Cortical Pathophysiology in Mouse Models of Huntington's Disease

亨廷顿病小鼠模型的皮质病理生理学

• 批准号: 9543575
• 负责人: Michael S. Levine
• 金额: $ 50.37万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9543575
• 关键词: Affect; Animal Model; Anterior; Applications Grants; Area; Automobile Driving; Basal Ganglia; Behavioral; Calcium; Cell Communication; Cell Nucleus; Cells; Cerebral cortex; Cognitive deficits; Collaborations; Communication; Complex; Corpus striatum structure; Development; Disease; Disease Progression; Disinhibition; Dorsal; Electrophysiology (science); Emotional Disturbance; Evaluation; Functional disorder; Genes; Genetic; Genetic Diseases; Glutamine; Goals; Grant; Huntington Disease; Huntington gene; Huntington protein; Image; Impaired cognition; In Vitro; Individual; Interneurons; Joints; Laboratories; Lead; Locomotion; Methodology; Modeling; Morphology; Motor; Motor Activity; Motor Cortex; Movement; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Nuclear; Pathway interactions; Patients; Phenotype; Play; Population; Publications; Rest; Role; Sensory; Signal Transduction; Silicon; Slice; Somatosensory Cortex; Symptoms; Synapses; Synaptic Transmission; Techniques; Technology; Testing; Thalamic Nuclei; Thalamic structure; Therapeutic; Trinucleotide Repeats; Vacuum; Ventroposterior Medial Nucleus of the Thalamus; Vibrissae; awake; calcium indicator; density; design; disease phenotype; experimental study; hippocampal pyramidal neuron; in vivo; in vivo imaging; insight; motor deficit; motor disorder; motor symptom; mouse model; mutant; nervous system disorder; new therapeutic target; novel; optogenetics; patch clamp; reduce symptoms; response; sensory input; sensory integration; somatosensory

Abstract 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.

摘要