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Characterization of cortical neuronal subtypes in cocaine self-administration

可卡因自我给药皮质神经元亚型的特征

基本信息

批准号：
10893672
负责人：
Susan Marie Ferguson
金额：
$ 7.84万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10893672
关键词：
Address Affect Apical Aversive Stimulus Axon Behavior Bilateral Biological Assay Cells Characteristics Chronic Cocaine Complex Contralateral Corpus striatum structure Coupled Cues Data Decision Making Dependovirus Desire for food Development Disease Drug Addiction Drug abuse Drug resistance Drug usage Electrophysiology (science)Enterobacteria phage P1 Cre recombinase Exhibits Extinction Fiber Ganglia Glutamates Goals Hyperactivity Image Immunohistochemistry Individual Ipsilateral Mediating Medical Molecular Monitor Morphology Motivation Neurobiology Neurons Pathologic Pattern Pharmaceutical Preparations Phenotype Photometry Play Population Predisposition Prefrontal Cortex Process Property Public Health Punishment Pyramidal Tracts Rattus Regulation Relapse Research Rewards Risk Role Self Administration Signal Transduction Social Impacts Societies Stimulus Stress Structure Sucrose System Testing Thalamic structure Thick Viral Vector Vulnerable Populations Work addiction cell type cocaine self-administration cocaine use conditioned place preference cost designer receptors exclusively activated by designer drugs drug development drug relapse drug seeking behavior economic impact hippocampal pyramidal neuron in vivo motivated behavior novel novel therapeutic intervention receptor selective expression therapeutic development therapeutically effective time use tool

项目摘要

Project Summary Drug addiction is a major public health issue that has profound medical consequences to individuals, as well as costly social and economic impacts on our society. Unfortunately, treatment options are limited and relapse rates remain high. Unraveling the complex neurobiological changes that contribute to the transition to addiction in vulnerable individuals, therefore, is critical for effective therapeutic development. The cortico-basal ganglia- thalamic (CBGT) network is involved in decision-making, motivation and reward, and alterations within this circuit regulate the development of drug addiction. The prefrontal cortex serves as a key modulator of this circuit, providing strong glutamatergic drive to the striatum, as well as widespread input throughout the CBGT system. Of note, cortical processing is crucial for the patterning of appropriate behavior and loss of top-down cortical control during drug use is thought to play a major role in the transition to addiction, as well as relapse. However, cortical pyramidal neurons can be subdivided into two major types with distinct inputs and projections targets, molecular and receptor profiles, morphologies and electrophysiological characteristics. Cortical neurons that have sparse apical tufts, minimal h-currents, and are regular spiking project bilaterally to striatum and contralateral cortex (Intratelencephalic; IT) whereas cortical neurons that have thick apical tufts, prominent h-currents, and are burst firing send their main axon into the pyramidal tract with collateral projections to ipsilateral striatum and other subcortical structures (Pyramidal Tract; PT). As a result of the distinct connectivity patterns and cellular properties of these two neuronal populations, they are poised to integrate and convey distinct signals for guiding decision-making processes and motivated behaviors. Nonetheless, the role of these two cell populations in the regulation of addiction behaviors has not been examined. The overall goal of this proposal, therefore, is to begin to address this issue by using novel imaging and molecular tools to characterize how IT and PT neurons in PFC regulate drug-context associations, as well as drug-taking and drug-seeking behaviors in rats expressing distinct addiction-risk phenotypes. The guiding hypothesis of this work is that IT and PT neurons in the cortex work in concert to maintain optimal functioning of the CBGT network by regulating aversive and appetitive motivation states, respectively, and dysregulation of these cell types following drug use leads to aberrant signal relays to drugs and associated stimuli that drive compulsive and persistent drug use. This work, therefore, has the potential to uncover novel, cell-type specific processes that contribute to the development of addiction and relapse.

项目摘要药物成瘾是一个重大的公共卫生问题，对个人有深远的医疗后果，对我们的社会产生了巨大的社会和经济影响。不幸的是，治疗选择有限，复发利率仍然很高。揭开复杂的神经生物学变化，有助于过渡到成瘾因此，在脆弱的个体中，对于有效的治疗开发至关重要。皮质基底神经节丘脑（CBGT）网络参与决策，动机和奖励，以及其中的变化神经回路调节着毒瘾的发展。前额叶皮层是这一过程的关键调节器电路，提供强大的纹状体，以及广泛的输入整个CBGT 系统值得注意的是，皮层处理对于适当行为的模式化和自上而下的丧失至关重要。人们认为，吸毒期间的皮层控制在成瘾和复发的转变中起着重要作用。然而，皮质锥体神经元可以细分为两种主要类型，具有不同的输入，预测目标，分子和受体概况，形态和电生理特性。皮质神经元有稀疏的顶丛，最小的h-电流，并定期发放双边项目，纹状体和对侧皮质（端脑内; IT），而皮质神经元具有厚的顶丛，突出的h-电流和突发放电将它们的主要轴突送入具有侧支的锥体束投射到同侧纹状体和其他皮质下结构（锥体束; PT）。的结果这两个神经元群体的不同连接模式和细胞特性，它们准备整合和传达不同的信号，以指导决策过程和激励行为。尽管如此，这两个细胞群在成瘾行为调节中的作用还没有被证实。考察因此，本提案的总体目标是开始通过使用新的成像技术来解决这一问题。以及分子工具来表征PFC中的IT和PT神经元如何调节药物背景关联，表现出不同成瘾风险表型的大鼠的吸毒和寻药行为。的指导这项工作的假设是，皮层中的IT和PT神经元协同工作以维持最佳功能 CBGT网络的调节厌恶和食欲动机状态，分别，和失调，这些细胞类型在药物使用后导致异常的信号传递给药物和相关的刺激，强迫性和持续性吸毒。因此，这项工作有可能揭示新的，细胞类型特异性的，这些过程有助于成瘾和复发的发展。