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：
10815221
负责人：
Susan Marie Ferguson
金额：
$ 43.07万
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/10815221
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.

项目摘要吸毒成瘾是一个主要的公共卫生问题，对个人以及昂贵的社会和经济对我们社会的影响。不幸的是，治疗方案有限且复发费率仍然很高。阐明有助于过渡到成瘾的复杂神经生物学变化因此，在弱势群体中，对于有效的治疗发展至关重要。 Cortico-Basal神经节 - Thalamic（CBGT）网络参与了决策，动机和奖励以及其中的改变电路调节药物成瘾的发展。前额叶皮层是此的关键调节器电路，为纹状体提供强大的谷氨酸能驱动以及整个CBGT的广泛输入系统。值得注意的是，皮质处理对于适当行为的模式和自上而下的丧失至关重要人们认为在吸毒期间的皮质控制在对成瘾的过渡和复发中起着重要作用。但是，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，投影靶标，分子和受体谱，形态和电生理特征。皮质神经元具有稀疏顶簇，最小的H-电流，并且是双侧的常规尖峰项目纹状体和对侧皮质（脑内脑; IT），而皮质神经元具有较厚的顶端簇，突出的H电流，并且正在爆裂发射，将其主轴突带入了带有抵押品的金字塔对同侧纹状体和其他下皮质结构（锥体纹； PT）的投射。由于这两个神经元种群的独特连通性模式和细胞特性，它们已准备就绪集成并传达不同的信号，以指导决策过程和动机行为。尽管如此，这两个细胞群在成瘾行为调节中的作用尚未检查。因此，该提案的总体目标是通过使用新颖的成像开始解决这个问题和分子工具以表征PFC中的IT和PT神经元如何调节药物秘密关联作为表达不同成瘾风险表型的大鼠的吸毒和寻求毒品行为。引导这项工作的假设是皮质中的IT和PT神经元协同工作以保持最佳功能通过调节厌恶和开胃动机状态和失调，通过调节CBGT网络的网络吸毒后的这些细胞类型导致异常信号继电器与药物和相关的刺激驱动强迫性和持续的毒品使用。因此，这项工作有可能发现新颖的细胞类型特异性有助于成瘾和复发发展的过程。