Microcircuit, cellular and molecular dissection of impaired hippocampal function in a mouse model of the 22q11.2 deletion

22q11.2 缺失小鼠模型海马功能受损的微电路、细胞和分子解剖

基本信息

批准号：
10044137
负责人：
JOSEPH A GOGOS
金额：
$ 80.04万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10044137
关键词：
22q11.2 Address Adult Affect Animal Model Animals Area Association Learning Automobile Driving Axon Behavior Behavioral Biological Biological Models Cells Cognitive Cognitive deficits Coupled Data DiGeorge Syndrome Disease Disease model Dissection Dorsal Employment Episodic memory Etiology Event Exhibits Expression Profiling Functional Imaging Functional disorder Gene Expression Gene Expression Profiling Generations Genetic Genetic Risk Genetic study Goals Head Hippocampus (Brain)Image Impaired cognition Impairment Individual Interneurons Knowledge Lead Learning Mediating Memory Memory impairment Mental disorders Molecular Mus Mutant Strains Mice Mutation Neurons Neurosciences Patients Pharmacogenetics Physiological Physiological Processes Play Population Process Property Psychotic Disorders Pyramidal Cells Regulation Resolution Rewards Risk Role Schizoaffective Disorders Schizophrenia Sensory Symptoms Synaptic plasticity Techniques Technology Time Transgenic Mice Wild Type Mouse associated symptom cell type cognitive task disabling symptom episodic memory impairment genetic risk factor in vivo insight learned behavior locus ceruleus structure mouse model multimodality neuropsychiatric disorder neuroregulation noradrenergic novel optogenetics patch sequencing recruit relating to nervous system transcriptomics two-photon virtual reality environment

项目摘要

Schizophrenia is a debilitating psychiatric disorder that effects 1% of the population, with an additional 2-3% developing a schizoaffective disorder. SCZ patients exhibit a spectrum of cognitive deficits including defective episodic memory, present prior to the onset of psychosis and frequently expressed in relatives of affected individuals. Episodic memory formation is dictated in part by spatially tuned (place cell) activity of principal cells in the hippocampus. The biological mechanisms driving this learning capacity in the healthy hippocampus remain largely unknown, let alone their disruption in schizophrenia, leaving large gaps in our knowledge that need to be addressed. Using in vivo functional imaging in mouse dorsal hippocampal area CA1 during head-fixed during learning behaviors, we recently uncovered specific alterations in in vivo physiological properties of CA1 pyramidal cells in the Df(16)A+/− transgenic mouse model of 22q11.2 deletion syndrome, the largest known genetic risk to develop SCZ. Df(16)A+/− CA1 place cells exhibit reduced long-term stability, impaired context- related and lack of reward-related reorganization. A novel form of synaptic plasticity, termed behavioral time- scale synaptic plasticity (BTSP), has been found to drive rapid formation of spatially selective firing fields in CA1 pyramidal cells; notably, our preliminary studies suggest that this form of plasticity is dysregulated in Df(16)A+/− mice. We thus hypothesize that BTSP, a major form of plasticity that drives place cell-recruitment during learning, is disrupted by SCZ risk mutations. These findings at the neuronal population level provide entry points for dissecting the underlying cellular, molecular and microcircuit dysfunctions caused by schizophrenia risk mutations. To gain these mechanistic insights we will unite the complementary expertise of the Losonczy lab and the Gogos lab in etiologically valid genetic mouse models of neuropsychiatric disorders to carry out multiscale dissection of microcircuit, cellular and molecular pathophysiology of schizophrenia-related memory deficits in the adult mouse hippocampal CA1 circuitry. Aim 1 is aimed at assessing altered synaptic plasticity in CA1 pyramidal cells during episodic learning in Df(16)A+/− mice. Aim 2 deals with dissecting inhibitory microcircuit dynamics during episodic learning, while Aim 3 is focused at dissecting altered excitatory and neuromodulatory input dynamics to CA1 during episodic learning in Df(16)A+/− mice. Taken together, Aims 1-3 provide a tractable path to a deeper, mechanistic understanding of hippocampus-related cognitive memory deficits in schizophrenia.

精神分裂症是一种使人衰弱的精神疾病，影响1％的人群，额外2-3％患有精神分裂症。 SCZ患者存在一系列认知缺陷，包括缺陷情节记忆，在精神病发作之前存在，并经常在受影响的亲属中表达个人。情节记忆形成部分由主调谐（位置单元）的主体作用海马中的细胞。在健康海马中推动这种学习能力的生物学机制保持不明的尚不清楚，更不用说它们在精神分裂症中的干扰，在我们的知识中留下了很大的差距需要解决。在头部固定期间，在小鼠背海马面积CA1中使用体内功能成像在学习行为期间，我们最近发现了CA1体内生理特性的特定变化 DF（16）A +/-转基因小鼠模型22Q11.2缺失综合征，已知最大的已知已知元素模型发展SCZ的遗传风险。 DF（16）A +/- CA1放置细胞暴露于长期稳定性降低，上下文受损 - 相关和缺乏与奖励相关的重组。一种新型的突触可塑性形式，称为行为时间 - 已经发现秤突触可塑性（BTSP）驱动CA1中空间选择性射击场的快速形成锥体细胞；值得注意的是，我们的初步研究表明，这种形式的可塑性在DF（16）A +/-中失调老鼠。因此，我们假设BTSP是一种主要形式的可塑性学习，通过SCZ风险突变被禁用。这些在神经元种群层面的发现提供了入口点为了解剖由精神分裂症风险引起的基础细胞，分子和微电路功能障碍突变。为了获得这些机械见解，我们将团结Losonczy Lab的完整专业知识和神经精神疾病的病因有效的遗传小鼠模型中的GoGos实验室进行多尺度与精神分裂症相关记忆缺陷的微电路，细胞和分子病理生理的解剖成年小鼠海马CA1电路。 AIM 1旨在评估CA1中的合成可塑性的改变 DF（16）a +/-小鼠中情节学习过程中的锥体细胞。 AIM 2处理剖析抑制微电路情节学习过程中的动力学，而AIM 3则集中于解剖兴奋性和神经调节性改变 DF（16）A +/-小鼠在情节学习过程中输入CA1的输入动力学。两者合计，目标1-3提供了可拖动的对海马相关认知记忆的更深入，机械理解的途径定义精神分裂症。