Corticostriatal circuits in behavioral flexibility

 描述(由申请人提供)：成功的目标导向行为需要能够选择导致奖励的行为，而避免导致不奖励或更糟糕的惩罚的行为。在现实世界中，将行动及其结果联系在一起的规则往往会发生变化，以至于曾经得到奖励的行动不再是这样，反之亦然。基于正反馈或负反馈更新决策策略的能力是行为灵活性的基础。平衡正面和负面反馈对选择的影响的权重，可能对最佳决策至关重要。人们认为，在成瘾等疾病中，从负面反馈中学习的能力会变得迟钝，追求奖励的能力会凌驾于正常的决策过程之上(考克斯等人，2015年；帕瓦兹等人，2015年)。众所周知，成瘾与纹状体D2受体表达降低有关(Bowirrat等人，2005年；Goldstein和Volkow，2011年；Besson等人，2013年)。来自我们实验室和其他实验室的先前数据表明，背内侧纹状体(DMS)的D2受体表达的中棘神经元(MSN)在发出非奖赏结果的信号和促进回避行为方面具有一定的作用(Kravitz等人，2012年；Tai等人，2012年)。然而，D2 MSN在从积极和消极结果中学习的因果作用仍不清楚。了解D2 MSN活动对行为灵活性的贡献将有助于阐明灵活性受损的神经回路机制 出现在几种精神疾病中。我建议研究学习诱导的皮质纹状体微回路的可塑性，以确定是否存在行为灵活性的神经标志。我将记录在侧化双选择决策任务(目标1)的辨别或反转阶段之后，从背侧前扣带回(DACC)到dMS的视紫红质诱发的兴奋性传递到d1或d2的MSN。此外，我将比较成人和青少年的皮质纹状体传播，后者的反转学习更有效。接下来，我将使用化学遗传学工具在基于T迷宫的空间反转任务、4选择非空间反转任务和概率转换任务中选择性地抑制或兴奋D2 MSN，这些任务都需要灵活地更新决策策略，尽管涉及不同的认知域和时间尺度(目标2)。这些数据将有助于建立支持灵活决策和逆转学习的纹状体回路机制。通过比较幼年和成年小鼠，这些实验还将有助于确定皮质纹状体回路如何在青春期成熟以改变决策策略。我和我的赞助商预计，我们来自小鼠的高度受控、敏感和细胞类型特定的实验数据将有助于更大的健康社区了解行为灵活性受损的神经基础。此外，它还可能阐明从正反馈和负反馈中学习发展变化的神经基础。

 DESCRIPTION (provided by applicant): Successful goal-directed behavior requires the ability to select actions that result in reward and avoid actions that result in no reward, or worse, punishment. In the real world, the rules that link actions and their outcomes often change, such that an action that was once rewarded ceases to be so and vice versa. The ability to update decision-making strategy based on positive or negative feedback is the basis for behavioral flexibility. A balance in the weighting of positive and negative feedback's influence over choice selection may be vital for optimal decision-making. It is believed that in disease such as addiction, the ability to learn from negative feedback becomes blunted and reward-seeking overrides normal decision-making processes (Cox et al., 2015; Parvaz et al., 2015). It is well-known that addiction is associated with lower D2 receptor expression in the striatum (Bowirrat et al., 2005; Goldstein and Volkow, 2011; Besson et al., 2013). Previous data from our lab and others implicate D2 receptor-expressing medium spiny neurons (MSNs) of the dorsomedial striatum (DMS) in signaling non-rewarded outcomes and promoting avoidance behavior (Kravitz et al., 2012; Tai et al., 2012). However, the causal role of D2 MSNs in learning from positive and negative outcomes remains unknown. Understanding the contribution of D2 MSN activity to behavioral flexibility will illuminate neural circuit mechanisms that underlie impaired flexibility seen in several psychiatric disorders. I propose to study learning-induced plasticity in the corticostriatal microcircuit to determine if there is a neural signature for behavioral flexibility I will record channelrhodopsin evoked excitatory transmission from the dorsal anterior cingulate (dACC) to the DMS onto D1 or D2 MSNs following the discrimination or reversal phase in a lateralized two-choice decision-making task (Aim 1). Furthermore, I will compare corticostriatal transmission in adults to juveniles, who enact more efficient reversal learning. Next, I will employ chemogenetic tools to selectively inhibit or excite D2 MSNs during a T-maze based spatial reversal task, a 4 choice nonspatial reversal task, and a probabilistic switching task, tha all require flexible updating of decision-making strategies, albeit across different cognitive domains and time-scales (Aim 2). These data will contribute to establishing the striatal circuit mechanisms that support flexible decision-making and reversal learning. By comparing juvenile and adult mice, these experiments will also help to establish how corticostriatal circuits mature during adolescence to alter decision-making strategies. My sponsors and I anticipate that our highly controlled, sensitive, and cell-type specific experimental data from mice will help the larger health community understand the neural basis of impairments in behavioral flexibility. In addition, it may also illuminate a neural basis to developmental changes learning from positive versus negative feedback.