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Developing an In Vitro Neurocircuitry Model of Addiction using Risk-Associated Hu

使用风险相关 Hu 开发成瘾的体外神经回路模型

基本信息

批准号：
8633033
负责人：
RONALD P HART
金额：
$ 19.74万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8633033
关键词：
Addictive Behavior Adopted Adult Affect Alcohols Alleles Amino Acids Aminobutyric Acids Asparagine Aspartate Award Axon Basic Science Behavior Biological Models Brain Brain imaging Calcium Cell Culture Techniques Cell Line Cell physiology Cells Derivation procedure Development Disease Drug abuse Electrophysiology (science)Gene Expression Profiling Genes Genetic Risk Genetic Variation Glutamates Goals Human Human Genetics Image In Vitro Individual Intervention Microfluidics Midbrain structure Modeling Modification Molecular Mutation Neurons Nicotine Nicotine Dependence Nicotinic Receptors Nucleus Accumbens Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Prefrontal Cortex Prosencephalon Protocols documentation Rewards Risk Risk Factors Role Single Nucleotide Polymorphism Somatic Cell Stem cells Synapses Synaptic plasticity System Techniques Technology Testing Ventral Tegmental Area addiction base cell type dopaminergic neuron drug abuse therapy drug of abuse flexibility gamma-Aminobutyric Acid genetic variant high risk in vivo induced pluripotent stem cell innovation mesolimbic system neuronal circuitry neuropsychiatry novel programs public health relevance risk variant stem cell biology tool

项目摘要

DESCRIPTION (provided by applicant): This is an exploratory/developmental (R21) application under the Cutting-Edge Basic Research Awards (CEBRA) program. The pathogenesis of drugs associated with abuse behavior, including nicotine and alcohol addictions, remains elusive in humans because studies of the human brain are limited to functional brain imaging and post-mortem analysis. These types of analyses make it difficult or impossible to prove hypotheses directly since the system usually cannot be manipulated or sufficiently controlled. A large number of genetic variants have been identified to be risk factors for addictive behavior in human, however, little is known about how these genetic variations impact the development of addictive behavior in humans. Recent advances in stem cell biology allow construction of induced pluripotent stem cells (iPSC) from adult cells derived from addicted individuals carrying identified genetic variants and provide possibilities for developing cell-based models of addiction. Addictive behavior in human is not only related to cellular level modifications in a specific cell type in the brain but it also affects neuronal function such as synaptic plasticity at the neurocircuitry level. However, there are currently no such in vitro neurocircuitry models that have been established using human neurons. We hypothesize that neurons derived from subjects with risk-associated genetic variants will desensitize reward circuit modulation in an in vitro mini-neurocircuitry model. By using a compartmentalized culturing system, we propose to construct a mini-neurocircuitry model mimicking mesolimbic nucleus accumbens (NAc) neurons and their synaptic inputs. Cellular and synaptic phenotypes of neurons derived from addictive patients will be investigated under the context of neurocircuitry and compared with wild-type controls. This mini-neurocircuitry model will be essential to identify mechanisms underlying risk-associated gene variants and addictive behavior. It will also serve to develop and screen novel interventions for drug abuse therapies.

描述（由申请人提供）：这是尖端基础研究奖（CEBRA）计划下的探索性/发展性（R21）申请。与滥用行为相关的药物（包括尼古丁和酒精成瘾）的发病机制在人类中仍然难以捉摸，因为对人脑的研究仅限于功能性脑成像和死后分析。这些类型的分析使得直接证明假设变得困难或不可能，因为系统通常无法被操纵或充分控制。大量的遗传变异已被确定为风险因素然而，对于人类的成瘾行为，人们对这些遗传变异如何影响人类成瘾行为的发展知之甚少。干细胞生物学的最新进展允许从来自携带已鉴定的遗传变异的成瘾个体的成体细胞构建诱导多能干细胞（iPSC），并为开发基于细胞的成瘾模型提供了可能性。人类的成瘾行为不仅与大脑中特定细胞类型的细胞水平改变有关，而且还影响神经元功能，例如神经回路水平的突触可塑性。然而，目前还没有使用人类神经元建立的这种体外神经回路模型。我们假设，来自风险相关遗传变异受试者的神经元将在体外微型神经回路模型中使奖赏回路调制脱敏。通过使用一个区室化的培养系统，我们建议构建一个迷你的神经回路模型，模仿中脑边缘核神经元（NAc）的神经元和它们的突触输入。来自成瘾患者的神经元的细胞和突触表型将在神经回路的背景下进行研究，并与野生型对照进行比较。这种微型神经回路模型对于识别风险相关基因变异和成瘾行为的潜在机制至关重要。它还将有助于开发和筛选药物滥用治疗的新干预措施。