The cerebellum has well-appreciated roles in motor behaviors, and increasingly well-established roles in nonmotor behaviors. Cerebellar dysfunction is known to cause ataxia, dystonia, and even some of the social deficits found in autism This wide array of functions is thought to be supported by the cerebellum's connections with structures throughout the brain. However, aside from a few canonical output pathways related to motor pathways, little is known about how else the cerebellum can modulate the rest of the brain. To improve our understanding of cerebellar output pathways, this proposal seeks to generate a connectivity map based on visualizing synapses from cerebellar output neurons. Next, as a first step in describing the synaptic properties underlying all cerebellar outputs, I will closely examine the properties underlying transmission of information at a relatively known output: the cerebellothalamic synapse. While this connection has been anatomically described, remarkably little is known about its synaptic properties. The computations within the cerebellum are overwhelmingly linear. It might follow that this linearity is a property that persists all the way to cerebellar outputs. Because cerebellar outputs are spontaneously active at relatively high rates, all cerebellar output targets will likely have specific mechanisms to encode this continuous barrage of activity. Thalamic neurons might be specialized for this purpose because they have two modes of operation: a nonlinear mode that can ?gate? inputs, and a linear one that faithfully relays inputs. Preliminary data indicates that these modes are dependent on whether the animal is stationary or moving. I hypothesize that the nonlinear mode of the thalamus can function as a gate to filter out spontaneous, ?noisy? cerebellar activity, and reliable and precise activity is only relayed from the thalamus in the linear mode. I will test these ideas by combining optogenetics, dynamic clamp, and whole cell recordings in vitro and in vivo with behavioral measurements during a lever pressing task. Completion of this project will unveil novel cerebellar output pathways, and demonstrate methods by which the brain can gate and transmit information.

Public Health Relevance

The cerebellum is clearly involved in numerous motor disorders, but has an underappreciated role in nonmotor disorders. This project has two aims related to public health: firstly, to uncover novel potential avenues by which the cerebellum can contribute to nonmotor functions (and thus, nonmotor disorders) and secondly, this project will focus specifically on the poorly understood cerebellothalamic circuit, which has been specifically implicated in intention tremor. Deeper understanding of cerebellar outputs will further our mechanistic understanding of the phenotypes associated with cerebellar dysfunctions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Chen, Daofen
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Harvard Medical School
Schools of Medicine
United States
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Jackman, Skyler L; Chen, Christopher H; Chettih, Selmaan N et al. (2018) Silk Fibroin Films Facilitate Single-Step Targeted Expression of Optogenetic Proteins. Cell Rep 22:3351-3361