# Dissecting the inhibitory architecture governing basal ganglia output

> **NIH NIH R00** · GEORGETOWN UNIVERSITY · 2021 · $249,000

## Abstract

The initiation and maintenance of organized movement through the basal ganglia is strongly influenced by its
feed-forward and feedback inhibitory architecture. The substantia nigra pars compacta (SNc) and
pedunculopontine nucleus (PPN) contribute to the overall output of the basal ganglia. Neurons in both structures
degenerate in Parkinson's Disease, resulting in impaired motion. While treatments such as deep brain
stimulation in the PPN (Snijders et al., 2016), and the implantation of stem cells into the SNc (Sonntag et al.,
2018) have both met with variable success, their potential efficacy is constrained by a fundamental lack of
knowledge about the circuitry of these two nuclei. The research proposed here will generate new insights into
the function of inhibitory circuitry in these two nuclei and represents the first step toward a full understanding of
the local and extended basal ganglia circuits which control organized motion. My long-term goal is to develop an
independent research program focused on identifying cellular and network interactions that underlie basal
ganglia control of motion. The overall objective of this K99/R00 application is to determine the extent to which
local functional connectivity between genetically-defined subpopulations modulates basal ganglia output. My
central hypothesis is that inhibition onto SNc and PPN neurons sculpts basal ganglia output by modulating
excitatory gain. This hypothesis is based on preliminary two-photon uncaging, calcium imaging, optogenetic
experiments, morphological reconstructions, and computational modeling. The rationale for this research is that
once the circuit connectivity of the PPN and SNc is functionally mapped, we can begin to define the connections
by which the basal ganglia select actions and control coordinated motion. To achieve my overall objective, I will
work with my mentor, Dr. Zayd Khaliq and co-mentor, Dr. Chris McBain to learn and implement multi-channel
optogenetic techniques and the simultaneous use of spatially-specific optogenetics with two photon glutamate
uncaging and calcium imaging. These new techniques, in combination with my computational modeling and
electrophysiological experience will allow me to complete my specific aims. During the mentored phase, I will
complete aims 1 by performing functional tests of inhibitory inputs onto SNc dopamine neurons, including a
comparison of the strength and location of inhibition from the striatal patch (striosome) compartments and the
striatal matrix. In aim 2, I will test the functional consequences of dendrite-specific inhibition on the excitatory
gain of SNc dopamine neurons. During the independent phase, I will utilize the same techniques to investigate
the inhibitory circuitry of the PPN. In aim 3, I will perform functional tests of inhibitory inputs to the glutamatergic
neurons of the PPN which have been identified with rabies tracing. In aim 4, I will define the intrinsic and genetic
characteristics of a projection...

## Key facts

- **NIH application ID:** 10304599
- **Project number:** 4R00NS112417-02
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Rebekah Coleman Evans
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 4N
- **Project period:** 2019-09-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10304599

## Citation

> US National Institutes of Health, RePORTER application 10304599, Dissecting the inhibitory architecture governing basal ganglia output (4R00NS112417-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10304599. Licensed CC0.

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