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

项目摘要 早期生活的逆境与成年期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会提供线索， 开发治疗焦虑症的新疗法。对人类和啮齿类动物的研究发现， 海马体的亚区域对焦虑调节很重要。θ波和 海马体中的伽马频率范围与焦虑行为有关， 由特定类别的抑制性中间神经元之间的协调活动驱动，小清蛋白阳性（PV+） 篮状细胞神经元周网（PNN），细胞外基质结构，调节可塑性， 与精神病理学相关，围绕许多PV+篮状细胞。在小鼠中，早期生活逆境增加PNN 在腹侧海马PV+细胞周围形成，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。成体腹侧神经发生 海马体也受到早期不良经历的影响，已知成人产生的颗粒细胞 与PV+篮状细胞突触。成年人产生的神经元和 抑制性中间神经元被出生后应激改变，可能是通过PNN的改变， 产生增强的神经元振荡和焦虑仍然是未知的。该提案旨在解决 我们对早期生活压力如何改变海马PNN，成年产生的颗粒， 细胞与抑制性中间神经元、神经元振荡和焦虑的联系，并探索这种联系 在这些影响中。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 成年人产生的神经元数量，成年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， 不是相互依赖的，目的是关于早期生活压力对成年后海马可塑性的影响， 长期目标是了解导致神经元振荡增加的细胞变化， 焦虑

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.