Habitual behavior and dopamine cell vulnerability in Parkinson disease

Ledia F. Hernández; Peter Redgrave; José A. Obeso

摘要

The cardinal features of Parkinson disease (PD) often begin focally, typically in one limb, and may remain relatively restricted to one side of the body for many years. It is now well established that dopaminergic neurons in the ventro-lateral tier of the substantia nigra pars compacta (SNpc), which project mainly to the caudal putamen, are the first to degenerate in the initial phase of PD (Fearnley and Lees, 1991 ; Halliday et al., 2008 ; Blesa et al., 2010 ) indicating differential vulnerability. The caudal region of the striatum (dorsolateral striatum in rodents) has been associated with habitual (or automatic) behavior (Redgrave et al., 2010 ), consequently the differential loss of dopamine (DA) from this region provides the pathophysiological substrate for the early impairment of automatic movements (walking, writing, …) in early PD. The brain has two major systems for controlling behavior: a goal directed mechanism (GD) and a mechanism mediating stimulus-response habits (Figure 1 ). The goal directed system entails conscious, voluntary control of actions aimed toward obtaining rewards or avoiding punishments. Action selection is determined by competitions between relative outcome values, i.e. if outcome A is more valuable than outcome B, then learned behavior that will lead to outcome A will be selected. Examples of goal-directed control would be: heading to the fridge or going to a restaurant when we are hungry, taking the elevator or taking the stairs back to the apartment. This goal-directed process engages the prefrontal cortex and dorsolateral striatum (Yin et al., 2004 ). On the other hand, the habitual system detects well-learned cues that have been associated with specific responses, and therefore elicit automatic stimulus-response behavior via the re-entrant loop that connect sensorimotor cortical areas with the posterior putamen (dorsolateral striatum in rodents) (Barnes et al., 2005 ). Habits are established gradually over time. They evolve after many repetitions of a task being performed under flexible goal-directed learning and depend heavily on the statistical regularities between specific stimuli and consequent responses. Examples of habitual control would be, walking, riding a bike or driving. The critical test for habits is that they are resistant to outcome-devaluation (Adams and Dickinson, 1981 ). Inappropriate habitual responses are frequently difficult to eradicate and have to be corrected by goal-directed interventions after they fail to achieve their original intention. In this Opinion article we put forward the hypothesis that a significant factor that confers vulnerability to the ventro-lateral tier of SNpc at the onset of PD may reside in the key functional role that these neurons play in the performance of habitual behavior, switching between habitual and goal-directed control, and engaging both goal-directed and habitual control when carrying out multiple tasks simultaneously. Figure 1 Diagram of the functional loops involved in goal-directed and habitual behavior . Functional anatomy of habitual vs. goal directed behavior The nigro-striatal system has two major components, the associative loop and the motor loop. The associative loop comprises the dorso-medial SNpc that projects to the head of the caudate and rostral putamen, regions that have been associated with goal-directed behavior and executive functions (Yin and Knowlton, 2006 ). On the other hand, the ventro-lateral SNpc projects to the posterior putamen, which engages the sensorimotor circuits and habitual performance (Jog et al., 1999 ; Haber et al., 2000 ; Packard and Knowlton, 2002 ; Redgrave et al., 2010 ). As humans, much of our thinking in daily life is made possible by engaging automatic or habitual control, e.g., walking, typing, etc…In fact, depending on the predictability of what we are doing, we frequently switch back and forth between goal-directed to habitual control. Goal-directed cognition (e.g. listening, talking) is often performed simultaneously while carrying out predictable sensorimotor tasks under habitual control (e.g. making tea, driving). Social interactions are characterized by the need to perform simultaneous and sequential activities while attending to multiple stimuli. We suggest that multi-tasking in humans could be an important vulnerability factor that puts the ventro-lateral subpopulation of dopaminergic neurons at greater pathological risk. Our hypothesis is that switching in and out of habitual control requires an unusually demanding anatomo-physiological network, which makes the dopaminergic neurons servicing sensorimotor territories of the basal ganglia especially vulnerable. We will argue that this represents a key factor for the neuronal degeneration associated with PD. As the ventro-lateral SNpc/caudal putamen (habitual system) becomes dysfunctional in PD, the goal-directed system has to be recruited to perform the previously automatic habitual tasks. This compensatory mech

