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.

社会攻击性的升高是一种动机性行为，通常与神经精神疾病有关 疾病。尽管我们对调节攻击行为的神经机制的理解并不完整，但 众所周知，外侧隔膜（LS）和腹侧下丘脑很重要。尽管 LS 收到了其中之一 最强的输入来自海马体，海马体是陈述性记忆的重要区域，但我们对其如何作用知之甚少。 海马体调节攻击性。此外，由于海马体与多种神经精神疾病有关 与社会行为改变和攻击性相关的疾病，对海马体如何 其调节攻击性的电路可能会给疾病机制带来重要的新见解。 在这里，我们重点关注海马 CA2 区域在社交攻击中的作用。知之甚少 关于 CA2，很大程度上是因为技术问题限制了传统损伤方法的研究。 因此，我们开发了 Cre 小鼠系列，使我们能够标记和操纵 CA2 的活性 锥体神经元。使用基因沉默方法，我们发现 CA2 在非攻击性行为期间至关重要 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 CA2。我们最近的 现在的结果表明，CA2 还通过对 LS 的兴奋性投射来促进社会攻击性 去抑制下丘脑腹侧内侧的一个亚核，该亚核对于攻击性很重要。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。 我们在这里问：单个大脑区域 CA2 如何参与非非活动期间的社会记忆存储？ 积极的社会探索并促进社会攻击？是否存在单一的 CA2 神经元群 在社会探索和社会攻击过程中都会被激活吗？或者每个都有专门的神经元 行为？ CA2 是否主动编码社会探索和社会攻击的不同表征，或者 CA2是否编码了一个单一的社会显着信号，该信号本身并不编码攻击性，而是由 动物的内部状态通过 CA2 输入到 LS 来促进攻击性？我们将检验假设 LS 中加压素的释放起到了这样一个许可门的作用。由于加压素还可以增强社交记忆 通过在 CA2 内起作用，我们会问：单个神经调节剂如何产生两种如此不同的作用？做 CA2 和 LS 的加压素输入的不同来源分别促进社会记忆和攻击性？ 我们将通过表征攻击性和攻击性期间的 CA2 回路和神经活动来解决这些问题。 非攻击性社交互动使用： 1. 活跃 CA2 整体的活动依赖性遗传标记； 2. CA2?LS 回路的电生理学特征及其在离体脑中加压素的调节 切片； 3. 利用化学遗传学和光遗传学控制攻击行为； 4.体内光学和 非攻击性和攻击性社交互动期间 CA2 活动的电生理记录。