Brain Circuits of Outcome-dependent vs. Habitual Avoidance

结果依赖与习惯性回避的大脑回路

• 批准号: 10197750
• 负责人: Christopher Kenneth Cain
• 金额: $ 36.97万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10197750
• 关键词: Address; Amygdaloid structure; Anxiety; Attention; Behavior; Behavioral; Biological Assay; Brain; Cognitive; Conflict (Psychology); Corpus striatum structure; Cues; Data; Dependence; Desire for food; Development; Disease; Dorsal; Environment; Extinction (Psychology); Feedback; Food; Fright; Goals; Habits; Human; Knowledge; Lead; Learning; Lesion; Mediating; Mental disorders; Methods; Modeling; Muscimol; Neurobiology; Operant Conditioning; Outcome; Pain; Pathway interactions; Pharmaceutical Preparations; Play; Positive Reinforcements; Prefrontal Cortex; Procedures; Process; Publishing; Punishment; Rattus; Reaction; Reflex action; Research; Research Personnel; Resistance; Response to stimulus physiology; Rewards; Safety; Series; Shock; Signal Transduction; Suggestion; Testing; Time; Training; Work; addiction; avoidance behavior; base; classical conditioning; conditioned fear; conditioning; coping; designer receptors exclusively activated by designer drugs; experimental study; innovation; interest; neurobiological mechanism; neuromechanism; novel; relating to nervous system; resilience; response; tool

Abstract During active avoidance (AA), subjects learn to emit instrumental actions that escape conditioned threats and avoid pain. Little is known about the neural mechanisms mediating avoidance responses (ARs), because AA research stalled in the 1970s amid heated theoretical debates, inconsistent results with crude brain manipulations, and suggestions that Pavlovian processes were sufficient to explain ARs. This is unfortunate, as AA is the prototypical paradigm for studying aversively-motivated instrumental behavior, a class of defensive learning that almost certainly contributes to both adaptive and maladaptive active coping strategies. AA has several advantages as an adaptive coping/resilience mechanism: 1) it blunts fear and anxiety reactions, 2) it is less context-dependent and more persistent than fear extinction, and, unlike passive avoidance, 3) it allows subjects to remain engaged in environments that include danger. Conversely, maladaptive ARs may be particularly problematic because AA is extremely resistant to extinction and occasionally, paradoxically, enhanced by punishment (“vicious circle behavior”); processes that may be operating in human disorders ranging from anxiety (i.e. OCD) to addiction. Since AA likely reflects instrumental learning layered over previously acquired fear conditioning, the experiments in this proposal will leverage knowledge about Pavlovian fear and appetitive instrumental brain circuits to determine training conditions and neural mechanisms mediating cognitive vs. reflexive avoidance. Shuttlebox avoidance and a novel outcome-devaluation procedure will be used to examine the development of AA habits in rats. Experiments will focus on resolving conflicting predictions of our “amygdala disengagement” model of habitual AA, derived from AA studies, and the “parallel pathways” model of habit formation, derived from studies of positive reinforcement with drugs or food. Based on converging lines of preliminary data, we hypothesize that asymptotic ARs transition from goal-directed to habitual with time, as basolateral amygdala (BLA) disengages and competition between parallel circuits in dorsal striatum shifts to favor stimulus-response (S-R) over response-outcome (R-O) control. Explicit feedback cues will be included during AA training, and outcome-devaluation will be achieved by counterconditioning (pairing response-produced safety signals with shock). Our objectives are to determine 1) whether training- or time-dependent processes lead to habitual AA, 2) whether BLA projections to dorsomedial striatum mediate outcome-dependent AA, and 3) whether dorsolateral striatum (DLS) mediates habitual ARs independent of central amygdala. Chemogenetic suppression of neural activity in specific amygdalostriatal pathways will be used with devaluation to probe avoidance circuits. If successful, these studies will demonstrate that avoidance habits depend on a time- dependent disengagement of BLA and a shift towards DLS control of habitual ARs. Disrupting this S-R circuit in DLS while undermining safety signals could facilitate treatments aiming to break AA habits.

摘要 在主动回避（AA）过程中，受试者学会发出逃避条件反射的工具性动作 威胁，避免痛苦。关于介导回避反应（AR）的神经机制知之甚少， 因为AA研究在20世纪70年代陷入了激烈的理论争论，结果与原油不一致， 大脑操作，以及巴甫洛夫过程足以解释AR的建议。 这是不幸的，因为AA是研究厌恶动机的工具的原型范式。 行为，一类防御性学习，几乎肯定有助于适应和适应不良 积极应对策略。AA作为一种适应性应对/弹性机制有几个优点：1）它钝化了 恐惧和焦虑反应，2）它比恐惧消退更少依赖于上下文，更持久，并且，不像 被动回避，3）它允许受试者继续参与包括危险的环境。相反地， 适应不良的AR可能特别成问题，因为AA对灭绝具有极强的抵抗力， 有时，矛盾的是，通过惩罚（“恶性循环行为”）增强;过程可能是 在从焦虑（即强迫症）到成瘾的人类疾病中起作用。 由于AA可能反映了工具性学习在先前获得的恐惧条件反射之上的分层， 这项提议中的实验将利用巴甫洛夫恐惧和欲望工具脑的知识 回路，以确定训练条件和神经机制介导的认知与反射性回避。 穿梭箱回避和一个新的结果贬值程序将被用来检查的发展， 大鼠的AA习惯。实验将重点解决我们“杏仁核脱离”的相互矛盾的预测 习惯性AA模型，来自AA研究，以及习惯形成的“平行途径”模型，来自 从药物或食物的正强化研究中。根据初步数据的收敛线，我们 假设渐进性AR随着时间从目标导向转变为习惯性，如基底外侧杏仁核 (BLA)背侧纹状体平行回路之间的分离和竞争转向有利于刺激反应 (S-R)反应-结果（R-O）控制。明确的反馈线索将包括在AA培训， 将通过反调节（将响应产生的安全信号与 休克）。我们的目标是确定1）是否训练或时间依赖性过程导致习惯性AA， 2)是否BLA投射到背内侧纹状体介导结果依赖性AA，以及3）是否 背外侧纹状体（DLS）介导的习惯性AR独立于中央杏仁核。化学发生的 在特定的杏仁核纹状体通路中抑制神经活动将被用于探测 回避回路如果成功，这些研究将证明回避习惯取决于时间- BLA的依赖性脱离和向习惯性AR的DLS控制的转变。扰乱这个S-R回路 在DLS中，同时破坏安全信号可以促进旨在打破AA习惯的治疗。

项目成果

Devaluation of response-produced safety signals reveals circuits for goal-directed versus habitual avoidance in dorsal striatum.

反应产生的安全信号的贬值揭示了背侧纹状体中目标导向与习惯性回避的回路。

• DOI: 10.1101/2024.02.07.579321
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Sears,RobertM;Andrade,ErikaC;Samels,ShannaB;Laughlin,LindsayC;Moloney,DanielleM;Wilson,DonaldA;Alwood,MatthewR;Moscarello,JustinM;Cain,ChristopherK
• 通讯作者: Cain,ChristopherK

Beyond Fear, Extinction, and Freezing: Strategies for Improving the Translational Value of Animal Conditioning Research.

超越恐惧、灭绝和冷冻：提高动物调理研究转化价值的策略。

• DOI: 10.1007/7854_2023_434
• 发表时间: 2023
• 期刊: Current topics in behavioral neurosciences
• 作者: Cain,ChristopherK