Experience dependent regulation of subcortical neural circuits for aggression

体验皮质下神经回路的攻击性依赖性调节

基本信息

批准号：
10548735
负责人：
Eartha Mae Guthman
金额：
$ 6.98万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548735
关键词：
Affect Aggressive behavior Algorithms American Animals Behavior Behavioral Bipolar Disorder Brain Calcium Calcium Signaling Color Complement Complex Data Detection Development Disease Disinhibition Electrophysiology (science)Exposure to Fellowship Female Fiber Future Glutamates Goals Human Hypothalamic structure Individual Influentials Life Link Maps Measures Medial Mental Health Mental disorders Methods Mus Neurons Neurosciences Neurosciences Research Output Pathologic Pathology Pathway interactions Patients Photometry Physiology Play Population Post-Traumatic Stress Disorders Posture Preoptic Areas Psychological reinforcement Recording of previous events Regulation Relaxation Reproduction Resources Risk Role Schizophrenia Site Slice Social Behavior Social Interaction Source Substance abuse problem Synapses System Techniques Territoriality Testing Training Treatment Protocols Update Work behavior change cell type excitatory neuron experience experimental study improved in vivo inhibitory neuron innovation male mental set neural neural circuit novel offspring optogenetics personalized medicine postsynaptic prevent sex social social neuroscience tool

项目摘要

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.

项目概要攻击性是动物社会生活的一个关键方面，在领土防御、资源保护等方面发挥着关键作用。与其他行为一样，攻击性也会通过经验得到强化。这种强化通常会起到有益的作用，改善领地防御和对后代的保护—— 然而，经验也可以促进病理水平。对于人类来说，这可能会损害个人的心理健康并使其他人处于危险之中。需要根据个人之前和当前的病史来改进治疗方案因此，我的目标是确定攻击性经历如何改变神经回路计算。具体来说，这项工作将探讨经验如何变化。在社交中发挥关键作用的两个皮层下区域之间的突触连接和神经活动行为：下丘脑腹外侧腹内侧（VMHvl）和内侧视前区（MPOA）。 VMHvl 神经活动对于攻击行为是必要且充分的。MPOA 是一个有影响力的节点。调节许多社会行为并向 VMHvl 发送 GABA 能输入的最大来源。然而，MPOA 在攻击行为中的作用仍然是个谜，并且尚不清楚 MPOA 是否会抑制攻击行为。 VMHvl 的输入可以关闭或控制攻击性或社会经验如何影响该回路。 MPOA VMHvl 电路，该提案结合了：（1）用于光遗传学的离体脑切片电生理学- 辅助电路映射和量化突触强度的经验依赖性变化 MPOA VMHvl 回路；(2) 社交互动小鼠中的细胞类型和途径特异性钙记录；用于跟踪动物姿势动态的新颖算法以及用于无监督行为的后续方法检测和定量；以及（4）体内光遗传学操作来识别电路的变化将攻击性经验与未来持续性攻击性联系起来的功能目标 1 测试攻击性的能力。体验放松 MPOA GABAergic (MPOAvgat) 输入之间的突触连接强度目标 2 是通过基因鉴定的不同 VMHvl 神经元群体决定攻击性体验。增加体内攻击相关的 VMHvl 群体活性最后，目标 3 测试 MPOAvgat 的能力。总而言之，这些实验将在攻击性经历之前和之后控制攻击性。实现识别新的攻击性回路和突触治疗目标的长期目标根据患者行为史的相关病理学的完成将获得博士。古斯曼的培训目标，为她提供系统神经科学的实验专业知识来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解决从突触到行为的社会神经科学研究问题。