Role of the cerebellum in temporal processing

 描述（由申请人提供）：小脑仅对运动控制至关重要的传统观点正受到越来越多的挑战，这些发现将其与认知和情感功能联系起来，因此，伴随小脑病变发生的运动缺陷现在被认为是各种认知和精神障碍的基础。最近的研究表明，认知功能，特别是时间感知，可能取决于小脑和前额叶皮质之间的相互作用;然而，这些相互作用，以及疾病状态下的紊乱，还不清楚。最近的解剖学研究表明，特别是小脑外侧，与处理时间信息的其他大脑区域（例如，前额叶皮层），这些通路为小脑参与涉及时间信息处理的网络提供了一个基底;然而，人们对小脑向这个网络的其他部分传达的信息知之甚少。因此，本实验的目的是研究小脑-前额叶皮层回路在时间行为中的功能，为理解小脑损伤如何导致认知缺陷提供基础。小脑被认为是时间处理的关键，特别是在短时间内（<1秒）;然而，基于这种时间信息的决策需要前额叶皮层参与。因此，必须有一个专门的系统，将这些信息从小脑传递到前额叶皮层。我们将研究小脑如何编码关于刺激的时间信息，以及它如何将这些信息传输到前额叶皮层，以存储在工作记忆中，并最终做出决定。此外，我们还将研究持续的小脑输入是否对参与工作记忆和决策的前额叶回路的正常运作是必要的。为了解决这些问题，我们将使用经过训练的啮齿动物，根据时间（持续时间）和非时间（例如，音调的音高）特征。在第一个目标中，光遗传学技术将用于以精确定时的方式操纵实际信号（即，齿状核细胞的活动），以研究对动物时间判断的影响。由此产生的行为改变应该提供有关小脑如何计算时间信息的信息，何时将信息传递到前额皮质，以及小脑活动是否影响前额皮质的记忆过程。在第二个目标中，我们将获得的齿状核神经元的活动在执行任务，以调查小脑的时间信息的具体编码的细胞外记录。这些信息将大大提高我们对小脑和大脑如何相互作用的理解，以及小脑和前额皮质功能障碍如何导致各种神经和精神障碍和疾病的理解。

 DESCRIPTION (provided by applicant): The traditional view of the cerebellum as being essential only for the control of movement is being increasingly challenged by findings that implicate it in cognitive and affective functions, and as a result, motor deficits that occur with cerebellar lesions are now being thought of in more generalized and extended forms as the basis of various cognitive and psychiatric disorders. Recent work indicates cognitive functions, and in particular, time perception, likely depend on interactions between the cerebellum and the prefrontal cortex; however, these interactions, and their derangement in disease states, are not understood. Recent anatomical studies have shown the lateral cerebellum, in particular, is strongly interconnected with other brain regions involved in processing temporal information (e.g., prefrontal cortex), and these pathways provide a substrate for the cerebellum's participation in a network involved in temporal information processing; however, little is known about the information conveyed from the cerebellum to other parts of this network. Thus, the goal of the proposed experiments is to investigate the function of the cerebellar-prefrontal cortical circuits in timing behavior to provide a basis for understanding how cerebellar damage leads to cognitive deficits. The cerebellum is thought to be critical for temporal processing, particularly for short durations (<1 second); however, decisions based on this temporal information require prefrontal cortex involvement. Thus, there must be a dedicated system involving the transfer of this information from cerebellum to the prefrontal cortex. We will investigate how the cerebellum encodes temporal information about a stimulus and how it transfers this information to the prefrontal cortex for storage in working memory and ultimately for making decisions. In addition, we will investigate whether continued cerebellar input is necessary for the proper functioning of the prefrontal circuits involved in working memory and decision-making. To address these issues we will use rodents trained to discriminate stimuli based on temporal (duration) and nontemporal (e.g., pitch of a tone) characteristics. In the first aim, optogenetic techniques will be used to manipulate in a precisely timed manner the actual signals (i.e., the activity of the dentate nucleus cells) that leave the cerebellum in order to investigate the effects on the timing judgments of the animal. The resulting alterations in behavior should provide information about how the cerebellum computes temporal information, when it transfers that information to the prefrontal cortex, and whether cerebellar activity affect memory processes in the prefrontal cortex. In the second aim we will obtain extracellular recordings of the activity of the dentate nuclear neurons during performance of the task to investigate the specific encoding of temporal information by the cerebellum. Such information would significantly improve our understanding of how the cerebellum and cerebrum interact, and of how dysfunction of the cerebellum and prefrontal cortex leads to a variety of neurological and psychiatric disorders and diseases.