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

研究 KIBRA 依赖性突触功能对复杂认知背后的海马和皮质网络机制的作用

基本信息

批准号：
10349494
负责人：
Lilyana Quigley
金额：
$ 3.64万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-12-31
项目状态：
已结题

项目摘要

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.

项目概要揭示单细胞内的分子相互作用如何促成依赖于经验的电路变化大规模大脑网络中的水平神经活动大脑是神经科学中的一个紧迫挑战。疾病包括精神分裂症、双向情感障碍和自闭症谱系障碍在内的复杂认知的最终表现通过功能失调的神经网络的新兴特性。虽然这些疾病具有很强的重叠性遗传贡献，清楚地了解遗传因素如何对病理症状产生功能性影响仍然难以捉摸。从广义上讲，我的职业目标是描绘不同的分子和细胞机制与神经发育精神疾病相关的神经回路动力学。我的毕业生工作重点是研究去除突触支架蛋白后的体内网络功能障碍 KIBRA，调节突触可塑性，与人类记忆的自然变异有遗传相关性。 KIBRA 及其组织的蛋白质复合物也与多种神经发育障碍有关。为了确定 KIBRA 依赖性可塑性机制是否调节行为相关的电路动力学，我监测了小鼠海马体 (HC) 和额叶皮层 (ACC) 的同时神经活动使用体内电生理学对自由行为的小鼠进行前脑特异性 KIBRA 缺失（KIBRA cKO）。我的研究结果表明，海马回路未能正确同步以应对新体验缺少基布拉。根据目标 1 的当前结果，目标 2 的研究将评估 KIBRA 的要求- 同步神经活动的依赖可塑性机制，促进空间信息的获取信息。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内部的网络通信。更远实验将重点关注单个神经元在经验及其一致性方面的放电模式 HC 和 ACC 网络的持续振荡。这些神经元的发射场可预测地发生变化依赖于经验和可塑性的方式，这将允许检查依赖于 KIBRA 的信息单细胞水平的处理。随后将评估 KIBRA 在产后晚期的功能作用通过对幼年 KIBRA KO 小鼠进行多日记录来开发 HC 和 ACC 网络。在目标 3，我描述了我的博士后研究计划，以研究线粒体代谢（一种尚未被研究的疾病）如何神经精神疾病的高置信度危险因素，影响大脑网络功能。我将会收获体内成像和光/化学遗传学方面的专业知识可以补充我在博士工作期间获得的专业知识。这我的博士和博士后培训的结合将为我的神经科学研究生涯奠定基础这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和行为，并可能突出诊断和治疗的新分子或神经生理学目标。