Characterization of cortical neuronal subtypes in cocaine self-administration

项目摘要 吸毒成瘾是一个重大的公共卫生问题，对个人以及 对我们的社会造成了代价高昂的社会和经济影响。不幸的是，治疗选择有限，而且会复发。 利率仍然居高不下。解开导致成瘾转变的复杂神经生物学变化 因此，对脆弱个体的治疗对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 回路调节药物成瘾的发展。前额叶皮质对此起关键的调节作用。 环路，为纹状体提供强大的谷氨酸能驱动，并在CBGT中广泛输入 系统。值得注意的是，皮质处理对于形成适当行为的模式和自上而下的损失至关重要。 在药物使用过程中的皮质控制被认为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，具有不同的输入和 投射靶标、分子和受体图谱、形态和电生理特征。 皮质神经元具有稀疏的顶束，最小的H电流，并且是规则的双侧棘突投射到 纹状体和对侧皮质(脑内；IT)，而皮质神经元有厚厚的顶束， 突出的H-电流，并发出爆发式发射，将其主轴突与侧支一起发送到锥体束 投射至同侧纹状体和其他皮质下结构(锥体束；PT)。作为结果， 这两个神经元群体截然不同的连接模式和细胞特性，他们准备 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控中的作用还没有得到证实。 检查过了。因此，这项提议的总体目标是通过使用新的成像技术来开始解决这个问题 以及分子工具，以表征PFC中的IT和PT神经元如何调节药物上下文关联 在表现出不同成瘾危险表型的大鼠中表现为吸毒和寻药行为。引路人 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 通过分别调节厌恶性和嗜食性动机状态，以及 药物使用后的这些细胞类型导致对药物和相关刺激的异常信号传递 强迫性和持续性的药物使用。因此，这项工作有可能揭示出新颖的、特定于细胞类型的 导致上瘾和复发的过程。

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.