Corticolimbic Circuits in Negative Affect

负面情绪中的皮质边缘回路

• 批准号: 10455035
• 负责人: Regina M Carelli
• 金额: $ 34.66万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10455035
• 关键词: Affect; Affective; Alcohol abuse; Alcohol consumption; Anhedonia; Animals; Appetitive Behavior; Automobile Driving; Behavior; Cessation of life; Disease; Drug usage; Electrophysiology (science); Emotional; Extinction (Psychology); Foundations; Frequencies; Goals; Health; Human; Impairment; Lead; Link; Measures; Medial; Mediating; Mental Depression; Mental disorders; Methods; Neurophysiology - biologic function; Neurosciences; Nucleus Accumbens; Optics; Pathway interactions; Play; Prefrontal Cortex; Rattus; Recovery; Regulation; Rewards; Role; Signal Transduction; Substance Use Disorder; Suicide; System; Taste Perception; Taste aversion; Time; United States; Work; cognitive control; comorbidity; drug relapse; drug withdrawal; effective therapy; experience; hedonic; insight; learning extinction; maladaptive behavior; negative affect; negative emotional state; negative mood; neural circuit; neuromechanism; neurotransmission; nonhuman primate; novel; optogenetics; pleasure; preservation; restoration; reward processing; sex; treatment strategy

Project Summary/Abstract The ability to seek out situations that elicit pleasure and avoid those that lead to aversion or discomfort is a fundamental ability we all share, yet dysfunctional hedonic processing is prevalent in numerous psychiatric illnesses including substance use disorders (SUDs), alcohol abuse, and depression. As such, it is critical to understand the basic neural mechanisms underlying aversive affective states to ultimately apply treatment strategies to restore normal hedonic processing and aid in the recovery of maladaptive behaviors in mental illness. Here, we seek to understand the role of ‘top-down’ medial prefrontal cortex (mPFC) to nucleus accumbens (NAc) processing of innate and conditioned negative affective processing, incorporating electrophysiology, optogenetics, and a rat transcranial alternating current stimulation (tACS) method we developed. We focus on one type of behavior (taste reactivity, TR), measured in innate (unconditioned) situations and during conditioned taste aversion (CTA) and its extinction (restoration of positive affect). Notably, TR has exceptional translational value since it is preserved across species with similar behaviors present in rats, nonhuman primates and humans. Using electrophysiology, we will first determine how oscillatory, coordinated rhythms in mPFC and NAc circuitry are linked to affective processing in real time in the naïve state, how this signaling shifts when the sweet becomes devalued through CTA, and when it is restored in extinction. Since human and animal studies indicate that strengthening the mPFC can reduce negative affect we will then determine if strengthening these circuits using two distinct approaches can restore positive affect and associated neural function. We will use optogenetics (channelrhodopsin) to determine if targeted optical strengthening of infralimbic (IL)-NAc shell and/or prelimbic (PrL)-NAc core is sufficient to reduce negative affect and enhance CTA extinction. We will also examine if our novel rat transcranial alternating current (tACS) system, a relatively noninvasive approach with great translational value, can also modulate disrupted cortical oscillations in CTA, strengthen overall mPFC-NAc circuit coherence, and determine if this approach can increase positive affect. In both optogenetics and tACS studies, we will focus on 20 Hz (beta) frequency given its role in ‘top-down’ cognitive control as well as 80 Hz (gamma) frequency given studies that implicate this signaling in reward processing. Collectively, this multi-faceted approach will provide important insight into how mPFC-NAc systems modulate normal hedonic processing, how these systems are disrupted as negative affective states emerge and provide the foundation for the ultimate goal of developing methods to restore aberrant circuit function and hasten recovery from negative emotional states.

项目摘要/摘要 寻找引起愉悦并避免导致厌恶或不适的情况的能力是 我们所有人都分享的基本能力，但是功能失调的享乐处理在许多精神病学中都普遍存在 包括药物使用障碍（SUD），酗酒和抑郁症在内的疾病。因此，至关重要 了解厌恶情感状态的基本神经机制，以最终应用治疗 恢复正常享乐处理的策略，并有助于恢复精神中适应不良行为的恢复 疾病。在这里，我们试图了解“自上而下”介质前额叶皮层（MPFC）对核的作用 伏尊（NAC）对先天和条件的负面情感处理的处理，合并 电生理学，光遗传学和大鼠trancranial替代电流刺激（TACS）方法 发达。我们专注于一种类型的行为（味觉反应性，TR），在先天（无条件）情况下测量 在条件味道厌恶（CTA）及其扩展期间（恢复积极影响）。值得注意的是，TR具有 特殊的翻译价值由于在大鼠中存在相似行为的物种中保存下来，因此 非人类隐私和人类。使用电生理学，我们将首先确定振荡性，协调的如何 MPFC和NAC电路中的节奏与在幼稚状态下实时的情感处理有关 当甜蜜通过CTA发展时，以及延伸恢复时，信号传导会移动。自从 人类和动物研究表明，加强MPFC可以减少负面影响，然后我们将 确定使用两种不同方法加强这些电路是否可以恢复积极影响并相关 神经功能。我们将使用光遗传学（ChannelRhopoptin）来确定是否有针对性的光学加强 Infralimbic（IL）-NAC壳和/或前比（PRL）-NAC核心足以减少负面影响并增强 CTA扩展。我们还将检查我们的新型大鼠trancranial替代电流（TAC）系统是否相对 具有巨大翻译价值的无创方法，还可以调节CTA中干扰的皮质振荡， 增强总体MPFC-NAC电路连贯性，并确定这种方法是否会增加积极影响。在 鉴于其在“自上而下”的认知中的作用，我们将重点关注20 Hz（beta）频率 鉴于研究将这种信号传导在奖励处理中暗示的研究以及80 Hz（伽马）频率。 总的来说，这种多方面的方法将提供有关MPFC-NAC系统如何调节的重要见解 正常的享乐处理，这些系统如何被破坏为负面影响的状态并提供 开发方法以恢复异常电路功能和促进方法的最终目标的基础 从负面的情绪状态中恢复。