Hippocampal CA2 sharp wave ripple oscillations in neuropsychiatric disease

神经精神疾病中海马 CA2 尖波波纹振荡

• 批准号: 10536654
• 负责人: STEVEN A SIEGELBAUM
• 金额: $ 63.21万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-10 至 2026-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536654
• 关键词: 22q11.2; Affect; Antisense Oligonucleotides; Area; Behavior; Behavioral; Behavioral Mechanisms; Bipolar Disorder; Brain; Code; DNA Sequence Alteration; Deep Brain Stimulation; DiGeorge Syndrome; Disease; Dominant-Negative Mutation; Down-Regulation; Event; Functional disorder; Funding; Genes; Genetic; Genetic Diseases; Genetic Risk; Goals; Golgi Apparatus; Hippocampus; Human; Human Genetics; Impaired cognition; Impairment; Individual; Infusion procedures; Light; Link; Membrane Proteins; Memory; Memory impairment; Messenger RNA; MicroRNAs; Modeling; Molecular; Mus; Mutation; Neurons; Pathology; Pattern; Population Dynamics; Potassium; Pyramidal Cells; Rest; Role; Schizophrenia; Shapes; Slow-Wave Sleep; Social Behavior; Synapses; Syndrome; Test Result; Testing; Up-Regulation; Validation; Viral; Wild Type Mouse; base; derepression; detector; effective therapy; experience; genetic risk factor; hippocampal pyramidal neuron; human disease; human model; in vivo; inhibitor; insight; interest; memory consolidation; microdeletion; mouse model; neural network; neural patterning; neuromechanism; neuropsychiatric disorder; novel; novel strategies; novel therapeutic intervention; novel therapeutics; optogenetics; pharmacologic; potassium channel protein TREK-1; protein complex; protein transport; rational design; restoration; schizophrenia risk; small hairpin RNA; social; social cognition; spatial memory; trafficking

Individuals with schizophrenia and other neuropsychiatric disorders suffer from abnormal social behaviors, for which there are few effective treatments. Here we aim to gain insight into the brain mechanisms responsible for such dysfunction, focusing on the role of altered patterns of neural network activity that may be amenable to treatment with brain stimulation paradigms. We focus on the social memory (SM) deficits in the Df(16)A+/- mouse model of the human 22q11.2 deletion syndrome, which confers one of the highest known genetic risk factors for schizophrenia. Our studies during the present funding period demonstrate that the mouse SM deficit results, at least in part, from abnormal activity of hippocampal CA2 pyramidal neurons, which are known to be critical for SM. At the cellular level, CA2 pyramidal neurons in the Df(16)A+/- mice are hyperpolarized due to an increase in the TREK-1 resting K+ current, leading to decreased excitability. Our in vivo recordings show that in wild-type, but not Df(16)A+/- mice, CA2 pyramidal neurons act as detector of social novelty, with CA2 firing differentially responding to a novel versus familiar mouse. Of particular interest, we found that pharmacological and/or genetic inhibition of TREK-1 could rescue both SM and CA2 coding for social novelty in Df(16)A+/- mice. Finally we found that upregulation of Mirta22/Emc10, a regulator of membrane protein trafficking that is de- repressed in Df(16)A+/- mice due to microRNA dysregulation, is a key molecular consequence of the 22q11.2 deletion that contributes to abnormal SM. Here we aim to provide deeper insight into how alterations in CA2 function produce an abnormal form of brain oscillations known as sharp-wave ripples, events that are critical for memory consolidation. We will examine how abnormal sharp-wave ripples affect SM, and whether reinstatement of normal sharp-wave ripples by optogenetic brain stimulation can rescue SM. As sharp-wave ripples are abnormal in CA1 of Df(16)A+/- mice, and as a significant fraction of sharp-wave ripples in CA1 arise in CA2, we hypothesize that the deficit in SM in Df(16)A+/- mice may result from abnormal CA2 sharp-wave ripples. Furthermore, we surmise that optogenetic activation of CA2 using appropriately shaped patterns of light that can trigger normal SWRs in wild-type mice may reinstate normal SWRS in Df(16)A+/- mice, and this may rescue SM. Finally to gain deeper insight into the link between molecular changes associated with the 22q11.2 genetic deletion and altered brain function, we will explore whether Mirta22/Emc10 upregulation underlies CA2 dysfunction, including increased CA2 TREK-1 activity, abnormal social coding and abnormal sharp-wave ripples. In this way we will provide a unified understanding linking the genetic, molecular, cellular, network, and behavioral mechanisms that contribute to social cognitive dysfunction associated with a human genetic mutation linked to neuropsychiatric disease, with the aim of identifying novel approaches to treatment based on the rational design of brain stimulation paradigms.

精神分裂症和其他神经精神疾病患有异常社会行为的人 几乎没有有效的治疗方法。在这里，我们旨在深入了解负责的大脑机制 这种功能障碍，重点关注神经网络活动的改变模式的作用，可能适合 用大脑刺激范例治疗。我们专注于DF（16）A +/-中的社交记忆（SM）缺陷 人类22q11.2缺失综合征的小鼠模型，该综合征赋予了最高已知遗传风险之一 精神分裂症的因素。我们在目前的资金期间的研究表明，鼠标SM缺陷 结果至少部分来自海马Ca2锥体神经元的异常活性，已知是 对于SM至关重要。在细胞水平上，DF（16）A +/-小鼠中的Ca2锥体神经元由于A +/-小鼠而被超极化 TREK-1静止的K+电流增加，导致兴奋性降低。我们的体内录音显示 野生型，但不是DF（16）A +/-小鼠，Ca2锥体神经元充当社会新颖性的检测器，CA2射击 差异地响应新颖的鼠标与熟悉的鼠标。我们特别有趣的是，药理学 和/或Trek-1的遗传抑制可以挽救DF（16）A +/-小鼠中的SM和CA2编码的CA2。 最终，我们发现MITERA22/EMC10的上调，这是一种膜蛋白运输的调节剂 由于microRNA失调而导致的DF（16）A +/-小鼠，是22q11.2的关键分子结果 导致异常SM的缺失。在这里，我们旨在更深入了解CA2中的改变 功能会产生一种称为锋利波波的脑振荡的异常形式，这是关键的事件 用于内存合并。我们将研究异常的锋利波纹波如何影响SM，以及是否如何 通过光遗传学大脑刺激恢复正常的锋利波纹波可以挽救SM。像锋利的波 DF（16）A +/-鼠标的CA1异常是涟漪，而Ca1中的锋利波纹波很大一部分 在CA2中，我们假设DF（16）A +/-小鼠中SM的赤字可能是由异常Ca2尖锐波造成的 涟漪。此外，我们推测使用适当形状的模式的CA2的光遗传学激活 可以触发野生型小鼠正常SWR的光可以恢复DF（16）A +/-小鼠中的正常SWR，这是 可能会营救SM。最后，以更深入地了解与 22Q11.2遗传缺失和大脑功能改变，我们将探讨MITERA22/EMC10是否上调 CA2功能障碍的基础，包括增加CA2 TREK-1活动，异常编码和异常 锋利的波浪。通过这种方式，我们将提供一个统一的理解，将遗传，分子，细胞， 网络和行为机制有助于与人类相关的社会认知功能障碍 与神经精神疾病有关的基因突变，目的是确定新的治疗方法 基于大脑刺激范式的合理设计。