Striatal Circuits In The Serotonergic Modulation Of Hedonic States

享乐状态的血清素调节中的纹状体回路

基本信息

批准号：
9139502
负责人：
Laurence H. Tecott
金额：
$ 57.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2015-09-10 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9139502
关键词：
Acute Address Affect Alcohol abuse Alcoholism Anxiety Disorders Area Attention Basal Ganglia Behavior Behavior assessment Behavior monitoring Behavioral Behavioral Assay Brain Cell Nucleus Chronic Clinical Collaborations Collection Complement Complex Corpus striatum structure Depressive disorder Detection Disease Dorsal Drug abuse Exhibits Functional disorder Genetic Health Home environment Huntington Disease Knowledge Lead Major Depressive Disorder Mediating Methods Molecular Genetics Monitor Mus Mutant Strains Mice Neural Pathways Neurons Obsessive-Compulsive Disorder Parkinson Disease Pathway interactions Pattern Pharmacogenetics Pharmacotherapy Phenotype Physiological Play Procedures Process Property Regulation Resolution Role Schizophrenia Selective Serotonin Reuptake Inhibitor Serotonergic System Serotonin Serotonin Receptor 5-HT2C Signal Transduction Specificity Structure Substance abuse problem Technology Testing Time Transgenic Mice Work autism spectrum disorder cell type clinically relevant designer receptors exclusively activated by designer drugs dorsal raphe nucleus genetic approach genetic manipulation genetic technology hedonic insight motivated behavior mouse model nerve supply neural circuit neurochemistry neuropsychiatric disorder neurotransmission novel strategies null mutation optogenetics receptor expression receptor function response reuptake serotonergic regulation serotonin receptor treatment duration treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Striatal pathways are essential to the regulation of diverse behaviors relevant to a wide array of neuropsychiatric disorders. Important roles for the STR in hedonic processes are relevant to depressive disorders, anxiety disorders, substance abuse disorders and alcoholism. Whereas much attention has focused on the functional significance of the dopaminergic innervation of the STR, much less is known about the regulation of STR function by serotonin systems. The importance of this issue is highlighted by the known, yet poorly understood impact of serotonin system manipulations on both STR function and hedonic processes. This is in part attributable to the complexity of serotonergic neurotransmission; the actions of serotonin are mediated by at least 14 distinct serotonin receptor subtypes. Multiple lines of evidence indicate that the 5- HT2C receptor (5HT2CR) subtype plays a particularly prominent role in mediating the serotonergic regulation of both hedonic states and STR function. Accordingly, we had found that a line of mutant mice lacking functional 5HT2CRs displayed diverse neurochemical, physiological and behavioral phenotypes indicative of perturbed STR function and alterations in motivated behavior. Despite the acknowledged prominence of 5HT2CRs in the serotonergic modulation of STR function, it has been very difficult to discern those neural circuits most responsible for these effects. Progress i this area has been hindered by the widespread expression of 5HT2CRs in multiple cell types in multiple basal ganglia structures, and by limitations in the specificity of pharmacological probes of 5HT2CR function. To address this challenge, we will combine methods for the induction of cell type-specific genetic manipulations with high-resolution behavioral assessment technology to determine the contribution of dorsal raphe striatal projections to the serotonergic regulation o hedonic states. We will determine the functional significance of 5HT2CRs expressed in two principal striatal circuits: the direct and indirect pathways.

描述（由适用提供）：纹状体途径对于调节与各种神经精神疾病相关的潜水行为至关重要。 STR在享乐过程中的重要作用与抑郁症，焦虑症，药物滥用障碍和酒精中毒有关。尽管很多关注集中在STR多巴胺能神经支配的功能意义上，但对5-羟色胺系统的调节功能的了解少得多。该问题的重要性是由5-羟色胺系统操纵对STR功能和享乐过程的已知但知之甚少的影响强调的。这部分归因于血清素能神经传递的复杂性； 5-羟色胺的作用由至少14个不同的5-羟色胺受体亚型介导。多种证据表明，5-HT2C受体（5HT2CR）亚型在介导Hedonic状态和STR功能的塞拉顿能调节中起着特别重要的作用。根据我们的说法，我们发现缺乏功能性5HT2CR的突变小鼠表现出不同的神经化学，物理和行为表型，表明了动机行为的扰动功能和改变。尽管5HT2CR在STR功能的血清能调节中得到了公认的突出性，但很难辨别那些对这些效果最大的神经循环。在多种基线神经节结构中的多种细胞类型中的5HT2CR的宽度表达以及5HT2CR功能的药物特异性的局限性，这一区域受到了这种区域的阻碍。为了应对这一挑战，我们将结合诱导细胞类型特异性遗传操作的方法与高分辨率行为评估技术，以确定背侧raphe纹状体项目对血清素能调节的贡献。我们将确定在两个主要纹状体电路中表达的5HT2CR的功能意义：直接和间接途径。