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A novel output pathway from the cerebellum for regulation of diverse non-motor behaviors


Abstract/Summary In addition to its well-established role in motor function and motor learning, the cerebellum is implicated in a myriad of non-motor behaviors. In humans, cerebellar damage can impair abstract reasoning and working memory, and result in PTSD. In animal models, the cerebellum regulates heart rate, breathing, aggression, appetite, fear conditioning and many other behaviors. In general, the role of the cerebellum in regulating these behaviors is not well understood. An important step in understanding these nonmotor behaviors is to determine the output pathway and downstream targets that allow the cerebellum to regulate these behaviors. It is known that Purkinje cells (PCs) relay signals from the cerebellar cortex to the deep cerebellar nuclei (DCN), which in turn activate the motor thalamus. It was assumed that DCN outputs are also responsible for nonmotor behaviors. Here, we describe powerful and direct inhibitory connections between PCs in regions of the cerebellum implicated in nonmotor behaviors, and neurons in the parabrachial nucleus (PBN). This is intriguing, because the PBN contributes to many of the same nonmotor behaviors influenced by the cerebellum. Based on our preliminary findings, we hypothesize that the PBN is a specialized cerebellar output that allows the cerebellum to regulate nonmotor behaviors. The first step in testing this hypothesis will be to characterize the connections between PCs and the PBN. The studies will determine the strength and prevalence of the direct PC to PBN synapse and determine the extent to which PCs regulate the activity of neurons in the PBN. The second major step is to identify the regions targeted by the PC?PBN pathway and to determine the contribution of this pathway to various behaviors. Preliminary studies suggest that this pathway projects to the hypothalamus, the amygdala, and the basal forebrain, and thus has the appropriate connectivity to allow the cerebellum to regulate diverse behaviors ranging from aggression to fear extinction. This promises to lead to a new appreciation of the roles of the cerebellum in numerous behaviors, it will provide insight into the circuits involved in these behaviors and it has important implications for many neurological disorders.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.