机译：帕金森氏病（PD）的主要特征通常是局灶性地开始，通常在一个肢体中开始，并且可能多年以来一直相对局限于身体的一侧。现已确定，黑质致密部（SNpc）腹侧外侧的多巴胺能神经元主要在PD的初期退化（Fearnley and Lees，1991; Halliday等人，2008; Blesa等人，2010）指出了不同的脆弱性。纹状体的尾部区域（啮齿类动物的背外侧纹状体）与习惯（或自动）行为相关（Redgrave等人，2010），因此，该区域多巴胺（DA）的差异损失为早期的病理生理学底物提供了条件。 PD早期的自动动作受损（走路，写字等）。大脑有两个主要的行为控制系统：目标导向机制（GD）和介导刺激反应习惯的机制（图1）。目标导向的系统需要有意识地，自愿地控制旨在获得奖励或避免惩罚的行为。行动选择取决于相对结果值之间的竞争，即如果结果A比结果B更有价值，那么将选择会导致结果A的学习行为。目标控制的例子包括：饿了就去冰箱或去餐馆，乘电梯或乘楼梯回到公寓。这个目标导向的过程涉及前额叶皮层和背外侧纹状体（Yin等，2004）。另一方面，习惯性系统会检测到与特定反应相关的学识丰富的线索，因此通过将感觉运动皮层区域与后壳（连接在啮齿动物的背侧纹状体）之间连接的折返环引起自动刺激-反应行为。（Barnes等，2005）。习惯随着时间的推移逐渐建立。在多次重复执行在灵活的目标导向的学习中执行的任务后，它们会进化，并且在很大程度上取决于特定刺激和随之而来的响应之间的统计规律。习惯性控制的例子包括散步，骑自行车或驾驶。习惯的关键测试是，他们能够抵抗结果贬值（Adams和Dickinson，1981年）。不适当的习惯性反应通常难以根除，在无法达到其最初意图后，必须通过目标导向的干预措施加以纠正。在这篇观点文章中，我们提出了一个假设，即在PD发作时赋予SNpc腹侧层脆弱性的重要因素可能在于这些神经元在习惯性行为的执行中扮演的关键功能角色，在习惯性行为之间切换和目标控制，并同时执行多个任务时同时进行目标控制和习惯控制。图1涉及目标导向和习惯行为的功能循环图。习惯性行为与目标性行为的功能解剖黑人纹状体系统有两个主要组成部分，即联想回路和运动回路。关联循环包括投射到尾状和壳状壳顶部的背中SNPC，这些区域已与目标行为和执行功能相关（Yin和Knowlton，2006年）。另一方面，腹侧SNpc伸入后壳状核壳，参与感觉运动回路和习惯性行为（Jog等人，1999; Haber等人，2000; Packard和Knowlton，2002; Redgrave等人， 2010）。作为人类，我们在日常生活中的许多思考都可以通过进行自动或习惯控制（例如步行，打字等）来实现。事实上，根据我们正在做的事情的可预测性，我们经常在目标之间来回切换：针对习惯控制。目标导向的认知（例如听，说）通常在习惯控制下执行可预测的感觉运动任务（例如泡茶，开车）时同时进行。社交互动的特点是需要在进行多种刺激的同时执行同时和顺序的活动。我们建议人类中的多任务可能是一个重要的易损性因素，会使多巴胺能神经元的腹侧亚群处于更大的病理风险中。我们的假设是，习惯控制的切入和退出需要异常苛刻的解剖生理网络，这使得服务于基底神经节感觉运动区的多巴胺能神经元特别脆弱。我们将争辩说，这代表了与PD相关的神经元变性的关键因素。由于腹侧SNpc /尾状壳核（习惯性系统）在PD中功能失调，必须招募目标导向系统来执行以前的自动习惯性任务。这种补偿机制

Habitual behavior and dopamine cell vulnerability in Parkinson disease

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