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

• 批准号: 10389196
• 负责人: Eartha Mae Guthman
• 金额: $ 6.76万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 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/10389196
• 关键词: Affect; Aggressive behavior; Algorithms; American; Animals; Behavior; Behavioral; Bipolar Disorder; Brain; Calcium; Color; Complement; Complex; Data; Detection; Development; Disease; Electrophysiology (science); Exposure to; Fellowship; Female; Fiber; Future; Glutamates; Goals; Human; Hypothalamic structure; Individual; Influentials; Life; Link; 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; Reproduction; Resources; Risk; Role; Schizophrenia; Signal Transduction; Site; Slice; Social Behavior; Social Interaction; Source; Substance abuse problem; Synapses; System; Techniques; Territoriality; Testing; Training; Treatment Protocols; Update; Work; base; behavior change; cell type; excitatory neuron; experience; experimental study; improved; in vivo; inhibitory neuron; innovation; male; mental set; neural circuit; novel; offspring; optogenetics; personalized medicine; postsynaptic; prevent; relating to nervous system; sex; social; social neuroscience; tool

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.

项目摘要 攻击性是动物社会生活的一个重要方面，在领土防御、资源利用、 获取和保护后代。像其他行为一样，攻击性通过经验得到加强。 这种强化往往是有益的，提高领土防御和保护后代- 对个体和物种生存至关重要的行为。然而，经验也可以促进病理水平 持续的侵略。在人类中，这可能会损害个人的心理健康，并使他人处于危险之中。因此，在本发明中， 需要基于个体的先前和正在进行的疾病史的改进的治疗选择 侵略因此，我的目标是确定攻击性经验如何改变神经回路计算 产生持续的攻击行为具体来说，这项工作将探讨如何经验的变化 在社交活动中起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：腹外侧腹内侧下丘脑（VMHvl）和内侧视前区（MPOA）。的 VMHvl神经活动对于攻击性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在攻击中的作用是神秘的，并且MPOA抑制剂是否能够抑制攻击仍然是未知的。 输入VMHvl可以关闭，或门，侵略性或社会经验如何影响这个电路。研究 MPOA VMHvl电路，该方案结合了：（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的经验依赖性变化的突触强度内 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;（3） 用于跟踪动物姿势动态的新算法和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，以鉴定回路中的变化。 将攻击性体验与未来持续攻击性联系起来的功能。目标1测试攻击能力 经验，放松MPOA GABA能（MPOAvgat）输入之间的突触连接强度， VMHv 1神经元的不同的、遗传上鉴定的群体。目标2确定是否有攻击性经验 增加体内攻击相关的VMHvl群体活性。最后，Aim 3测试了MPOAvgat的能力 神经元门攻击之前和之后的侵略经验。综合起来，这些实验将 实现确定攻击性的新回路和突触治疗目标的长期目标- 根据病人的行为史来判断相关的病理。完成本奖学金将实现博士。 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，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。