Adolescent intermittent ethanol induction of neuroimmune signaling disrupts the mature phenotype of surviving hippocampal neuroprogenitors

青少年间歇性乙醇诱导神经免疫信号破坏存活海马神经祖细胞的成熟表型

• 批准号: 10591757
• 负责人: Victoria Alice Macht
• 金额: $ 12.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10591757
• 关键词: Abstinence; Address; Adolescence; Adolescent; Adult; Alcohols; Anti-Inflammatory Agents; Astrocytes; Automobile Driving; Behavior; Behavioral; Brain; CCL2 gene; Cells; Cholinesterase Inhibitors; Cognitive; Data; Deoxyuridine; Development; Electrophysiology (science); Equilibrium; Ethanol; FOS gene; Female; Future; Galantamine; Gatekeeping; Gene Expression; Glial Fibrillary Acidic Protein; Glycyrrhizic Acid; HMGB1 gene; Hippocampus (Brain); Histologic; Immediate-Early Genes; Immune; Immunofluorescence Immunologic; Impaired cognition; Impairment; Indomethacin; Intervention; Knowledge; Label; Learning; Link; Longevity; Maps; Mediating; Memory; Microglia; Morphology; Mus; N-Methylaspartate; Neuroglia; Neuroimmune; Neuronal Plasticity; Neurons; Newborn Infant; PTGS2 gene; Performance; Pharmacology; Phenotype; Phosphodiesterase Inhibitors; Physiological; Population; Proliferating; Property; Regulation; Reporter; Research; Research Training; Reversal Learning; Signal Transduction; Social Dominance; Stress; Synapses; TLR4 gene; Tamoxifen; Techniques; Testing; Training; Transgenic Mice; Transgenic Model; Transgenic Organisms; Trees; Tube; adolescent alcohol exposure; adolescent binge drinking; adult neurogenesis; alcohol exposure; antagonist; brain behavior; brain circuitry; brain research; experimental study; flexibility; functional disability; insight; intraperitoneal; male; memory recognition; morris water maze; nerve stem cell; neural circuit; neurogenesis; neuroinflammation; neuronal excitability; newborn neuron; novel; object recognition; optogenetics; p65; postnatal; programs; restoration; sex; social stress; therapeutic target; tool

PROJECT SUMMARY Adolescent binge drinking hijacks the developing brain, resulting in long-lasting increases in neuroinflammation which are paralleled by decreases in hippocampal neurogenesis and deficits in learning and memory-related tasks. Unlike adult alcohol exposure, the cellular and behavioral effects of adolescent binge drinking do not recover following periods of abstinence, suggesting that alcohol exposure across adolescence permanently disrupts the brain’s developmental trajectory. However, while prior research has focused on the underlying mechanisms driving this loss and restoration of newborn hippocampal neurons, no research has investigated how adolescent intermittent ethanol (AIE) impacts the ability of surviving hippocampal neuroprogenitor cells (NPCs) to appropriately integrate into adult hippocampal circuitry. Newborn neurons assimilate into dentate circuitry in an activity dependent manner which is sensitive to shifts in the balance between neuronal excitation and inhibition as well as neuroinflammatory signaling. Any disruption in this integration could have profound consequences on learning and memory functions as granular cells are a gatekeeper for downstream activation of hippocampal circuitry. To test the impact of adolescent alcohol on network integration of developing neurons, we will use a reporter mouse line (DCX-CreERT2/tdtomato) which was developed to specifically tag and then fate-map NPCs across their lifespan. This technique will allow us to track how alcohol impacts the ability of adolescent maturing neurons to effectively integrate into mature dentate circuitry. By combining this transgenic model with 5-ethynyl-2'-deoxyuridine, we will test whether adolescent alcohol exposure induces adult innate immune gene expression preferentially in adolescent-maturing NPCs and glia, and we will also test whether AIE impairs formation of dendritic arborization in adolescent-maturing NPCs (AIM 1/K99). We will then test whether adolescent alcohol impairs the electrophysiological properties of these adolescent-maturing NPCs in adulthood (AIM 2/K99). As it remains unclear whether maturational changes in adolescent maturing neurons mediate cognitive-behavioral deficits, we will test whether AIE disrupts immediate early gene expression in adolescent-maturing NPCs following reversal learning in the Morris water maze, novel object recognition memory, and social dominance behaviors in adulthood (AIM 3/K99). Finally, while preliminary data suggest that anti-inflammatory interventions can reverse neurogenic and behavioral deficits after AIE in both sexes, whether anti-inflammatory pharmacological interventions (e.g., indomethacin) can similarly restore morphological and physiological maturation, circuit integration, and innate immune gene expression in adolescent-maturing NPCs in adulthood is unknown (AIM 4/R00). Collectively, these experiments will provide critical insight into the impact of adolescent alcohol on the resulting phenotypic fate and circuit regulation of surviving NPCs in both sexes.

项目摘要 青少年酗酒劫持了发育中的大脑，导致神经炎症的长期增加 这是由海马神经发生减少和学习和记忆相关的缺陷引起的。 任务与成人酒精暴露不同，青少年酗酒对细胞和行为的影响并不 在禁欲期后恢复，这表明青春期的酒精暴露 扰乱大脑的发育轨迹。然而，虽然先前的研究集中在潜在的 驱动新生海马神经元丢失和恢复的机制，没有研究调查 青少年间歇性乙醇（AIE）如何影响海马神经祖细胞存活的能力 （NPC）适当整合到成人海马电路。新生神经元同化成齿状核 以活动依赖的方式，其对神经元兴奋之间的平衡的变化敏感 和抑制以及神经炎症信号。这种整合的任何中断都可能产生深远的影响。 颗粒细胞是下游激活的看门人， 海马体回路。测试青少年饮酒对发展中国家网络整合的影响， 神经元，我们将使用报告小鼠系（DCX-CreERT 2/tdtomato），其被开发用于特异性标记 然后绘制NPC的一生命运图这项技术将使我们能够跟踪酒精如何影响 青少年成熟神经元有效整合到成熟齿状回的能力。通过组合该 转基因模型与5-乙炔基-2 '-脱氧尿苷，我们将测试是否青少年酒精暴露诱导 成人先天性免疫基因表达优先在发育成熟的NPC和神经胶质细胞，我们还将 测试AIE是否损害在促分化成熟的NPC（AIM 1/K99）中树突状分支的形成。我们将 然后测试青少年饮酒是否会损害这些神经元的电生理特性， 成年期的NPC（AIM 2/K99）。由于尚不清楚青少年成熟过程中的成熟变化 神经元介导认知行为缺陷，我们将测试AIE是否破坏了即刻早期基因， 在Morris水迷宫中逆转学习后， 再认记忆和成年期社会优势行为（AIM 3/K99）。虽然初步数据显示 提示抗炎干预可以逆转AIE后的神经和行为缺陷， 性别，是否抗炎药物干预（例如，吲哚美辛）可以类似地恢复 形态和生理成熟，电路整合和先天免疫基因表达， 成年期的NPC是否会发育成熟尚不清楚（AIM 4/R 00）。总的来说，这些实验将提供 关键洞察到青少年酒精对由此产生的表型命运和电路调节的影响， 两种性别的幸存NPC。