# Behavioral and brain network effects of dysfunction in the cognitive cerebellum

> **NIH NIH R21** · LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER · 2023 · $222,029

## Abstract

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.

## Key facts

- **NIH application ID:** 10651608
- **Project number:** 5R21MH126359-02
- **Recipient organization:** LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
- **Principal Investigator:** Paul James Mathews
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $222,029
- **Award type:** 5
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10651608

## Citation

> US National Institutes of Health, RePORTER application 10651608, Behavioral and brain network effects of dysfunction in the cognitive cerebellum (5R21MH126359-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10651608. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*