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.
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 proposed in more generalized and extended forms as the basis of various cognitive and psychiatric disorders, including fetal alcohol syndrome, autism, and schizophrenia. These 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. Thus, the major 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.
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