Neuronal mechanisms of cerebellar cognitive function

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Understanding human cognition is one of the cornerstones of the CDC's Healthy Brain Initiative (see https://www.cdc.gov/aging/healthybrain/). The cerebellum was long perceived as an exclusively motor-related structure, but it is now also increasingly recognized for its involvement in cognition, in both humans and animals. In recent years clinical and animal studies have shown that cerebellar activation is correlated with cognitive functions such as spatial working memory, and that cerebellar neuropathology can cause deficits in those functions. Cerebellar neuropathology is also known to be correlated with mental illnesses like autism, schizophrenia, dementia and Alzheimer's disease. Thus, understanding cognitive function and mental illnesses requires understanding the role of the cerebellum in cognition. However, existing evidence is purely correlational and a neuronal mechanism for cerebellar cognitive involvement has yet to be identified. The main barrier to investigating cerebellar cognitive function is that obtaining causal evidence and exploring neuronal mechanisms requires experiments involving controlled manipulations of cerebellar function while simultaneously observing cognitive behavior and neuronal activity. The availability of neuro- and optogenetic tools, awake-behaving electrophysiological techniques and quantitative tests for cognitive behaviors in mice now allow this barrier to be surmounted. We propose studies designed to answer fundamental questions about the role of the cerebellum in cognition using mice as our model organism and spatial working memory (SWM) as a quantifiable cognitive function known to involve the cerebellum in both humans and rodents. Our central hypothesis is that the cerebellum controls SWM decision-making by controlling decision-related coherence of neuronal oscillations between the medial prefrontal cortex (mPFC) and the hippocampus (HC). The mPFC and HC each are reciprocally connected with the cerebellum and play key roles in SWM. The decision-making process in SWM tasks is characterized by a temporary increase in coherence between the mPFC and HC. This decision-related coherence is believed to be a requirement for normal SWM performance. We propose to use a new mouse model of cerebellar dysfunction created by co-PI Sillitoe and electrophysiological recordings in freely moving mice to test the hypothesis that loss of cerebellar function causes severe SWM deficits and loss of SWM decision-related coherence increase. We propose to employ optogenetic techniques to manipulate cerebellar activity during SWM behavior to provide causal evidence for cerebellar involvement in SWM and to map cerebellar cortical areas involved in controlling SWM. Our preliminary data strongly support our hypotheses. Our work will broadly impact our understanding of the role of the cerebellum in cognitive brain function and the mechanisms linking cerebellar neuropathology to mental illness, which makes this project directly relevant to the mission of the NIH.