# Roles of Descending Forebrain Pathways to the Cerebellum in Behavioral Timing

> **NIH NIH R21** · UNIVERSITY OF IOWA · 2024 · $226,177

## Abstract

Cognitive deficits in schizophrenia and bipolar disorder are associated with altered cerebellar activity and this
altered activity is thought to play a causal role in the cognitive deficits observed in these disorders. However,
the neural mechanisms underlying cerebellar contributions to intact and impaired cognition have not been fully
elucidated. We will address this gap in knowledge by examining the neural mechanisms underlying cerebellar
communication with forebrain systems during interval timing – a cognitive task requiring attention, working
memory, and precise response timing. The primary emphasis of the previous research on the role of the
cerebellum in interval timing has been on the ‘ascending’ cerebello-thamo-frontal cortical pathway. However,
the medial frontal cortex also projects back to the cerebellum via the pontine nucleus. This ‘descending’
pathway consists of the medial frontal cortical projection to the rostral pontine nucleus and its mossy fiber
projection to the cerebellum. A major goal of the current project is to determine the role(s) of the descending
pathway in interval timing. The descending pathway could plausibly modulate cerebellar activity with ramping
activity or a tonic increase in activity. We hypothesize that both tonic and ramping activity from the descending
pathway modulates activity in the cerebellum by increasing the overall firing rate and precision of ramping,
respectively. We also hypothesize that sensory information from the start cues in interval timing combines with
information from the medial frontal cortex to support cue-specific and interval-specific ramping of cerebellar
output. We will test these hypotheses in two aims that examine the pathways for cue information (Aim 1) and
mFC timing information (Aim 2) using optogenetics and electrophysiology in rats during performance of a dual-
interval timing task. A broad impact of this project is that we will be able to establish whether there are common
mechanisms for cerebellar organization and function in motor learning and cognition. The current proposal is a
basic research project, but the findings may have important implications for translational research on the role of
the cerebellum in schizophrenia and bipolar disorder. Studies of schizophrenia and bipolar disorder have
generally focused on how altered cerebellar function affects frontal cortical function, but it is plausible that the
altered activity originates in the cortex (or in both areas) and affects the cerebellum via the descending frontal
cortical-pontine-cerebellum pathway. The findings of our project could form the foundation for translational
research into how descending pathway abnormalities relate to cognitive symptoms in schizophrenia and
bipolar disorder.

## Key facts

- **NIH application ID:** 10901110
- **Project number:** 1R21MH136675-01
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** John H Freeman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $226,177
- **Award type:** 1
- **Project period:** 2024-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901110

## Citation

> US National Institutes of Health, RePORTER application 10901110, Roles of Descending Forebrain Pathways to the Cerebellum in Behavioral Timing (1R21MH136675-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10901110. Licensed CC0.

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