Mapping experience-dependent change in a circuit for aggression

摘要 大脑如何产生并维持一种持久的高攻击性状态？而当 病理性、持续性攻击是许多不同心理健康障碍的常见症状。 包括精神分裂症、双相情感障碍、创伤后应激障碍、自闭症、雷特综合征以及 创伤性脑损伤，我们缺乏对潜在的神经机制的基本了解 持久的社会状态。许多攻击性模型认为，这种失调是通过 “自上而下”的皮层下回路攻击抑制控制失败，通过回路和 这些模型的突触基础仍不清楚。在这里，我们提出病理性攻击可能 用于在自适应环境中生成持久攻击状态的劫持电路机制。在……里面 特别是，攻击性的经历早已为人所知，有助于出现持久的 高度攻击性状态，使动物能够在很长一段时间内捍卫领土和地位。 研究体验如何“更新”健康大脑中的神经回路以促进未来的攻击性 为这些电路如何在病理条件下变得失调提供了一个独特的窗口。 依赖经验的更新背后的神经机制是什么？为了探索这一点， 我们将纵向观察腹内侧部神经活动之间的变化关系 下丘脑腹外侧区(VMHvl)，攻击输出区，在 两性的攻击性及其“上游”抑制性输入。在这个提案中，我们将测试这部小说 攻击体验通过回路稳定持续攻击状态的假说 而不是改变抑制控制点的活性。 使用各种方法进行监督和非监督行为分析， 介导的解剖示踪、突触生理学、光遗传学和细胞分辨率高密度 记录，我们将纵向查看经验如何改变这个电路的基本属性 来实施行为改变。首先，我们将电路节点的假定标识映射到 改变抑制的构筑能力和表征突触强度的变化 环游整个体验。接下来，我们将具体考察 调节输入和电路级输出跨越体验。最后，我们将执行高密度 人口记录，以阐明由 稳定高攻击性状态的电路。总而言之，这些数据将提供全面的 用于理解体验如何产生持久行为状态的集成框架，以及 将为新的依赖活动的工具铺平道路，这些工具可能能够检测到 处于攻击性调节障碍风险人群中的经验和行为持续性。

Abstract How does the brain generate and maintain a persistent high-aggression state? While pathological, persistent aggression is a common symptom in many diverse mental health disorders including schizophrenia, bipolar disorder, post-traumatic stress disorder, autism, Rett syndrome, and traumatic brain injury, we lack a fundamental understanding of the neural mechanisms underlying persistent social states. Many models of aggression posit that this dysregulation occurs through the failure of “top-down” inhibitory control of subcortical circuits for aggression, through the circuit and synaptic basis for these models remain unclear. Here, we propose that pathological aggression may hijack circuit mechanisms used to generate persistent aggressive states in adaptive contexts. In particular, the experience of aggression has long been known to facilitate the emergence of a persistent high-aggression state, enabling animals to defend territory and status across long periods of time. Examining how experience “updates” neural circuits in the healthy brain to facilitate future aggression provides a unique window on how these circuits become dysregulated under pathological conditions. What are the neural mechanisms underlying experience-dependent updating? To explore this, we will look longitudinally at the changing relationship between neural activity in the ventromedial hypothalamus, ventrolateral area (VMHvl), an aggression output area with a well-described role in aggression in both sexes, and its “upstream” inhibitory inputs. In this proposal, we will test the novel hypothesis that aggression experience stabilizes a persistent aggressive state through a circuit “rerouting” mechanism rather than changes in the activity of inhibitory control loci. Using a variety of methods for supervised and unsupervised behavioral analysis, virally mediated anatomical tracing, synaptic physiology, optogenetics and cellular resolution high-density recordings, we will look longitudinally at how experience alters the fundamental properties of this circuit to implement behavioral change. First, we will map the putative identity of circuit nodes with the architectural capacity to reroute inhibition and characterize the changes in synaptic strength of this circuit across experience. Next, we will specifically examine the relationship between the activity of the regulatory input and the circuit-level output across experience. Lastly, we will perform high-density population recordings to elucidate the changes in the underlying computations being performed by the circuit to stabilize a high aggression state. Together, these data will provide a comprehensive integrated framework for understanding how experience generates a persistent behavioral state, and will pave the way for novel activity-dependent tools that may be able to detect neural signatures of experience and behavioral persistence in patient populations at risk for aggression dysregulation.