Dissection of mediodorsal thalamic circuitry underlying flexible behavior

描述(申请人提供)：行为灵活性是所有哺乳动物的基本认知能力。当我们的环境发生变化时，我们必须能够调整我们的行动。例如，在经常光顾一家特定的餐厅一段时间后，我们会回忆起准确的路线，并将其与我们最喜欢的菜肴联系在一起。然而，有时情况会改变--餐厅可能会改变地点--我们必须调整一种行为(我们采取的路线)，才能得到同样的结果(我们最喜欢的菜肴)。在包括毒瘾、精神分裂症和强迫症在内的许多精神疾病中都可以观察到这种能力的缺陷，这些障碍通常对治疗具有抵抗力。为了开发改进的治疗和诊断工具，有必要对行为灵活性受损的潜在机制有更深入的了解。人类的功能成像研究以及跨物种的损伤研究都将前额叶皮质(PFC)与包括灵活行为在内的认知功能联系在一起。然而，这个大脑区域并不是孤立工作的；相反，它是连接包括丘脑内侧背侧核(MD)在内的其他结构的更大回路的一部分。事实上，功能成像研究表明，MD对于灵活的行为很重要。然而，通过成像研究，无法确定因果关系。因此，为了检验直接操纵大脑活动的效果，必须建立动物模型。为了确定MD是否因果地支持灵活的行为，我们最近建立了一个MD活动减少的小鼠模型，并表明这种操作导致了行为灵活性的损害。然而，行为灵活性需要多个认知过程。有机体不仅必须将行动与结果联系起来，而且还必须认识到导致该结果的环境刺激。因此，我们接下来研究了在评估这些基本认知过程的任务中，MD活动减少的影响。我们发现，MD在动作-结果关联的形成以及使用巴甫洛夫刺激塑造未来动作方面发挥了作用。这些发现确立了MD在支撑灵活行为的特定认知过程中的作用。然而，MD是上述更大的神经回路的一部分。因此，特定的MD输入和输出在灵活行为的基本认知过程中的作用仍然未知。这项提议实施了新的技术来可逆地操纵小鼠的大脑活动，以识别支持灵活行为的MD神经回路。从这些研究中获得的知识将有助于开发新的治疗策略。

DESCRIPTION (provided by applicant): Behavioral flexibility is a fundamental cognitive capacity in all mammals. When our environments change, we must be able to adapt our actions. For example, after frequenting a particular restaurant for some time, we recall the precise route and associate this with our favorite dish. However, sometimes circumstances change-the restaurant may change locations-and we must adapt an action (the route we take) in order to receive the same outcome (our favorite dish). A deficit in this capacity is observed in numerous psychiatric disorders including drug addiction, schizophrenia, and obsessive-compulsive disorder and these impairments are generally resistant to treatment. In order to develop improved therapeutics and diagnostic tools, a deeper understanding of the mechanisms underlying impaired behavioral flexibility is necessary. Functional imaging studies in humans as well as lesion studies across species have linked the prefrontal cortex (PFC) with cognitive functions including flexible behavior. However, this brain region does not work in isolation; rather it is part of a larger circuit connecting other structures including the mediodorsal thalamu (MD). Indeed, functional imaging studies show that the MD is important for flexible behavior. However, with imaging studies, causal relationships cannot be determined. Therefore, animal models must be implemented in order to examine the effect of direct manipulation of brain activity. In order to determine whether the MD causally supports flexible behavior, we recently created a mouse model with decreased MD activity and showed that this manipulation led to impairments in behavioral flexibility. However, behavioral flexibility requires multiple cognitive processes. Not only must an organism associate an action with an outcome, but it must also recognize the environmental stimuli that lead to that outcome. Therefore, we next examined the effect of decreasing MD activity during tasks assessing these elementary cognitive processes. We found that the MD plays a role in the formation of action-outcome associations as well as the use of Pavlovian stimuli to shape future actions. These findings establish a role of the MD in specific cognitive processes underlying flexible behavior. However, the MD is part of a larger neural circuit described above. Thus, the roles of specific MD inputs and outputs in the elementary cognitive processes of flexible behavior remain unknown. This proposal implements novel techniques to reversibly manipulate brain activity in the mouse in order to identify the MD neuronal circuitry supporting flexible behavior. The knowledge gained from these studies will aid in the development of new therapeutic strategies.