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.

项目总结 知道如何对环境中的暗示做出反应是一种关键行为。做出最佳选择涉及到 利用必要的神经网络寻求奖励(例如食物等)，避免负面结果(例如伤害 等)，并忽略无关信息。对线索作出反应的异常网络活动导致适应不良 行为反应，许多精神障碍的特征，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 去甲肾上腺素(NE)，其中大部分来自LC，是从事适当行为的关键。 对暗示的反应。最近的发现强调了LC及其组织结构中尚未探索的复杂性 在对引出行为的暗示作出反应时的作用。不同的LC神经元集合编码不同的认知 流程和行为。此外，需要离散的LC子电路来解析各种LC函数。我的 长期目标是分离LC和NE在调节适应和不适应行为中的复杂作用。 这项拟议研究的具体目标是确定功能性LC神经丛和投影 对积极和消极的强化提示做出适当反应所需的目标。为了实现这一目标，我 将(1)表征从高密度电生理探头获得的LC神经活动和(2)识别和 在主动回避和奖励期间使用依赖于活动的病毒标记策略调节LC投射 寻找任务。我的中心假设是，相反的线索-结果关联招募独立的LC神经元 适当的行为反应所必需的集合和回路，即使是在与结果相关的情况下 行为是相似的。在目标1中，我将分析从高密度获得的大规模电生理数据 神经素探针用于表征主动回避和奖赏提示呈现过程中LC神经元的活动。我 假设将会有单独和不同的神经元集合，它们对提示类似的提示做出反应 要么采取行动，要么获得积极的结果，要么避免消极的结果。在目标2中，我将使用钙依赖 基因标记，Cal-Light，用于识别和抑制由行为唤起线索驱动的离散LC投射。我 假设LC整合主动回避和奖赏寻求线索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子回路中的活动 对于适当的行为是必要的。拟议的研究将确定LC合奏和投影 最优行为的基础，突出可能导致不适应行为的电路，并告知电路- 基于创伤后应激障碍和其他精神疾病的治疗目标。