Mapping experience-dependent change in a circuit for aggression

摘要 大脑是如何产生并维持持续的高攻击性状态的？而 病理性的、持续的攻击性是许多不同精神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， 创伤性脑损伤，我们缺乏对神经机制的基本了解， 持续的社会状态。许多攻击性模型认为，这种失调是通过 “自上而下”的抑制控制皮层下电路的侵略失败，通过电路和 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 劫持电路机制，用于在自适应上下文中生成持久攻击状态。在 特别是，侵略的经验早已被称为促进持久性的出现， 高侵略性状态，使动物能够在很长一段时间内捍卫领土和地位。 研究经验如何“更新”健康大脑中的神经回路，以促进未来的攻击 提供了一个独特的窗口，这些电路如何在病理条件下变得失调。 经验依赖性更新背后的神经机制是什么？要对此进行研究， 我们将纵向观察腹内侧核神经活动之间的变化关系， 下丘脑腹外侧区（VMHvl）是一个攻击性输出区，在 在两性的侵略，其“上游”抑制输入。在这个提案中，我们将测试小说 攻击性经历通过一个回路稳定了一个持续的攻击性状态 “改道”机制，而不是抑制控制位点的活性变化。 使用各种方法进行监督和非监督行为分析， 介导的解剖追踪，突触生理学，光遗传学和细胞分辨率高密度 我们将纵向观察经验是如何改变这个回路的基本特性的 实施行为改变。首先，我们将电路节点的假定身份映射到 结构能力，重新路由抑制和表征突触强度的变化，这 穿越经验的循环接下来，我们将具体研究 监管输入和整个经验的电路级输出。最后，我们将执行高密度 人口记录，以阐明正在进行的基础计算的变化， 电路以稳定高侵略状态。这些数据将提供全面的 理解经验如何产生持久行为状态的综合框架，以及 将为新型活动依赖工具铺平道路，这些工具可能能够检测神经信号， 在有攻击性失调风险的患者群体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.