Corticostriatal circuits in behavioral flexibility

行为灵活性中的皮质纹状体回路

• 批准号: 9403124
• 负责人: Kristen Marie Delevich
• 金额: $ 0.06万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403124
• 关键词: Adolescence; Adolescent; Adult; Animals; Anterior; Basal Ganglia; Behavior; Behavioral; Behavioral Model; Brain; Cognitive; Community Health; Contralateral; Corpus striatum structure; DRD2 gene; Data; Decision Making; Development; Discrimination; Disease; Dopamine D1 Receptor; Dopamine D2 Receptor; Dorsal; Electrophysiology (science); Environment; Equilibrium; Exhibits; Feedback; Functional disorder; Genetic Variation; Goals; Human Genetics; Impaired cognition; Impairment; In Vitro; Individual; Ipsilateral; Learning; Link; Measures; Mediating; Mental disorders; Methods; Movement; Mus; Neurons; Outcome; Pathway interactions; Pharmacology; Phase; Process; Property; Punishment; Reversal Learning; Rewards; Role; Schizophrenia; Signal Transduction; Specificity; Synapses; Time; Training; Update; Variant; Weight; addiction; avoidance behavior; base; cell type; experimental study; flexibility; in vivo; innovation; insight; neural circuit; public health relevance; receptor expression; relating to nervous system; response; success; tool; transmission process

 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.

 描述（由适用提供）：成功的目标指导行为需要选择导致奖励的行动并避免行动的能力，并避免没有奖励或更糟的惩罚。在现实世界中，经常将行动及其结果联系起来的规则，使得曾经得到奖励的行动不再是这样，反之亦然。基于正面反馈或负面反馈更新决策策略的能力是行为灵活性的基础。积极反馈和负面反馈对选择选择的影响的平衡对于最佳决策可能至关重要。人们认为，在成瘾之类的疾病中，从负面反馈中学习的能力变得钝化，寻求奖励覆盖了正常的决策过程（Cox等，2015； Parvaz等，2015）。众所周知，成瘾与纹状体中的D2受体表达较低有关（Bowirrat等，2005； Goldstein和Volkow，2011； Besson等，2013）。我们实验室和其他植入D2受体表达培养基神经元（MSN）的先前数据在信号传导非奖励结果和促进回避行为中（Kravitz等，2012; Tai等，2012）。但是，D2 MSN在从正面和负面结果中学习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 在几种精神病中看到。我建议研究皮质纹状体微电路中的学习诱导的可塑性，以确定行为柔韧性是否存在神经签名，我将记录从背扣带回（DACC）引起的兴奋性传播（DACC），直到DMS到DMS到D1或D2 MSN，遵循歧视或重新验证的阶段。此外，我将比较成年人的皮质纹状体传播与少年，他们进行了更有效的逆转学习。接下来，我将使用化学遗传学工具在基于T迷宫的空间逆转任务，4选择非空间逆转任务以及概率切换任务的过程中有选择地抑制或激发D2 MSN，这都需要灵活地更新决策策略，无论是在不同的认知领域和时间范围内跨越不同的认知领域和时间 - 时间范围（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电路机制。通过比较少年和成年小鼠，这些实验还将有助于确定青少年期间皮质纹状体电路如何成熟以改变决策策略。我的赞助商和我预计我们的高度控制，敏感和细胞类型的特定实验数据将有助于更大的健康社区了解行为灵活性障碍的神经基础。此外，它还可以阐明神经元基础，以从正面反馈和负面反馈中发展学习变化。