Regulation of social aggression through hippocampal CA2 inputs to lateral septum

通过海马 CA2 输入至外侧隔膜调节社会攻击行为

• 批准号: 10002290
• 负责人: STEVEN A SIEGELBAUM
• 金额: $ 53.01万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-26 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002290
• 关键词: Address; Aggressive behavior; Alzheimer' s Disease; Animals; Argipressin; Behavior; Behavior Control; Brain; Brain region; Cell Nucleus; Disease; Dorsal; Electrophysiology (science); Genetic; Hippocampus (Brain); Hypothalamic structure; Immediate-Early Genes; Impairment; Label; Lateral; Lesion; Locales; Mediating; Memory; Middle Hypothalamus; Monitor; Mus; Nature; Neuromodulator; Neurons; Neuropeptides; Optics; Output; Patient Care; Play; Population; Presynaptic Terminals; Regulation; Role; Schizophrenia; Signal Transduction; Slice; Social Behavior; Social Interaction; Societies; Source; Specialist; Synapses; Testing; Vasopressins; anatomical tracing; autism spectrum disorder; base; experimental study; extracellular; hippocampal pyramidal neuron; in vivo; insight; machine learning algorithm; male; maternal aggression; motivated behavior; neuromechanism; neuropsychiatric disorder; neuroregulation; novel; optogenetics; presynaptic; receptor; relating to nervous system; selective expression; social; tool

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.

社交侵略水平的提高，一种动机行为，通常与神经精神病学有关 疾病。尽管我们对调节侵略的神经机制的理解是不完整的 已知侧间隔（LS）和下丘脑很重要。即使LS收到其中之一 海马最强的输入是对声明性记忆很重要的区域，对如何如何了解 海马调节侵略性。此外，由于海马与几种神经精神病学有关 与改变社会行为和侵略性有关的疾病，对海马的基本了解 它的电路调节攻击可能会产生对疾病机制的重要新见解。 在这里，我们关注海马CA2地区在社会侵略中的作用。相对鲜为人知 大约CA2，主要是因为技术问题限制了其研究的常规病变方法。 因此，我们开发了一条CRE小鼠线，使我们能够标记和操纵CA2的活动 金字塔神经元。使用遗传沉默方法，我们发现CA2在非攻击性过程中至关重要 社会记忆形成的社会探索，动物识别和记住的能力 另一种鼠标（同种），但其他形式的海马记忆不需要CA2。我们最近 现在的结果表明，CA2还通过对LS的兴奋性投射来促进社会侵略 DISIS抑制腹侧下丘脑中的核肠下核对攻击很重要。而且，我们发现 社会神经肽精氨酸加压素通过增强Ca2到LS突触来促进侵略。 在这里我们问：一个大脑区域CA2如何参与非 - 积极的社会探索并促进社会侵略？是否有一个人群的Ca2神经元 在社会探索和社会侵略期间都被激活吗？或每个都有专家神经元 行为？ CA2是否会积极编码社会探索和社会侵略的不同表示，或者 CA2是否编码一个本身并非编码侵略的单一社会显着性信号，但这是由 动物的内部状态通过CA2输入到LS促进侵略性？我们将检验假设 在LS中释放的加压素释放是这样宽容的门。由于加压素还可以增强社交记忆 通过在CA2内部起作用，我们会问：单个神经调节剂如何产生两种这种不同的动作？做 加压素输入到Ca2和LS的不同来源分别促进社会记忆和侵略？ 我们将通过表征CA2电路和侵略性期间的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合奏的活动依赖性遗传标记； 2。 Ca2？LS电路的电生理表征及其在离体脑中加压素调节 切片； 3。使用化学遗传学和光遗传学对攻击的行为控制；和4。体内光学和 在非攻击性和积极的社交互动过程中，CA2活性的电生理记录。