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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.

项目摘要揭示了单细胞内的分子相互作用如何有助于电路中经验依赖的变化- 跨大规模脑网络大脑的水平神经活动是神经科学中的一个紧迫挑战。精神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和重叠的遗传因素，清楚地描述了可遗传因素如何对病理症状起作用仍然难以捉摸。概括地说，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回路动力学。我的毕业生工作重点是研究移除突触支架蛋白后体内网络功能障碍 Kibra，它调节突触的可塑性，与人类记忆中的自然变异有关。 Kibra和它组织的蛋白质复合体也与几种神经发育障碍有关。为了确定Kibra依赖的可塑性机制是否调节行为相关的电路动力学，我监测了小鼠海马区(HC)和额叶皮质(ACC)的同步神经活动前脑特异缺失Kibra(Kibra CKO)在自由行为小鼠体内的电生理学研究。我的研究结果表明，海马环路未能正确同步，以响应新的经验在基布拉的缺席。根据目标1的当前结果，目标2的研究将评估Kibra的需求- 促进空间习得的同步神经活动的依赖可塑性机制信息。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，以深入了解这些地区之间和这些地区内的网络通信。进一步实验将集中于单个神经元的放电模式与经验及其连贯性与HC和ACC网络的持续振荡有关。这些神经元的发电场可以预测地在经验和可塑性依赖的方式，这将允许检查Kibra依赖的信息在单细胞级别进行处理。接下来将评估Kibra在出生后期的功能作用通过对幼年Kibra KO小鼠进行多天记录来发展HC和ACC网络。在……里面目的3，我描述了我的博士后研究计划，以调查线粒体代谢是如何进行的，一个未被研究的和神经精神疾病的高可信风险因素，影响大脑网络功能。我会有所收获的在活体成像和光/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。这个我的博士和博士后培训的结合将为我在神经科学研究领域的职业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的精神疾病相关分子机制如何影响大脑网络功能和行为，并可能突出新的分子或神经生理靶点用于诊断和治疗。