权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Phasic Dopamine and Symptom Domains of Mental Illness

阶段性多巴胺和精神疾病的症状域

基本信息

批准号：
8883158
负责人：
LARRY S ZWEIFEL
金额：
$ 37.77万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-04 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8883158
关键词：
Action Potentials Address Affective Attention Behavior Behavioral Biological Assay Biological Models Biological Neural Networks Brain Calcium Confocal Microscopy Corpus striatum structure Coupled DNA Sequence Alteration Dimensions Disease Dissection Dominant-Negative Mutation Dopamine Dopamine D1 Receptor Electric Stimulation Elements Equilibrium Etiology Fiber Optics Gene Delivery Gene Targeting Generations Genes Genetic Genetic Techniques Goals Human Image Impairment Indium Ion Channel Learning Maps Mediating Memory Mental disorders Midbrain structure Monitor Motivation Mus Mutation N-terminal Neurons Neurotransmitters Nucleus Accumbens Optics Pathway interactions Patients Pattern Physiology Play Prefrontal Cortex Process Regulation Regulatory Element Research Role Schizophrenia Sensory Signal Transduction Structure Symptoms System Techniques Ventral Striatum Ventral Tegmental Area Viral Viral Vector approach behavior base behavioral response brain circuitry brain tissue calcium indicator calcium-activated potassium channel small-conductance combinatorial dopamine system dopaminergic neuron in vivo innovation mutant neural circuit optical imaging optogenetics public health relevance recombinase response selective expression sensory gating sensory input

项目摘要

DESCRIPTION (provided by applicant): Activity patterns in the brain establish the manner in which sensory information is perceived and salience is assigned. Disruptions of these patterns through genetic mutations are likely a major cause of mental illness. The midbrain dopamine system plays an essential role in salience assignment and mutations within several ion channels known to regulate action potential firing patterns by dopamine neurons have been identified, yet virtually nothing is known of the impact of these mutations on dopamine physiology, circuit function, and behavior. We have demonstrated that a mutation in the calcium activated, small conductance potassium channel, SK3, identified in a patient with schizophrenia alters dopamine neuron activity pattern regulation. Selective, expression of this dominant-negative human SK3 mutant in dopamine neurons of mice shifts balance between tonic and phasic activity of dopamine neurons towards a more phasic state. The resulting dysregulation of activity patterns in dopamine neurons leads to impairments in sensory and attention gating processes. The major challenge that lies ahead is discovering how alterations in tonic-to-phasic dopamine ratios impact cortical and striatal circuits important for gating sensory information and to further defin behavioral domains impacted by such disruptions. Here, I outline several innovate approaches that we will utilize to determine how imbalances in dopamine activity patterns impact corticostriatal connectivity and function. Utilizing combinatorial viral vector gene delivery, we wll optogentically isolate inputs from the prefrontal cortex to the nucleus accumbens region of the striatum and define how expression of the human SK3 mutation in dopamine neurons impacts the connectivity of these two structures using in vivo fiber-optic confocal microscopy and imaging of a genetically encoded calcium indicator. We will monitor activity- dependent process in the nucleus accumbens using fiber-optic confocal microscopy and define how alterations in tonic-to-phasic dopamine activity influences activity in direct and indirect pathway neurons of the striatum in freely behaving mice during an attention gating task. Finally, we will use viral-mediated circuit dissection to define the minimal network elements in the brain required for dopamine-dependent modulation of sensory and attention gating.