Regulation of social aggression through hippocampal CA2 inputs to lateral septum

社会攻击水平的提高，一种有动机的行为，通常与神经精神疾病有关。 疾病尽管我们对调节攻击性的神经机制的理解还不完全， 已知外侧隔（LS）和腹侧下丘脑是重要的。即使LS收到其 海马体是陈述性记忆的重要区域， 海马体调节攻击性。此外，由于海马体与几种神经精神疾病有关， 与改变的社会行为和攻击性相关的疾病，对海马体如何 而它的神经回路调节攻击性，可能会对疾病机制产生重要的新见解。 在这里，我们专注于海马CA 2区在社会攻击中的作用。知之甚少 关于CA 2，很大程度上是因为技术问题，限制了其研究与传统的病变方法。 因此，我们开发了一种Cre小鼠系，使我们能够标记和操纵CA 2的活性 锥体神经元使用遗传沉默方法，我们发现CA 2在非侵袭性的过程中是至关重要的。 社会探索形成社会记忆，动物识别和记忆的能力 另一只小鼠（同种），但其他形式的海马记忆不需要CA 2。我们最近 现在的结果表明，CA 2也通过对LS的兴奋性投射促进社会攻击， 解除对攻击性很重要的下丘脑腹内侧亚核的抑制。此外，我们发现， 社会神经肽精氨酸加压素通过增强CA 2到LS突触来促进攻击性。 在这里，我们问：一个单一的大脑区域，CA 2，如何参与社会记忆存储在非- 积极的社会探索和促进社会侵略？是否有一个单一的CA 2神经元群体， 在社会探索和社会攻击中都会被激活或者每一种都有专门的神经元 行为？CA 2是否积极编码社会探索和社会攻击的不同表征， CA 2是否编码了一个单一的社会显著性信号，该信号本身并不编码攻击性，而是由 动物的内部状态，以促进侵略通过CA 2输入LS？我们将检验这个假设 在LS中加压素的释放就像一个"许可门“。因为后叶加压素也能增强社交记忆 通过在CA 2内起作用，我们会问：一个单一的神经调质如何产生两种如此不同的作用？做 不同来源的加压素输入CA 2和LS，分别促进社会记忆和侵略？ 我们将通过描述CA 2回路和攻击性和攻击性期间的神经活动来解决这些问题。 非侵略性的社会交往使用：1。活性CA 2系综的活性依赖性遗传标记; 2. CA 2的电生理特性？离体脑LS回路及其加压素的调节 切片; 3.使用化学遗传学和光遗传学的攻击行为控制;和4.体内光学和 在非攻击性和攻击性社会互动期间的CA 2活动的电生理记录。

Heightened levels of social aggression, a motivated behavior, are often associated with neuropsychiatric disease. Although our understanding of the neural mechanisms regulating aggression is incomplete, both lateral septum (LS) and ventral hypothalamus are known to be important. Even though LS receives one of its strongest inputs from hippocampus, a region important for declarative memory, little is known about how hippocampus regulates aggression. Moreover, as hippocampus is implicated in several neuropsychiatric disorders associated with altered social behavior and aggression, a basic understanding of how hippocampus and its circuitry regulate aggression will likely yield important new insights into disease mechanisms. Here we focus on the role of the hippocampal CA2 region in social aggression. Relatively little is known about CA2, largely because of technical problems that limit its study with conventional lesioning approaches. We therefore developed a Cre mouse line that enables us to label and manipulate the activity of CA2 pyramidal neurons. Using a genetic silencing approach, we found that CA2 was critical during non-aggressive social exploration for the formation of social memory, the ability of an animal to recognize and remember another mouse (conspecific), but CA2 was not needed for other forms of hippocampal memory. Our recent results now show that CA2 also promotes social aggression, through an excitatory projection to LS that disinhibits a subnucleus in ventral medial hypothalamus important for aggression. Moreover, we find that the social neuropeptide arginine vasopressin promotes aggression by enhancing the CA2 to LS synapse. Here we ask: How does a single brain region, CA2, participate in social memory storage during non- aggressive social exploration and promote social aggression? Is there a single population of CA2 neurons that is activated during both social exploration and social aggression? Or are there specialist neurons for each behavior? Does CA2 actively encode distinct representations of social exploration and social aggression, or does CA2 encode a single social salience signal that does not in itself encode aggression but that is gated by the internal state of an animal to promote aggression through CA2 inputs to LS? We will test the hypothesis that vasopressin release in LS acts as such a permissive gate. As vasopressin also enhances social memory by acting within CA2, we will ask: How can a single neuromodulator produce two such distinct actions? Do distinct sources of vasopressin input to CA2 and LS promote, respectively, social memory and aggression? We will address these questions by characterizing CA2 circuits and neural activity during aggressive and non-aggressive social interactions using: 1. Activity-dependent genetic marking of active CA2 ensembles; 2. Electrophysiological characterization of CA2?LS circuits and their regulation by vasopressin in ex vivo brain slices; 3. Behavioral control of aggression using chemogenetics and optogenetics; and 4. In vivo optical and electrophysiological recordings of CA2 activity during non-aggressive and aggressive social interactions.