Regulation of social aggression through hippocampal CA2 inputs to lateral septum

高水平的社会攻击性是一种有动机的行为，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了解还不完全，但两者 外侧隔(LS)和下丘脑腹侧被认为是重要的。即使LS收到了它的一个 海马区是陈述性记忆的重要区域，来自海马区的最强输入信号是如何产生的，人们对此知之甚少 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障碍，对海马体如何 而它调节攻击性的电路可能会对疾病机制产生重要的新见解。 在这里，我们将重点放在海马区CA2区在社会攻击中的作用。我们所知的相对较少 关于CA2，很大程度上是因为技术问题限制了它用传统的放血方法进行研究。 因此，我们开发了一种Cre小鼠品系，使我们能够标记和操纵CA2的活性 锥体神经元。使用遗传沉默的方法，我们发现CA2在非侵袭性的过程中是关键的 对社会记忆形成的社会探索，即动物识别和记忆的能力 另一只小鼠(同种)，但其他形式的海马体记忆不需要CA2。我们最近 现在的结果表明，CA2也通过向LS的兴奋性投射促进社交攻击性 去抑制下丘脑腹侧内侧的一个亚核，该亚核对攻击很重要。此外，我们发现， 社会神经肽精氨酸加压素通过增强CA2到LS突触来促进攻击性。 在这里，我们问：单个大脑区域CA2是如何参与非社会记忆存储的 积极的社会探索和促进社会攻击性？是否有一个单一的CA2神经元群体 在社会探索和社会攻击中都被激活了吗？或者每个神经元都有专门的神经元 行为？CA2是否主动编码社会探索和社会攻击性的不同表征，或者 CA2编码的单个社交显著信号本身并不编码攻击性，但受 通过向LS输入CA2来促进攻击性的动物的内部状态？我们将检验这一假设 LS中的加压素释放起到了这样的允许门的作用。因为加压素还能增强社会记忆 通过在CA2中发挥作用，我们将会问：一个神经调节剂如何产生两种不同的作用？做 不同来源的加压素分别输入CA2和LS促进社会记忆和攻击性？ 我们将通过表征CA2神经回路和神经活动来解决这些问题 非攻击性社会互动使用：1。活动CA2集合的活动依赖的遗传标记； 离体脑CA2？LS环电生理特性及加压素的调节作用 切片；3.使用化学遗传学和光遗传学控制攻击性的行为；以及4.体内光学和 非攻击性和攻击性社会互动中CA2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.