Corticostriatal circuits in behavioral flexibility

 描述（由申请人提供）：成功的目标导向行为需要有能力选择导致奖励的行为，避免导致没有奖励或更糟的惩罚的行为。在真实的世界中，联系行动和结果的规则经常发生变化，因此，曾经获得奖励的行动不再如此，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柔性的基础。平衡正面反馈和负面反馈对选择的影响对于最优决策可能至关重要。据信，在诸如成瘾的疾病中，从负反馈中学习的能力变得迟钝，并且寻求奖励压倒了正常的决策过程（考克斯等人，2015; Parvaz等人，2015年）。众所周知，成瘾与纹状体中较低的D2受体表达相关（Bowirrat等人，2005年; Goldstein和Ellow，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受体表达中型多刺神经元（MSN）在信号传导非奖励结果和促进回避行为中起作用（Kravitz等人，2012; Tai等人，2012年）。然而，D2 MSN在学习积极和消极结果中的因果作用仍然未知。了解D2 MSN活动对行为灵活性的贡献将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可塑性在皮质纹状体微回路，以确定是否有一个神经签名的行为灵活性，我将记录通道视紫红质诱发的兴奋性传输从背侧前扣带（dACC）到DMS到D1或D2 MSNs的歧视或逆转阶段后，在偏侧的两个选择决策任务（目标1）。此外，我将比较成年人的皮质纹状体传输青少年，谁制定更有效的逆转学习。接下来，我将采用化学遗传学工具，选择性地抑制或激发D2 MSNs在T-迷宫为基础的空间反转任务，4选择非空间反转任务，和概率切换任务，这都需要灵活更新的决策策略，虽然在不同的认知领域和时间尺度（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，这些实验也将有助于确定皮质纹状体回路在青春期如何成熟以改变决策策略。我和我的赞助商预计，我们从小鼠身上获得的高度可控、敏感和细胞类型特异性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，它还可以阐明从积极与消极反馈中学习的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.