Brain Circuits of Outcome-dependent vs. Habitual Avoidance

摘要 在主动回避(AA)过程中，受试者学习发出逃避条件的工具性动作 威胁和避免痛苦。对调节回避反应(AR)的神经机制知之甚少， 由于AA研究在20世纪70年代在激烈的理论辩论中停滞不前，结果与原油不一致 大脑操作，以及巴甫洛夫过程足以解释ARS的建议。 这是不幸的，因为AA是研究厌恶动机的工具性学习的典型范例 行为，一种几乎肯定会导致适应性和适应性不良的防御性学习 积极的应对策略。AA作为一种自适应应对/恢复机制有几个优点：1)它钝化 恐惧和焦虑反应，2)它不那么依赖于背景，比恐惧消退更持久，而且，不像 被动回避，3)它允许受试者保持在包括危险的环境中。相反， 适应不良的AR可能特别有问题，因为AA对灭绝和 偶尔，矛盾的是，通过惩罚(“恶性循环行为”)来加强；过程可能是 在从焦虑(即强迫症)到上瘾等各种人类疾病中运作。 由于再生障碍性贫血可能反映了工具性学习叠加在先前获得的恐惧条件反射之上， 这项计划中的实验将利用关于巴甫洛夫恐惧和食欲工具脑的知识 用于确定训练条件和神经机制的电路，这些神经机制调节认知与反射性回避。 将使用Shuttlebox回避和一种新的结果贬值程序来检查 大鼠的AA习性。实验将集中于解决关于我们的“杏仁核脱离接触”的相互矛盾的预测。 来自再生障碍性贫血研究的习惯性再生障碍性贫血模型和习惯形成的“平行路径”模型 来自药物或食物的积极强化的研究。基于初步数据的汇聚线，我们 假设随着时间的推移，渐近的ARS从目标导向型转变为习惯性型，如杏仁基底外侧核 背侧纹状体(BLA)的分离和平行环路之间的竞争转向有利于刺激反应 (S-R)反应-结果(R-O)控制过度。AA培训期间将包括明确的反馈提示，以及 结果-贬值将通过反条件作用实现(将响应产生的安全信号与 震惊)。我们的目标是确定1)训练或时间依赖的过程是否会导致习惯性再生障碍性贫血， 2)BLA投射到背内侧纹状体是否介导结果依赖型再生障碍性贫血，以及3)是否 背外侧纹状体(DLS)介导不依赖中央杏仁核的习惯性ARs。化学发生 特定杏仁纹状体通路中神经活动的抑制将与贬值一起用于探测 避让电路。如果成功，这些研究将证明回避习惯取决于一段时间- 血乳酸的依赖脱离和向DLS控制习惯性ARs的转变。扰乱S-R的这条赛道 在DLS中，虽然破坏了安全信号，但可以促进旨在打破AA习惯的治疗。

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.