Dopaminergic regulation of striatal ensembles during cognitive performance: Implications for Parkinson's disease

摘要 帕金森病患者运动和认知功能减退 减损。这些症状在很大程度上是由纹状体多巴胺耗竭引起的 这种疾病。在健康个体中，纹状体多巴胺调节不同的中纹状体池 表达d1或d2受体的刺状神经元(MSN)。首点及第二点MSNS项目至 不同的下游结构，在运动中起着不可分离的作用。然而，第一被告和 D2 MSN对高阶认知功能的调节尚不清楚。这项提案将针对这一点 通过研究D1MSN和D2MSN如何在计时过程中调节性能来实现知识差距 任务。在计时任务中，受试者会得到一个提示，告诉他们做马达 在一定时间间隔后响应(例如，在6秒后按下按钮)。 计时任务招募了几种认知功能(例如，工作记忆、注意力和决策-- 制作)。此外，时间在很大程度上依赖于纹状体，对多巴胺能很敏感。 在帕金森氏症患者和这种疾病的动物模型中都受到了干扰。 在目标1中，我们将评估纹状体多巴胺如何调节d1和d2 msn活性。 在计时任务期间。具体地说，在计时任务期间，许多MSN逐渐增加或 随着时间的推移线性降低他们的射速。这种“斜坡”活动对性能至关重要。 似乎一直在进行，直到达到活动的“门槛”水平，在这一点上，决定 做出了回应。阻断纹状体D_1或D_2受体延迟作出决定 在计时任务期间。此外，受d1或d2封锁影响的决策类型 是不能与人交往的。我们将结合局部药理学、细胞类型特异性光遗传学和 电生理学测试多巴胺调节D1阈值活动水平的假说 和D2斜坡式MSN。在目标2中，我们将检验假设D1之间的本地连通性 纹状体内的D2 MSN对计时性能至关重要。具体地说，阻断纹状体 D2受体实质上损害了计时行为。令人惊讶的是，停用下游 D2 MSN的结构不影响定时性能。因此，我们将测试 假设D2 MSN通过对纹状体内D1MSN的侧向抑制来调节计时， 而不是通过它们的下游产量。具体地说，我们将在以下时间中断D2 MSN活动 同时利用光遗传学阻断D2MSN的下游输出。如果D2 MSN 通过纹状体内的侧抑制来调节计时，在纹状体内操纵D2 MSN的活动 纹状体应该仍然发挥作用，即使它们的下游输出被阻止。

Abstract Patients with Parkinson's disease suffer from debilitating motor and cognitive impairments. These symptoms are largely driven by the striatal dopamine depletion caused by the disease. In healthy individuals, striatal dopamine modulates distinct pools of medium striatal spiny neurons (MSNs) that express either D1 or D2 receptors. D1 and D2 MSNs project to different downstream structures and play dissociable roles in movement. However, how D1 and D2 MSNs mediate higher-order cognitive functions is unclear. This proposal will target this knowledge gap by investigating how D1 and D2 MSNs mediate performance during timing tasks. During timing tasks, subjects are presented with a cue that informs them to make a motor response after a certain interval of time elapses (e.g., press a button after 6 seconds passes). Timing tasks recruit several cognitive functions (e.g., working-memory, attention, and decision- making). Furthermore, timing is heavily dependent on the striatum, sensitive to dopaminergic manipulations, and disrupted in both Parkinson's patients and animal models of this disease. In Aim 1, we will evaluate how striatal dopamine modulates D1 and D2 MSN activity during timing tasks. Specifically, during timing tasks, many MSNs progressively increase or decrease their firing rates linearly across time. This `ramping' activity is critical for performance and appears to progress until a `threshold' level of activity is reached, at which point a decision to respond is made. Blocking striatal D1 or D2 receptors delays when decisions are made during timing tasks. Furthermore, the types of decisions that are impacted by D1 or D2 blockade are dissociable. We will combine focal pharmacology, cell-type specific optogenetics, and electrophysiology to test the hypothesis that dopamine tunes the threshold activity level of D1 and D2 ramping MSNs. In Aim 2, we will test the hypothesis that local connectivity between D1 and D2 MSNs within the striatum is critical for timing performance. Specifically, blocking striatal D2 receptors substantially impairs timing behavior. Surprisingly, inactivating the downstream structures of D2 MSNs does not impact timing performance. Therefore, we will test the hypothesis that D2 MSNs mediate timing via lateral inhibition to D1 MSNs within the striatum, rather than through their downstream output. Specifically, we will disrupt D2 MSN activity while simultaneously blocking the downstream output of D2 MSNs with optogenetics. If D2 MSNs mediate timing via lateral inhibition within the striatum, manipulating D2 MSN activity within the striatum should still exert an effect, even when their downstream output is blocked.