# Organization of inhibition in the cerebellar cortex

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2023 · $570,725

## Abstract

Project Summary
The project remains the same as the original application. Below is a summary overview.
Our long-term goal is to generate a complete understanding of how the cerebellum learns to improve
movement in response to motor errors. Climbing fibers are thought to play an essential role in this process
because they fire during erroneous movement. Their activity reliably excites Purkinje cells, eliciting calcium
spikes in their dendrites that can trigger long-term synaptic plasticity at coactive parallel fiber inputs. Plasticity
induction ultimately leads to corrective behavior by altering the cerebellum's response to sensorimotor stimuli
that predict mistakes. Importantly, inhibition from molecular layer interneurons (MLIs) that target Purkinje cell
dendrites suppresses climbing-fiber-evoked calcium signaling, opposing or `gating' plasticity induction.
Because MLIs are activated by movement, this suggests Purkinje cell disinhibition is required during motor
learning. As MLIs inhibit other MLIs, their interconnections could support a circuit for Purkinje cell disinhibition
during behavior. The objective of this proposal is to examine the possibility that MLI circuits are structured to
support a context-dependent engagement that allows climbing fibers to instruct plasticity and learning in
response to motor errors. To accomplish this, we will employ a multidisciplinary approach using cutting-edge
molecular-genetic techniques, functional recordings, circuit mapping, and behavioral analysis. In the first aim,
we will test whether ablating MLI-to-MLI connections that normally support Purkinje cell disinhibition affect the
ability of climbing fibers to evoke full-blown calcium signals in response to motor errors, and whether loss of
MLI-MLI circuit function affects cerebellar-dependent motor learning. In the second aim, we will establish an
MLI taxonomy and use it to survey for previously unknown MLI subtypes. We will also use functional
recordings to test whether there is evidence for bias connectivity within the MLI network that supports a
dedicated circuit for Purkinje cell disinhibition. In the third aim, we will use anatomical tracing to ascertain the
MLI connectome. In this way we will determine if there is a structural basis for the independent actuation of MLI
subtypes through their afferent inputs and the cell-type selectivity of their efferent outputs. Completion of these
aims will lead to an unprecedented understanding of the organizational logic of the molecular layer. In
particular, we expect to reveal how circuits within the molecular layer control the induction of climbing-fiber-
mediated learning. This knowledge will not only help develop theories/models of cerebellum function but will
also provide insight into the processes underlying learning in general.

## Key facts

- **NIH application ID:** 10877237
- **Project number:** 4R01NS118401-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jason M Christie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $570,725
- **Award type:** 4N
- **Project period:** 2020-08-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877237

## Citation

> US National Institutes of Health, RePORTER application 10877237, Organization of inhibition in the cerebellar cortex (4R01NS118401-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10877237. Licensed CC0.

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