Genetic targeting of hippocampal CA2 pyramidal neurons

海马 CA2 锥体神经元的基因靶向

• 批准号: 10089486
• 负责人: STEVEN A SIEGELBAUM
• 金额: $ 41.48万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-11 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089486
• 关键词: Acute; Address; Aggressive behavior; Anatomy; Animals; Anxiety; Area; Behavior; Behavioral; Bipolar Disorder; Brain; Chronic; Cognition; Disease; Dorsal; Electrophysiology (science); Emotional; Enterobacteria phage P1 Cre recombinase; Event; Funding; Generations; Genetic; Goals; Hippocampus (Brain); Hypothalamic structure; Impairment; Individual; Injections; Label; Laboratories; Lateral; Light; Memory; Mental Depression; Mus; Neurons; Output; Patients; Pattern; Play; Population; Process; Property; Quality of life; Regulation; Reporting; Role; Schizophrenia; Silicon; Sleep; Slice; Social Behavior; Testing; Tetanus Toxin; Transgenic Mice; Viral; Wakefulness; anatomical tracing; awake; base; density; dentate gyrus; emotional behavior; feeding; hippocampal pyramidal neuron; in vivo; interest; memory consolidation; memory encoding; mental state; motivated behavior; mouse model; neural circuit; neuromechanism; neuropsychiatric disorder; novel therapeutic intervention; optogenetics; relating to nervous system; social; social cognition; spatial memory

Neuropsychiatric disorders, such as schizophrenia and bipolar disorder, are often associated with changes in social behavior. Recent studies from our laboratory and others have identified the hippocampal CA2 region, a relatively unexplored brain area, as critical for both social memory and social aggression. Moreover, alterations in CA2 have been found in individuals with schizophrenia and bipolar disorder, and we have recently discovered similar changes in a mouse model of schizophrenia that is deficient in social memory. In this competitive renewal application we propose to extend our previous findings on the role of CA2 in social behavior in two important ways. Previous studies on CA2, including those from our laboratory, have focused on the dorsal region of CA2. However, CA2 extends along the dorsal-ventral longitudinal axis of the hippocampus yet nothing is known about the role of ventral regions of CA2. Such studies are important because whereas dorsal hippocampus has been implicated in spatial cognition and spatial memory, ventral hippocampus is thought to be more important for emotional behaviors, such as anxiety and depression Thus, our first goal is to explore the behavioral role and neural circuitry of ventral CA2. We will use a mouse line expressing Cre relatively selectively throughout the CA2 longitudinal axis to label ventral CA2 inputs and outputs and to silence ventral CA2 through optogenetic or chemogenetic approaches,similar to those used to explore dorsal CA2. We will assess the functional strength of ventral CA2 inputs and outputs using brain slice electrophysiological recordings. We will compare the behavioral role of ventral and dorsal CA2 in social memory, social aggression, anxiety and depression. We are particularly interested in testing the hypothesis, suggested by our preliminary anatomical tracing, that ventral CA2 may suppress social aggression, opposite to the effect of dorsal CA2 to promote aggression. Our second goal is to explore the in vivo role of CA2 in coordinating network activity important for memory. In the current funding period we examined the effect of acute optogenetic and chemogenetic CA2 silencing, which revealed that CA2 is critical for encoding, consolidation and recall of social memory. It has recently been suggested that CA2 is important for generating sharp wave ripples (SWRs), a synchronous form of hippocampal network activity observed during sleep and quiet wakefulness that is thought to be important for memory encoding and consolidation. However, neither the causal role of CA2 in generating sharp wave ripples nor the role of CA2 ripples in social memory have yet been examined. Moreover, there have been no studies of the importance of ventral CA2 in SWRs in ventral hippocampus. We will thus examine the role of dorsal and ventral CA2 in SWR generation, as well as the role of these events in social and non-social memory.

神经精神障碍，如精神分裂症和双相情感障碍，通常与以下变化有关： 社会行为我们实验室和其他人最近的研究已经确定了海马CA2区， 相对未开发的大脑区域，对社交记忆和社交攻击至关重要。此外， 在精神分裂症和双相情感障碍患者中发现了CA2，我们最近发现， 在缺乏社会记忆的精神分裂症小鼠模型中发现了类似的变化。 在这个竞争性的更新应用中，我们建议扩展我们先前关于CA2在社会中的作用的发现。 行为的两个重要方面。以前对CA2的研究，包括我们实验室的研究，都集中在 CA2的背侧区域。然而，CA2沿着海马体的背腹纵轴延伸 然而，对于CA2的腹侧区域的作用还一无所知。这些研究很重要，因为 背侧海马与空间认知和空间记忆有关，腹侧海马与空间记忆有关。 被认为对焦虑和抑郁等情绪行为更重要 因此，我们的第一个目标是探索腹侧CA2的行为作用和神经回路。我们将使用鼠标 在整个CA2纵轴上相对选择性地表达Cre的线，以标记腹侧CA2输入， 输出和沉默腹侧CA2通过光遗传学或化学遗传学方法，类似于那些用于 探索背侧CA2。我们将使用脑切片评估腹侧CA2输入和输出的功能强度 电生理记录。我们将比较腹侧和背侧CA2在社交中的行为作用， 记忆、社交攻击、焦虑和抑郁。我们特别感兴趣的是检验这个假设， 我们初步的解剖学追踪表明，腹侧CA2可能抑制社会攻击，相反， 背侧CA2促进攻击性的作用。 我们的第二个目标是探索CA2在协调对记忆重要的网络活动中的体内作用。在 在当前的资助期内，我们检查了急性光遗传学和化学遗传学CA2沉默的作用， 这表明CA2对社会记忆的编码、巩固和回忆至关重要。最近有人 提出，CA2是重要的产生尖锐的波波纹（SWR），一种同步形式的 在睡眠和安静的清醒状态下观察到的海马网络活动被认为对 记忆编码和巩固。然而，CA2在产生尖波涟漪中的因果作用 也没有研究过CA2在社会记忆中的作用。此外，还没有关于 腹侧海马CA2在腹侧海马SWRs中的重要性。因此，我们将研究背侧和 腹侧CA2在SWR生成中的作用，以及这些事件在社会和非社会记忆中的作用。