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% 的人口，另有 2-3% 的人患有精神分裂症 SCZ 患者表现出一系列认知缺陷，包括缺陷。情景记忆，出现在精神病发作之前，并且经常在受影响的亲属中表达个体的情景记忆形成部分取决于主要的空间调整（位置细胞）活动。海马体中的细胞驱动健康海马体的这种学习能力。仍然很大程度上不为人知，更不用说它们对精神分裂症的破坏作用，这在我们的知识中留下了巨大的空白需要解决在头部固定期间在小鼠背侧海马区 CA1 中使用体内功能成像的问题。在学习行为过程中，我们最近发现了 CA1 体内生理特性的特定改变 22q11.2 缺失综合征的 Df(16)A+/- 转基因小鼠模型中的锥体细胞，这是已知最大的 Df(16)A+/- CA1 位置细胞表现出长期稳定性降低、环境受损的遗传风险。相关的和缺乏奖励相关的重组。尺度突触可塑性 (BTSP)，已被发现可驱动 CA1 空间选择性放电场的快速形成值得注意的是，我们的初步研究表明，这种形式的可塑性在 Df(16)A+/- 中失调。因此，我们研究了 BTSP，这是一种可塑性的主要形式，可驱动小鼠的位置细胞募集。 SCZ 风险突变会扰乱学习能力，这些在神经元群体水平上的发现提供了切入点。用于剖析精神分裂症风险引起的潜在细胞、分子和微电路功能障碍为了获得这些机制见解，我们将结合 Losonczy 实验室的互补专业知识和 Gogos 实验室在神经精神疾病的病因学有效的遗传小鼠模型中进行了多尺度研究精神分裂症相关记忆缺陷的微电路、细胞和分子病理生理学剖析成年小鼠海马 CA1 回路的目标 1 旨在评估 CA1 突触可塑性的改变。 Df(16)A+/- 小鼠情景学习期间的锥体细胞目标 2 涉及解剖抑制性微电路。情景学习期间的动态，而目标 3 则专注于剖析改变的兴奋性和神经调节 Df(16)A+/- 小鼠情景学习期间 CA1 的输入动态综上所述，目标 1-3 提供了一个易于处理的方法。更深入、机械地理解海马体相关认知记忆缺陷的途径精神分裂症。