Investigating the Role of KIBRA-Dependent Synaptic Function on Hippocampal and Cortical Network Mechanisms Underlying Complex Cognition

项目摘要 揭示了单细胞内的分子相互作用如何促进电路中的经验依赖性变化- 大规模脑网络中的水平神经活动是神经科学中的一个紧迫挑战。障碍 包括精神分裂症、双相情感障碍和自闭症谱系障碍在内的复杂认知最终表现为 通过功能失调的神经网络的涌现特性。虽然这些疾病有强烈的和重叠的 遗传贡献，清楚地了解遗传因素如何在功能上影响病理症状 仍然难以捉摸大体上，我的职业目标是描述不同的分子和细胞机制 与神经发育性精神疾病相关的神经元回路动力学的贡献。我在研究 工作集中于研究突触支架蛋白去除后的体内网络功能障碍 KIBRA，它调节突触可塑性，并与人类记忆中的自然变异有遗传联系。 KIBRA和它组织的蛋白质复合物也与几种神经发育障碍有关。 为了确定依赖KIBRA的可塑性机制是否调节行为相关的回路动力学， 我同时监测了小鼠海马（HC）和额叶皮层（ACC）的神经活动， 在自由行为小鼠中使用体内电生理学检测前脑特异性KIBRA缺失（KIBRA cKO）。我 研究结果表明，海马回路在对新的经历做出反应时不能正确地同步， 没有KIBRA。根据目标1的当前结果，目标2中的研究将评价KIBRA的需求， 同步神经活动的依赖性可塑性机制，促进获得空间 信息.这将通过首先检查HC和ACC网络振荡的完整性和同步性来完成 关于行为，以深入了解这些区域之间和这些区域内的网络通信。进一步 实验将集中在个别神经元的放电模式方面的经验和他们的连贯性 HC和ACC网络中的持续振荡。这些神经元的放电场可以预见地在一个 经验和可塑性依赖的方式，这将允许审查依赖KIBRA的信息 在单细胞水平上进行处理。随后将评估KIBRA在出生后晚期的功能作用。 通过在幼年KIBRA KO小鼠中进行多日记录来开发HC和ACC网络。在 目的3，我描述了我的博士后研究计划，以调查如何线粒体代谢，一个欠研究 神经精神疾病的高可信度危险因素，影响脑网络功能。我会得到 在体内成像和光学/化学遗传学方面的专业知识，以补充我在博士工作期间获得的专业知识。的 我的博士和博士后培训的整合将为我在神经科学研究领域的职业生涯奠定基础 有助于理解复杂认知障碍。这些研究的结果将提供 深入了解特定精神疾病相关分子机制如何促进大脑网络功能 并可能突出新的分子或神经生理学靶点用于诊断和治疗。

Project Summary Revealing how molecular interactions within single cells contribute to experience-dependent changes in circuit- level neural activity across large-scale brain networks brain is an urgent challenge in neuroscience. Disorders of complex cognition including schizophrenia, bipolar disorder and autism spectrum disorder ultimately manifest via emergent properties of dysfunctional neural networks. While these disorders have strong and overlapping genetic contributions, a clear picture of how heritable factors contribute functionally to pathological symptoms remains elusive. Broadly, my career goal is to delineate how distinct molecular and cellular mechanisms associated with neurodevelopmental psychiatric disease contribute to neuronal circuit dynamics. My graduate work focuses on investigating in vivo network dysfunction following removal of the synaptic scaffolding protein KIBRA, which regulates synaptic plasticity and is genetically associated with natural variation in human memory. KIBRA and the protein complexes it organizes are also associated with several neurodevelopmental disorders. To determine whether KIBRA-dependent plasticity mechanisms regulate behaviorally relevant circuit dynamics, I monitored simultaneous neural activity in both the hippocampus (HC) and frontal cortex (ACC) of mice with forebrain-specific deletion of KIBRA (KIBRA cKO) using in vivo electrophysiology in freely behaving mice. My findings indicate a failure of hippocampal circuits to properly synchronize in response to novel experience in the absence of KIBRA. Based on current results from Aim 1, studies in Aim 2 will evaluate the requirement of KIBRA- dependent plasticity mechanisms for synchronized neural activity that promotes the acquisition of spatial information. This will be done by first examining the integrity and synchrony of HC and ACC network oscillations with respect to behavior to gain insight into network communication between and within these regions. Further experiments will focus on the firing patterns of individual neurons with respect to experience and their coherence to ongoing oscillations in the HC and ACC networks. Firing fields of these neurons predictably change in an experience- and plasticity-dependent manner, which will allow examination of KIBRA-dependent information processing at the single cell level. This will be followed by evaluating the functional role of KIBRA in late postnatal development of the HC and ACC networks by conducting multi-day recordings in juvenile KIBRA KO mice. In Aim 3, I describe my postdoctoral research plan to investigate how mitochondrial metabolism, an understudied and high confidence risk factor for neuropsychiatric disease, influences brain network function. I will gain expertise in in vivo imaging and opto/chemogenetics to complement expertise gained during my PhD work. The integration of my PhD and postdoctoral training will lay the groundwork for a career in neuroscience research that contributes to an understanding of disorders of complex cognition. Findings from these studies will provide insight into how specific psychiatric disease-relevant molecular mechanisms contribute to brain network function and behavior and may highlight new molecular or neurophysiological targets for diagnosis and treatment.