Experience dependent regulation of subcortical neural circuits for aggression

项目总结 攻击性是动物社会生活的一个重要方面，在领土防御、资源配置等方面发挥着至关重要的作用 获取和保护后代。和其他行为一样，攻击性也会通过经验得到加强。 这种加固通常具有有益的目的，改善领土防御和保护后代- 对个体和物种的生存至关重要的行为。然而，经验也可以提高病理水平。 持续的攻击性。在人类中，这会损害个人的心理健康，并将他人置于危险之中。因此， 需要根据个人既往和正在进行的疾病史来改进治疗方案 攻击性。因此，我的目标是确定攻击性体验如何改变神经回路计算 以产生持久的攻击性行为。具体地说，这项工作将探索体验是如何变化的 在社会生活中起关键作用的两个皮质下区域之间的突触连接和神经活动 行为：腹外侧腹内侧下丘脑(VMHvl)和内侧视前区(MPOA)。这个 VMHvl神经活动是攻击行为的必要条件和充分条件。MPOA是一个有影响力的节点 调节许多社会行为，并将GABA能输入的最大来源发送到VMHvl。 然而，MPOA在攻击性中的作用仍是个谜，目前还不清楚MPOA是否具有抑制作用 VMHvl的输入可以关闭或开启攻击性，或者社会经验如何影响这一回路。为了研究 MPOA VMHvl电路，本方案结合：(1)体外脑片电生理学用于光发生- 脑内突触强度随经验变化的辅助电路标测和量化 MPOA VMHvl回路；(2)社会互动小鼠的细胞类型和途径特异性钙记录；(3) 跟踪动物姿势动态的新算法和后续的无监督行为方法 检测和量化；以及，(4)活体光遗传操作以识别电路的变化 将攻击性体验与未来持续攻击性联系起来的功能。目标1测试攻击性能力 放松MPOA GABA能(MPOAvgat)传入至 不同的、经遗传鉴定的VMHvl神经元群体。目标2确定攻击性体验是否 增加体内与攻击相关的VMHvl群体活动。最后，Aim 3测试了MPOAvgat的能力 神经元在攻击体验之前和之后开启攻击之门。总而言之，这些实验将 实现识别攻击的新回路和突触治疗目标的长期目标- 以患者的行为史为基础的相关病理。完成这项奖学金将获得博士学位。 Guthman的培训目标，为她提供系统神经科学方面的实验专业知识以补充 她目前对单神经元突触生理学的掌握。拟议的计划将为她提供 培训以解决从突触到行为的社会神经科学研究问题。

PROJECT SUMMARY Aggression is a key aspect of animal social life, playing critical roles in territorial defense, resource acquisition, and protection of offspring. Like other behaviors, aggression is reinforced through experience. This reinforcement often serves beneficial purposes, improving territory defense and protection of offspring – vital behaviors for individual and species survival. However, experience can also promote pathological levels of persistent aggression. In humans, this can harm an individual’s mental health and put others at risk. Thus, there is a need for improved treatment options based on an individual’s prior and on-going history with aggression. Accordingly, my goal is to identify how aggressive experience alters neural circuit computations to generate persistent aggressive behavior. Specifically, this work will probe how experience changes synaptic connectivity and neural activity between two subcortical regions that play critical roles in social behavior: the ventrolateral ventromedial hypothalamus (VMHvl) and medial preoptic area (MPOA). The VMHvl neural activity is necessary and sufficient for aggressive behavior. The MPOA is an influential node regulating many social behaviors and sends the largest source of GABAergic input to the VMHvl. Nevertheless, the role of the MPOA in aggression is enigmatic, and it remains unknown if MPOA inhibitory input to VMHvl can shut down, or gate, aggression or how social experience affects this circuit. To study the MPOA VMHvl circuit, this proposal combines: (1) ex vivo brain slice electrophysiology for optogenetic- assisted circuit mapping and quantification of experience-dependent changes in synaptic strength within the MPOA VMHvl circuit; (2) cell-type and pathway specific calcium recordings in socially interacting mice ; (3) novel algorithms for tracking animal posture dynamics and subsequent methods for unsupervised behavior detection and quantification; and, (4) in vivo optogenetic manipulations to identify the changes in circuit function that link aggressive experience to future persistent aggression. Aim 1 tests the ability of aggressive experience to relax the strength of the synaptic connections between MPOA GABAergic (MPOAvgat) input to distinct, genetically-identified populations of VMHvl neurons. Aim 2 determines if aggressive experience increases in vivo aggression-related VMHvl population activity. Finally, Aim 3 tests the ability of MPOAvgat neurons to gate aggression before and after aggressive experience. Taken together, these experiments will achieve the long-term objective of identifying novel circuit and synaptic treatment targets for aggression- related pathologies based on patients’ behavioral history. Completion of this fellowship will achieve Dr. Guthman’s training goals, providing her with experimental expertise in systems neuroscience to complement her current command of single neuron synaptic physiology. The proposed plan will provide her with the training to tackle social neuroscience research questions from synapse to behavior.