Dissection of mediodorsal thalamic circuitry underlying flexible behavior

描述（由申请人提供）：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，我们必须能够适应我们的行动。例如，在经常光顾某家餐馆一段时间后，我们会回忆起确切的路线，并将其与我们最喜欢的菜联系起来。然而，有时情况会改变——餐馆可能会改变位置——我们必须调整行动（我们采取的路线），以获得同样的结果（我们最喜欢的菜）。这种能力的缺陷在许多精神疾病中都可以观察到，包括吸毒成瘾、精神分裂症和强迫症，这些缺陷通常对治疗有抵抗力。为了开发更好的治疗方法和诊断工具，有必要对行为灵活性受损的机制有更深入的了解。人类的功能成像研究以及跨物种的病变研究已经将前额皮质（PFC）与包括灵活行为在内的认知功能联系起来。然而，这个大脑区域并不是孤立地工作的；相反，它是连接其他结构的更大回路的一部分，包括丘脑中背侧（MD）。事实上，功能成像研究表明，MD对灵活行为很重要。然而，通过影像学研究，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，必须实施动物模型。为了确定MD是否支持灵活的行为，我们最近创建了一个MD活动减少的小鼠模型，并表明这种操作导致行为灵活性的损害。然而，行为灵活性需要多个认知过程。生物体不仅要将行动与结果联系起来，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减少脑皮层活动的影响。我们发现，MD在形成行动-结果关联以及使用巴甫洛夫刺激来塑造未来行动方面发挥作用。这些发现确立了MD在特定认知过程中作为灵活行为基础的作用。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。本研究提出了一种新的技术来可逆地操纵小鼠的大脑活动，以确定支持灵活行为的神经回路。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.