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

• 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
• 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

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.

项目概要 吸毒成瘾是一个重大的公共卫生问题，对个人以及对健康产生深远的影响 对我们的社会造成代价高昂的社会和经济影响。不幸的是，治疗选择有限并且会复发 利率仍然很高。揭示导致成瘾转变的复杂神经生物学变化 因此，在易受伤害的个体中，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改变 电路调节药物成瘾的发展。前额皮质是这一过程的关键调节器 电路，为纹状体提供强大的谷氨酸驱动，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 吸毒期间的皮质控制被认为在成瘾过渡以及复发中发挥着重要作用。 然而，皮质锥体神经元可以分为两种主要类型，具有不同的输入和 预测目标、分子和受体概况、形态和电生理特征。 皮层神经元具有稀疏的顶端簇、最小的 h 电流，并且双边有规律的尖峰投射 纹状体和对侧皮质（端脑内；IT），而具有厚厚顶端簇的皮质神经元， 突出的 h 电流，并且爆发性发射，将其主轴突发送到带有侧支的锥体束中 投射到同侧纹状体和其他皮质下结构（锥体束；PT）。由于 这两个神经元群的不同连接模式和细胞特性，它们准备好 整合和传达不同的信号来指导决策过程和动机行为。 尽管如此，这两种细胞群在成瘾行为调节中的作用尚未得到证实。 检查了。因此，该提案的总体目标是通过使用新颖的成像技术来开始解决这个问题 和分子工具来表征 PFC 中的 IT 和 PT 神经元如何调节药物-背景关联 作为表达不同成瘾风险表型的大鼠的吸毒和寻求药物行为。指导性的 这项工作的假设是皮质中的 IT 和 PT 神经元协同工作以维持最佳功能 CBGT 网络通过分别调节厌恶和食欲动机状态以及失调 使用药物后的这些细胞类型会导致药物和相关刺激信号传递异常，从而驱动 强迫性和持续性吸毒。因此，这项工作有可能发现新颖的、细胞类型特异性的 导致成瘾和复发的过程。