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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：
10350049
负责人：
Susan Marie Ferguson
金额：
$ 9.08万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10350049
关键词：
Address Apical Axon Basal Ganglia Behavior Bilateral Cells Characteristics Complex Contralateral Corpus striatum structure Decision Making Desire for food Development Drug Addiction Drug abuse Drug usage Electrophysiology (science)Glutamates Goals Image Individual Ipsilateral Medical Molecular Morphology Motivation Neurobiology Neurons Pattern Pharmaceutical Preparations Phenotype Play Population Prefrontal Cortex Process Property Public Health Pyramidal Tracts Rattus Regulation Relapse Research Rewards Risk Role Signal Transduction Social Impacts Societies Stimulus Structure System Thalamic structure Thick Work addiction cell type cocaine self-administration cost drug development drug relapse drug seeking behavior economic impact hippocampal pyramidal neuron motivated behavior novel novel therapeutic intervention receptor therapeutic development therapeutically effective 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.

项目总结