# Cortico-basal ganglia connectivity in a non-human primate model of Huntington's disease

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $530,054

## Abstract

PROJECT SUMMARY
The goal of the proposed research in this application is to characterize alterations in cortico-basal ganglia
connectivity in a novel non-human primate model of Huntington's disease (HD) recently developed in my
laboratory. Previous K99/R00 funding (2010-2015) from the NINDS supported the development of this new
model, wherein we found that AAV-mediated expression of mutant HTT in the caudate and putamen of rhesus
macaques lead to a wide array of behavioral manifestations of disease including the progressive development
of both motor and cognitive phenotypes also seen in human HD patients. Brains from HD NHPs showed
DARPP-32 loss, inclusion formation and gliosis, along with reduced levels of key striatal transcripts, including
reduced glutamate and dopamine receptor levels (manuscript in preparation). In addition to striatal pathology,
we found mHTT expression, inclusion bodies and gliosis in numerous cortical areas (frontal and motor) and
regions throughout the basal ganglia (globus pallidus, substantia nigra), likely owing to transport of the AAV
vector. These findings strongly suggest that basal ganglia connectivity may be disrupted in our NHP HD model.
The objective of this current proposal is to characterize cortico-basal ganglia connectivity in the brains of our
HD NHPs using resting state fMRI and diffusion tensor imaging to assess functional connectivity and white
matter integrity, respectively (Aim 1). Additionally, we will evaluate glutamate and dopamine neurotransmission
in the caudate and putamen using electrophysiological analyses (Aim 2). We will test our central hypothesis
that there is a progressive decline in basal ganglia connectivity in our HD NHP brains that correlates with 1) the
longitudinal development of cognitive and motor phenotypes, 2) reduced glutamate and dopamine
transmission in cortico-striatal and nigro-striatal connections with medium spiny neurons in the caudate and
putamen and 3) neuropathology including inclusion formation, gliosis and neuronal dysfunction. I have
assembled an excellent team of scientists to accomplish these goals with cumulative expertise in resting state
fMRI analysis of cortico-striatal functional connectivity (Dr. Christopher Kroenke), electrophysiological
recordings of medium spiny neurons in the rhesus macaque striatum (Dr. Verginia Cuzon Carlson), statistical
analysis of complex datasets (Dr. Byung Park), as well as my background and expertise in HD neurobiology,
AAV-mediated gene transfer, NHP MRI-guided neurosurgery, complex NHP motor and cognitive behavioral
assessment and the use of molecular and histological techniques to assess HD neuropathology. By the end of
the studies proposed here, we will have characterized alterations in basal ganglia connectivity in a novel AAV-
mHTT mediated monkey model of HD, elucidating potential pathophysiological mechanisms that underlie
motor and cognitive decline. Additionally, the data obtained from these studies will provide the un...

## Key facts

- **NIH application ID:** 9967161
- **Project number:** 5R01NS099136-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Jodi L. McBride
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $530,054
- **Award type:** 5
- **Project period:** 2016-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967161

## Citation

> US National Institutes of Health, RePORTER application 9967161, Cortico-basal ganglia connectivity in a non-human primate model of Huntington's disease (5R01NS099136-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9967161. Licensed CC0.

---

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