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Mapping experience-dependent change in a circuit for aggression

绘制攻击性回路中依赖于经验的变化

基本信息

批准号：
10394392
负责人：
Annegret Lea Falkner
金额：
$ 50.36万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-17 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10394392
关键词：
Adaptive Behaviors Affective Aggressive behavior Animal Model Animals Architecture Area Behavior Behavioral Bipolar Disorder Brain Calcium Classification Computing Methodologies Control Locus Data Development Doctor of Philosophy Electrophysiology (science)Failure Future Generations Goals Health Human Hypothalamic structure In Vitro Individual Intervention Life Experience Light Maps Measures Mediating Mental disorders Methods Modeling Motivation Neurons Optical Methods Optics Output Pathologic Pathology Pathway interactions Pharmaceutical Preparations Physiologic pulse Physiology Population Population Density Population Dynamics Populations at Risk Post-Traumatic Stress Disorders Property Resolution Rett Syndrome Role Route Schizophrenia Signal Transduction Slice Social Behavior Source Supervision Synapses Target Populations Testing Time Traumatic Brain Injury Update Viral Weight anatomical tracing autism spectrum disorder base cell type common symptom density diagnostic tool experience experimental study human model in vivo lens neural circuit neuromechanism novel optogenetics patient population postsynaptic presynaptic rabies viral tracing relating to nervous system response sex social tool

项目摘要

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.

摘要