Investigating perineuronal nets and hippocampal plasticity in early life adversity-induced anxiety

研究早期生活逆境引起的焦虑中的神经周围网和海马可塑性

• 批准号: 9923465
• 负责人: Elizabeth Gould
• 金额: $ 40.5万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923465
• 关键词: Address; Adult; Adverse event; Anterior; Anxiety; Anxiety Disorders; Behavior; Brain; Cell physiology; Cells; Chemicals; Cholecystokinin; Confocal Microscopy; Data; Development; Electroencephalography; Electron Microscopy; Electrophysiology (science); Extracellular Matrix; Feedback; Female; Frequencies; Goals; Hippocampus (Brain); Human; Incidence; Individual Differences; Interneurons; Label; Lead; Light; Link; Mental Health; Moods; Mus; Myoepithelial cell; Neurons; Outcome; Parvalbumins; Pattern; Play; Process; Psychopathology; Regulation; Reporting; Risk Factors; Rodent; Role; Stress; Structure; Synapses; Testing; Transgenic Organisms; Treatment Efficacy; abuse neglect; adult neurogenesis; anxiety-like behavior; anxious; anxious behavior; critical period; dentate gyrus; design; early life adversity; early life stress; excessive anxiety; experimental study; granule cell; in vivo; male; mouse model; nerve supply; neuroimaging; neuropsychiatric disorder; neuropsychiatry; novel therapeutics; pediatric trauma; postnatal; prevent; retroviral-mediated

PROJECT SUMMARY Early life adversity is associated with an increased incidence of anxiety disorders in adulthood. Understanding the cellular processes that connect early life stress with excessive anxiety may provide clues for the development of new therapies to treat anxiety disorders. Studies in humans and rodents have identified subregions of the hippocampus as important for anxiety regulation. Neuronal oscillations in both theta and gamma frequency ranges in the hippocampus have been linked to anxious behavior and these oscillations are driven by coordinated activity among a specific class of inhibitory interneurons, the parvalbumin positive (PV+) basket cells. Perineuronal nets (PNNs), extracellular matrix structures that modulate plasticity and have been linked to psychopathology, surround many PV+ basket cells. In mice, early life adversity increases PNN formation around PV+ cells in the ventral hippocampus, raising the possibility that this change leads to early life adversity-induced enhancement of neuronal oscillations and anxiety. Adult neurogenesis in the ventral hippocampus is also impacted by early adverse experience and adult-generated granule cells are known to synapse with PV+ basket cells. The possibility that connections between adult-generated neurons and inhibitory interneurons are altered by postnatal stress, potentially through alterations in PNNs, and thus produce enhanced neuronal oscillations and anxiety remains unknown. This proposal is designed to address the gaps in our understanding about how early life stress alters hippocampal PNNs, adult-generated granule cell connections with inhibitory interneurons, neuronal oscillations and anxiety and to explore the connections among these effects. The proposed experiments will use a mouse model of early life stress, manipulations of PNNs in the hippocampus, retroviral labeling of new granule cells in the hippocampus, immunolabeling combined with confocal microscopy and electron microscopy, transgenic and retroviral-mediated manipulation of adult-generated neuron number, in vivo electrophysiology during behavior and anxiety test analyses in adult male and female mice. The studies in this proposal are designed to achieve three significant and related, but not interdependent, aims regarding the influence of early life stress on hippocampal plasticity in adulthood with the long-term goal of understanding the cellular changes that lead to increased neuronal oscillations and anxiety.

项目摘要 早期逆境与成年后焦虑症的发生率增加有关。理解 将早期生活压力与过度焦虑联系起来的细胞过程可能会为 开发新疗法以治疗焦虑症。在人类和啮齿动物的研究已经确定 海马的子区域对焦虑调节很重要。 Theta和Theta的神经元振荡 海马中的伽马频率范围与焦虑行为有关，这些振荡是 由特定类别的抑制性中间神经元之间的协调活性驱动，白蛋白蛋白阳性（PV+） 篮细胞。会内神经元网（PNN），调节可塑性的细胞外基质结构 与心理病理学有关，围绕许多PV+篮细胞。在小鼠中，早期逆境增加了PNN 腹侧海马围绕PV+细胞形成，增加了这种变化导致早期变化的可能性 逆境引起的神经元振荡和焦虑的增强。成人神经发生在腹侧 海马还受到早期不良经历的影响，成人生成的颗粒细胞已知 使用PV+篮细胞突触。成人生成的神经元与 抑制性中间神经元会因产后应力而改变，可能会因PNN的改变而改变，从而改变 产生增强的神经元振荡，焦虑仍然未知。该建议旨在解决 我们对早期生活压力如何改变海马PNN的差距，成人生成的颗粒 与抑制性神经元，神经元振荡和焦虑的细胞连接，并探索连接 在这些效果中。提出的实验将使用早期生活压力的小鼠模型，对 海马中的PNN，海马中新颗粒细胞的逆转录病毒标记，免疫标记 结合共聚焦显微镜和电子显微镜，转基因和逆转录病毒介导的操纵 成人产生的神经元数，在成人行为和焦虑测试期间的体内电生理学 雄性和雌鼠。该提案中的研究旨在实现三个重要且相关的研究，但 不是相互依存的，目的是关于早期生活压力对成年后海马可塑性的影响 理解导致神经元振荡增加的细胞变化的长期目标 焦虑。