Locus coeruleus ensembles in active avoidance and reward seeking

蓝斑集合了主动回避和寻求奖励

• 批准号: 10678364
• 负责人: Ellen Marie Rodberg
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-16 至 2025-03-15
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678364
• 关键词: Adaptive Behaviors; Amygdaloid structure; Anxiety; Auditory; Auditory area; Behavior; Behavioral; Brain; Brain Stem; Brain region; Calcium; Cell Nucleus; Characteristics; Complex; Computational Technique; Cues; Data; Data Analyses; Detection; Disease; Dissociation; Electrophysiology (science); Environment; Evaluation; Extinction; Food; Freezing; Fright; Genetic; Goals; Heterogeneity; Histology; Individual; Injury; Intervention; Label; Learning; Light; Maps; Mental Depression; Mental disorders; Mentorship; Motor Cortex; Negative Reinforcements; Neurons; Norepinephrine; Outcome; Population; Positive Reinforcements; Post-Traumatic Stress Disorders; Process; Property; Rattus; Research; Research Personnel; Rewards; Rodent; Role; Schizophrenia; Shock; Testing; Training; Ventral Tegmental Area; Viral; Work; addiction; autism spectrum disorder; behavioral response; cognitive process; density; extracellular; large scale data; locus ceruleus structure; maladaptive behavior; neural; neural network; neurochemistry; neuropsychiatric disorder; noradrenergic; novel; novel therapeutic intervention; optogenetics; oral communication; recruit; response

PROJECT SUMMARY Knowing how to act in response to cues in our environment is a critical behavior. Making optimal choices involves engaging the necessary neural networks to seek rewards (e.g., food etc.), avoid negative outcomes (e.g., injury etc.), and ignore irrelevant information. Aberrant network activity in response to cues leads to maladaptive behavioral responses, something characteristic in many psychiatric disorders including PTSD, addiction, autism spectrum disorder, and schizophrenia. The brainstem nucleus locus coeruleus (LC) and brain-wide levels of norepinephrine (NE), a majority of which originates from LC, are vital for engaging appropriate behaviors in response to cues. Recent discoveries emphasize the unexplored complexity in the organization of LC and its role in responding to cues that elicit behavior. Distinct ensembles of LC neurons encode different cognitive processes and behaviors. Furthermore, discrete LC subcircuits are required to parse various LC functions. My long-term goal is to dissociate the complex role of LC and NE in regulating adaptive and maladaptive behaviors. The specific objective of this proposed research is to identify the functional LC neural ensembles and projection targets necessary to appropriately respond to positive and negative reinforcement cues. To achieve this goal, I will (1) characterize LC neural activity acquired from high density electrophysiology probes and (2) identify and modulate LC projections with an activity dependent viral labelling strategy during an active avoidance and reward seeking task. My central hypothesis is that opposing cue-outcome associations recruit separate LC neuron ensembles and circuits necessary for appropriate behavioral responses, even when outcome-associated behaviors are similar. In Aim 1 I will analyze large scale electrophysiology data obtained from high-density Neuropixel probes to characterize LC neuronal activity during active avoidance and reward cue presentation. I hypothesize that there will be separate and distinct ensembles of neurons that respond to cues prompting similar actions to either receive a positive outcome vs avoid a negative outcome. In Aim 2 I will use calcium-dependent genetic tagging, Cal-Light, to identify and inhibit discrete LC projections driven by behavior-evoking cues. I hypothesize that LC ensembles for active avoidance and reward seeking cues preferentially target different brain regions forming functional subcircuits. Furthermore, I will test my hypothesis that activity in these LC subcircuits is necessary for appropriate behavior. The proposed research will identify LC ensembles and projections underlying optimal behavior, highlight circuits that may contribute to maladaptive behavior, and inform circuit- based treatment targets for PTSD and other psychiatric disorders.

项目摘要 知道如何对我们环境中的线索做出反应是一个关键的行为。做出最佳选择包括 使用必要的神经网络来寻求奖励（例如，食物等），避免负面结果（例如，损伤 等等），忽略无关信息对线索的异常网络活动导致适应不良 行为反应，这是许多精神疾病的特征，包括创伤后应激障碍，成瘾，自闭症， 谱系障碍和精神分裂症脑干蓝斑核（LC）和全脑水平的 去甲肾上腺素（NE），其中大部分来源于LC，对于参与适当的行为至关重要， 对线索的反应最近的发现强调了LC组织中未被探索的复杂性及其 在对引发行为的线索做出反应中的作用。LC神经元的不同集合编码不同的认知 过程和行为。此外，需要离散LC子电路来解析各种LC函数。我 长期目标是分离LC和NE在调节适应和适应不良行为中的复杂作用。 这项研究的具体目标是确定功能性LC神经系综和投射 目标是对积极和消极的强化线索做出适当反应所必需的。为了实现这一目标，我 将（1）表征从高密度电生理学探针获得的LC神经活动，以及（2）识别和 在主动回避和奖励期间，用活性依赖性病毒标记策略调节LC投射 寻找任务。我的中心假设是，相反的线索-结果关联招募单独的LC神经元 适当的行为反应所必需的整体和回路，即使与结果相关 行为相似。在目标1中，我将分析从高密度脑电中获得的大规模电生理数据。 神经像素探针表征LC神经元活动在主动回避和奖励线索介绍。我 假设会有独立的和不同的神经元集合，对提示类似的线索作出反应， 要么接受积极的结果，要么避免消极的结果。在目标2中，我将使用钙依赖性 遗传标记，Cal-Light，以识别和抑制由行为诱发线索驱动的离散LC投射。我 假设主动回避和奖励寻求线索LC集合优先针对不同的大脑 形成功能子电路的区域。此外，我将测试我的假设，在这些LC分支电路的活动 是行为得体的必要条件拟议的研究将确定LC合奏和预测 潜在的最佳行为，突出可能导致适应不良行为的电路，并告知电路- 基于PTSD和其他精神疾病的治疗目标。