Sunday, May 11, 2025
5/11/2025
Behavioral and brain network effects of dysfunction in the cognitive cerebellum - PROJECT SUMMARY Cerebellar dysfunction has been implicated in various cognitive disorders (e.g., autism spectrum disorder, schizophrenia, and attention deficit and hyperactivity disorder) associated with the inability to adaptively alter previously learned behaviors. Several independent studies point to disease related cerebellar dysfunction as a causal or at least contributing factor in this behavioral deficit as experimental disruption of the cerebellum decreases the ability of mice to adaptively change previously learned behaviors in the face of a changing environment. Moreover, certain neurons in the cognitive cerebellum (i.e., Purkinje neurons) are consistently found to be damaged in cognitive disorders where behavioral inflexibility is a prominent feature. The fields working hypothesis is that dysfunction of the “cognitive cerebellum” (e.g., crus I and lobule VI) causes abnormal states of communication between the cerebellum and forebrain areas involved in flexible behavior (e.g. prefrontal cortex). There remains however major gaps in our understanding of the cerebellum's role in flexible and inflexible behavior, this includes: 1) what types of abnormal cerebellar activity can cause inflexible behavior; 2) which specific anatomical/functional sub-regions of the cerebellar cortex are involved; 3) what information does the cerebellum encode pertinent to behavioral flexibility; 4) what downstream forebrain regions communicate with the cerebellum during flexible behavior, and are these the same regions impacted by cerebellar dysfunction; and 5) what is the effect of abnormal communication on downstream forebrain regions and network activity and does it match abnormal brain states associated with mental disorder. In AIM 1 we will address questions 1 & 2 by disrupting defined subregions of the cerebellum (crus I, crus II, and lobule VI) using DREADD technology and then measuring flexible behavior in a 2-cue reward-association paradigm in mice. We will also address question 3 by recording from the cerebellum using dense-electrode arrays during flexible behavior to establish what information the cerebellum encodes to support adaptive reversal of previously learned stimulus-reward associations. In Aim 2, we will address questions 4 & 5 by combining chemo-genetic disruption of those same defined subregions of the cerebellum with whole-brain neuroimaging, specifically resting-state functional Magnetic Resonance Imaging (rs-fMRI) in mice. Here, we propose two distinct approaches that will allow us to establish mechanistic hypotheses related to questions 1 - 5 that will set the stage for multiple follow-on studies. Our overall goal is to determine how disparate brain regions collaborate to influence normal and abnormal cognitive behaviors, provide clues as to how neurocognitive dysfunction arises, and explore how disease development impacts—or is impacted by— abnormal brain neurocircuitry.
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