The fatal mutation in Huntington's disease (HD) leads to an expanded glutamine repeat within the huntingtin protein which causes neuronal dysfunction typically followed by selective neurodegeneration especially within the striatum and cortex. These dysfunctions in neurons and circuits occur during the development of the disease phenotype, well before there is significant cell loss. Recent studies in animal models have emphasized that synaptic cell-cell interactions play a role in the pathophysiology of this disease. For example, removing mutant huntingtin from the cerebral cortex ameliorates some HD symptoms. The experiments in this application are designed to understand the functional changes that occur in specific populations of cortical neurons during the progression of the HD phenotype and to uncover new targets and approaches for therapies. However, little is known about functional changes in cortical neurons, although these neurons also degenerate in HD. Before motor symptoms become apparent, sensory, cognitive and emotional disturbances occur and these seem to depend on aberrant communication in the cortex that probably involves thalamocortical pathways. These pathways have never been examined in HD. Our overarching hypothesis is that sensory and motor cortical areas are differentially and asynchronously affected during HD progression. We propose that sensory thalamocortical pathways are downregulated early leading to faulty integration and interpretation of sensory signals. In turn, the motor cortex becomes upregulated and disorganized, leading to altered corticostriatal communication and motor symptoms. In this grant proposal we will use state-of-the-art techniques in three different laboratories at UCLA.
Aim 1 uses optogenetics and slice electrophysiology to examine mechanistically altered synaptic communication between thalamic sensory and motor nuclei and their corresponding cortical projection areas.
Aim 2 uses high-density silicon microprobes to record firing of hundreds of neurons simultaneously in sensory and motor cortical areas as well as thalamic nuclei in awake mice.
Aim 3 uses genetically encoded calcium indicators to visualize neuronal activity in sensory and motor cortical areas in awake mice. Together, the studies will provide new and important mechanistic insights into the understudied cortical dysfunction and will provide the basis for novel and rational treatments for HD by delineating more restricted targets spatially and temporally. These studies also will be relevant for understanding other CAG triplet repeat diseases and neurodegenerative disorders.

Public Health Relevance

Huntington's disease, a genetic, autosomal dominant neurodegenerative disorder, is always fatal and presently no successful treatments exist. Patients carrying the mutation display motor dysfunction, cognitive impairments and psychiatric disturbances. Genetic mouse models have been instrumental in understanding the dysfunctions underlying behavioral phenotypes, neuronal abnormalities and neurodegeneration and they permit examination of the progression of the disease, the discovery of cause-effect relationships and evaluation of potential therapies. This proposal uses state-of-the-art techniques to examine mechanisms that lead to dysfunction in specific neuronal populations in the cerebral cortex during the progression of the phenotype and will uncover new targets for therapies to alleviate symptoms and slow the progression of this devastating genetic disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS096994-04
Application #
9983497
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Miller, Daniel L
Project Start
2017-08-15
Project End
2021-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095