Genetic targeting of hippocampal CA2 pyramidal neurons

神经精神障碍，如精神分裂症和双相情感障碍，通常与 社交行为。我们实验室和其他实验室最近的研究已经确定了海马区CA2区，一个 相对未被开发的大脑区域，对社会记忆和社会攻击性都至关重要。此外，改建 在精神分裂症和双相情感障碍患者中发现了CA2，最近我们发现了 在一种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。 在这项竞争性续订申请中，我们建议扩展我们之前关于CA2在社交网络中的角色的发现 行为有两个重要的方面。以前对CA2的研究，包括我们实验室的研究，都集中在 CA2背侧区。然而，CA2沿着海马体的背腹纵轴延伸 然而，关于CA2腹侧区域的作用尚不清楚。这类研究很重要，因为 背侧海马区与空间认知和空间记忆有关，腹侧海马区 被认为对情绪行为更重要，如焦虑和抑郁 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CA2纵轴上相对选择性地表达Cre的线，以标记腹侧CA2输入和 并通过光遗传或化学遗传方法抑制腹侧CA2，类似于过去 探索背侧CA2。我们将使用脑片评估腹侧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 记忆力、社交攻击性、焦虑和抑郁。我们对检验这一假说特别感兴趣， 我们的初步解剖追踪表明，腹侧CA2可能抑制社交攻击，而不是 背侧CA2促进攻击性的作用。 我们的第二个目标是探索CA2在体内协调对记忆重要的网络活动中的作用。在……里面 在目前的资助期间，我们研究了急性光遗传和化学发生CA2沉默的影响， 这揭示了CA2在社会记忆的编码、巩固和回忆中起着关键作用。它最近一直在 提示CA2对于产生尖锐的波纹(SWR)很重要，SWR是一种同步形式的 在睡眠和安静清醒状态下观察到的海马网活动被认为对 内存编码和合并。然而，无论是CA2在产生尖锐波纹中的因果作用 CA2信号在社会记忆中的作用也尚未被研究过。此外，目前还没有关于 腹侧CA2在腹侧海马区SWRS中的重要性。因此，我们将研究背侧和背侧的作用 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。

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.