Understanding human cognition is one of the cornerstones of the CDC's Healthy Brain Initiative (see 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 (AD). Thus, understanding cognitive function and mental illnesses like AD requires understanding the role of the cerebellum in cognition and cognitive decline. Existing evidence is purely correlational and thus far, no neuronal mechanism has been 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 and cognitive decline in AD using 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 are both connected with the cerebellum and play key roles in SWM. Decision-making in SWM is characterized by an increase in mPFC-HC coherence, which is believed to be a requirement for normal SWM performance and which we hypothesize requires the cerebellum. For this AD-specific administrative supplement we propose to investigate the role of the cerebellum in cognitive decline in AD using use two different mouse models AD: the APP KI mice, which replicate A? plaque accumulation in human AD, and the PS19 mice, which replicate tau tangle accumulation in human AD. We will conduct electrophysiological recordings in freely moving mice to test the hypothesis that AD results in deficits in cerebellar control of mPFC-HC coherence and SWM. We propose to use optogenetic manipulation of cerebellar activity to provide causal evidence for our hypothesis that AD results in reduced cerebellar control of mPFC-HC coherence deficits in SWM. Our preliminary data support our hypotheses. Our work will significantly impact our understanding of the role of the cerebellum in cognitive decline in AD, which makes this project directly relevant to the purpose of the AD-focused Administrative Supplement NOT-AG-18-039.
The cerebellum was long regarded as a structure exclusively dedicated to motor control, but new research has linked the cerebellum to a variety of cognitive functions and has shown that mental illnesses such as Alzheimer's disease (AD) are often associated with cerebellar neuropathology. However, current evidence of cerebellar involvement in cognitive function and cognitive deficits in AD and other diseases is purely correlational and neuronal mechanisms have yet to be identified before potential targets for treatment development could be identified. We propose an approach that will use a cutting-edge experimental tools to manipulate cerebellar function during cognitive behavior in mouse models of AD to determine whether the cerebellum is causally involved in cognitive decline in AD and to identify underlying neuronal mechanisms.
| Lackey, Elizabeth P; Heck, Detlef H; Sillitoe, Roy V (2018) Recent advances in understanding the mechanisms of cerebellar granule cell development and function and their contribution to behavior. F1000Res 7: |
| Miterko, Lauren N; Lackey, Elizabeth P; Heck, Detlef H et al. (2018) Shaping Diversity Into the Brain's Form and Function. Front Neural Circuits 12:83 |
