptor for advanced glycation endproducts; relating to nervous system; sex; social; synaptogenesis; tool; underage drinking; Adolescence; Adolescent; Adolescent and Young Adult; Adult; Affective; Alcohols; Animals; Anxiety; Area; Aricept; Attenuated; Behavior; Behavioral; Brain; Brain region; CASP3 gene; Cell Death; Cell Survival; Cells; Child; Childhood; Choline; Cholinesterase Inhibitors; Cognition; Cognitive; Development; Diet; Dietary Supplementation; Diffuse; Ethanol; Exposure to; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Genes; Grant; Hippocampal Formation; Hippocampus (Brain); Human; Lead; Long-Term Effects; Longevity; Mediation; Memory; Memory impairment; Methylation; Neurologic; Neurons; Neurophysiology - biologic function; Parents; Perinatal; Prevention; Production; Public Health; Rattus; Regulation; Reporting; Risk; Rodent; Safety; Severities; Structure; Synapses; Testing; activity marker; adolescent alcohol effect; adolescent alcohol exposure; alcohol effect; alcohol exposure; anxiety-like behavior; basal forebrain; behavioral study; brain behavior; choline supplementation; cholinergic; cholinergic neuron; clinically significant; conditioned fear; critical period; dietary; dietary control; donepezil; excitotoxicity; immunoreactivity; inflammatory milieu; male; memory recognition; neurogenesis; neuroinflammation; neuron loss; neurotransmission; object recognition; parent grant; perinatal alcohol exposure; prevent; promoter; receptor for advanced glycation endproducts; relating to nervous system; sex; social; synaptogenesis; tool; underage drinking

Adolescence is critical for cognitive, affective, social, and neurological maturation. Repeated alcohol exposure during adolescence produces brain and behavioral deficits that persist into adulthood and possibly throughout the lifespan. We have reported enduring effects of adolescent intermittent ethanol (AIE) exposure on hippocampal structure and function and the behaviors they regulate, such as memory and anxiety, and that many of these AIE effects can be ameliorated by the anticholinesterase drug, donepezil (Aricept). This cholinergic mediation of AIE effects lead us to hypothesize that dietary choline supplementation during AIE could prevent or ameliorate the long-term effects of AIE on brain and behavior. We have shown that early dietary choline supplementation enhances memory-related hippocampal function and is neuroprotective for hippocampal cells. Importantly, recent studies indicate that both perinatal and adolescent choline supplementation reduce the severity of neural and behavioral deficits associated with perinatal alcohol exposure. Adolescent choline supplementation (ACS), specifically, has been shown to reverse memory deficits induced by perinatal ethanol exposure and to diminish anxiety-like behavior in adult rats (which is elevated by AIE and driven, in part, by hippocampal circuits), and has also been shown to alter gene promoter methylation in the hippocampus. Moreover, dietary choline supplementation has been shown to ameliorate memory deficits in children with fetal alcohol spectrum disorder (FASD), underscoring the safety of choline supplementation in humans. Thus, we hypothesize that dietary choline supplementation during adolescence will prevent or ameliorate AIE-induced memory deficits, loss of Ch1-2 cholinergic neurons, hippocampal neuroinflammatory markers, and dysregulation of neurogenesis and cell death cascades. Specific Aim 1 will test the hypothesis that dietary ACS will prevent AIE-induced memory deficits in adulthood. Male and female rats will receive either ACS or a matched control diet during AIE exposure. Later, in adulthood, spatial and temporal object recognition (stOR) memory will be tested as in our previous studies. Specific Aim 2 will test the hypothesis that ACS will prevent the AIE-induced reduction of ChAT immunoreactive cells in the upstream hippocampal projection areas, Ch1-2, which we have previously reported. One week after stOR testing Under Aim 1, animals will be sacrificed, and brains prepared for immunohistochemical (IHC) quantification of ChAT- positive immunoreactive neurons in Ch1-2. Specific Aim 3 will test the hypothesis that ACS will prevent the AIE- induced promotion of neuroinflammatory and cell death marker activity, and decrease of neurogenesis marker activity, in the hippocampus that we have reported previously. Hippocampi from the brains of animals in Aim 1 will undergo IHC analysis and quantification of the receptor for advanced glycation end-products (RAGE - neuroinflammation), doublecortin (neurogenesis), and caspase-3 (cell death) immunoreactivity in the hippocampal formation. These studies will have translational, mechanistic, and public health significance.

青春期对于认知，情感，社会和神经系统成熟至关重要。重复酒精 青春期的暴露会导致大脑和行为缺陷，这些缺陷持续到成年，可能 在整个生命周期中。我们报道了青少年间歇性乙醇（AIE）暴露的持久影响 关于海马结构和功能以及它们调节的行为，例如记忆和焦虑， 这些AIE效应中的许多可以通过抗胆碱酯酶Donepezil（Aricept）改善。这 AIE效应的胆碱能介导使我们假设AIE期间的饮食胆碱补充剂可以 预防或改善AIE对大脑和行为的长期影响。我们已经表明早期饮食 补充胆碱可增强与记忆相关的海马功能，并具有神经保护作用 海马细胞。重要的是，最近的研究表明围产期和青少年胆碱 补充减少了与围产期酒精暴露有关的神经和行为缺陷的严重程度。 具体来说 围产期乙醇暴露并减少成年大鼠的焦虑样行为（由AIE升高， 部分由海马电路驱动），也已证明可以改变基因启动子甲基化 海马。此外，饮食胆碱补充剂已被证明可以改善记忆缺陷 患有胎儿酒精谱系障碍（FASD）的儿童，强调了补充胆碱的安全性 人类。因此，我们假设青春期饮食中补充饮食胆碱将预防或 改善AIE引起的记忆缺陷，CH1-2胆碱能神经元的丧失，海马 神经炎症标志物以及神经发生和细胞死亡级联反应的失调。具体目标1 将检验以下假设：饮食ACS将防止AIE引起的成年后的记忆缺陷。男女 在AIE暴露期间，大鼠将接受ACS或匹配的对照饮食。后来，成年后，空间和 时间对象识别（Stor）记忆将与我们先前的研究一样进行测试。具体目标2将测试 假设ACS将防止AIE引起的上游聊天免疫反应性细胞的减少 我们先前报道的海马投影区CH1-2。 Stor测试后一周 AIM 1，将牺牲动物，并为聊天的免疫组织化学（IHC）量化准备大脑。 CH1-2中的阳性免疫反应性神经元。具体目标3将检验以下假设：ACS将防止AIE- 诱导的神经炎症和细胞死亡标记活性的促进，以及神经发生标记的降低 活动，在我们之前报告的海马中。 AIM 1中动物大脑的海马1 将接受IHC分析和量化晚期糖基化终产物的受体（RAGE- 神经炎症），双核素（神经发生）和caspase-3（细胞死亡）免疫反应性 海马形成。这些研究将具有转化，机械和公共卫生的意义。