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

研究早期逆境引起的焦虑中的神经周围网和海马可塑性

• 批准号: 10074705
• 负责人: Elizabeth Gould
• 金额: $ 20万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10074705
• 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.

项目概要 早年的逆境与成年后焦虑症的发病率增加有关。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为以下问题提供线索： 开发治疗焦虑症的新疗法。对人类和啮齿动物的研究发现 海马体的亚区域对于焦虑调节很重要。 θ 和 θ 神经元振荡 海马体中的伽马频率范围与焦虑行为有关，这些振荡与 由特定类别的抑制性中间神经元之间的协调活动驱动，小白蛋白阳性 (PV+) 篮状细胞。神经元周围网 (PNN) 是调节可塑性的细胞外基质结构，已被 与精神病理学相关，围绕着许多 PV+ 篮状细胞。在小鼠中，早年的逆境会增加 PNN 腹侧海马中 PV+ 细胞周围的形成，增加了这种变化导致早期 生活逆境引起的神经元振荡和焦虑的增强。腹侧成体神经发生 海马体也受到早期不良经历的影响，众所周知，成人产生的颗粒细胞 突触与 PV+ 篮状细胞。成人产生的神经元和神经元之间的连接的可能性 抑制性中间神经元会因产后应激而改变，可能是通过 PNN 的改变，因此 产生增强的神经元振荡和焦虑仍然未知。该提案旨在解决 我们对早期生活压力如何改变海马 PNN（成人产生的颗粒）的理解存在差距 细胞与抑制性中间神经元、神经元振荡和焦虑的连接，并探索其中的联系 在这些影响之中。拟议的实验将使用早期生活压力的小鼠模型， 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作 成人生成的神经元数量、成人行为和焦虑测试分析期间的体内电生理学 雄性和雌性小鼠。本提案中的研究旨在实现三个重要且相关的目标，但是 不相互依赖，目标是关于早期生活压力对成年期海马可塑性的影响 了解导致神经元振荡增加的细胞变化的长期目标 焦虑。