Development of novel viral vector tools for pathway specific targeting of CreTTC

描述（申请人提供）：皮质-基底神经节系统是一个涉及动机和奖励的复杂神经网络。这种神经回路的功能障碍与许多神经精神疾病有关，包括药物成瘾。纹状体是该回路的主要接口，主要通过直接和间接两种途径指导行为输出。这些纹状体通路在成瘾相关行为中发挥着重要但独特的作用。此外，纹状体神经元的可塑性受来自皮质的谷氨酸信号调节。纹状体神经元的可塑性促进了基于先前经验的适当行为的选择，并因滥用药物而发生深刻改变。然而，针对特定纹状体细胞群的皮质纹状体传入事件如何调节药物的行为和神经生物学影响从未被分离出来。此外，这些皮质纹状体锥体神经元可分为两大类，它们具有不同的投射目标、形态和电生理特征。具有稀疏的顶簇和最小的h电流的皮质神经元在脑内向纹状体和对侧皮层投射（it型），而具有厚的顶簇和突出的h电流的皮质神经元将其主轴突送入锥体束，并向纹状体投射（pt型）。尽管有证据表明it型神经元优先靶向直接通路纹状体神经元，而pt型神经元优先靶向间接通路纹状体神经元，但这一观点仍存在争议。皮层处理对于成瘾相关行为的模式至关重要，因此了解哪些类型的皮层细胞以纹状体神经元群体为目标，以及离散的皮层输入如何在直接和间接纹状体通路中产生适应性，对于揭示奖励和动机行为背后的回路至关重要。因此，本提案的总体目标是开发新的分子靶向方法，以评估直接和间接途径纹状体神经元的皮质神经元的表型，并确定针对这两种纹状体通路的皮质传入事件在一种形式的药物诱导行为可塑性，精神运动敏化中的作用。通过模拟从皮层输入到基底神经节的自上而下控制的丧失如何导致与成瘾相关的行为，我们将更好地理解这一回路的复杂性，这可能对成瘾治疗的发展和应用产生重大影响。

DESCRIPTION (provided by applicant): The cortico-basal ganglia system is a complex neural network involved in motivation and reward. Dysfunction of this circuitry has been implicated in many neuropsychiatric disorders, including drug addiction. The striatum acts as the principal interface of this circuit, and guides behavioral output primarily through two pathways, the direct and the indirect. These striatal pathways have been shown to play important, but distinct roles, in addiction-related behaviors. In addition, plasticity at striatal neurons, which promotes the selection of appropriate actions based on prior experience and is profoundly altered by exposure to drugs of abuse, is regulated by glutamatergic signaling from the cortex. However, how corticostriatal afferents targeting specific striatal cell populations regulate the behavioral and neurobiological impact of drugs has never been isolated. Furthermore, these corticostriatal pyramidal neurons can be subdivided into two major types with distinct projections targets, morphologies and electrophysiological characteristics. Cortical neurons that have sparse apical tufts and minimal h-currents project intratelencephalically to striatum and contralateral cortex (IT-type) whereas cortical neurons that have thick apical tufts and prominent h-currents send their main axon into the pyramidal tract with collateral projections to striatum (PT-type). Although some evidence suggests that IT-type neurons preferentially target direct pathway striatal neurons and PT-type neurons target indirect pathway striatal neurons, this idea remains of debate. Cortical processing is crucial for the patterning of addiction- related behavior, so understanding which types of cortical cells target populations of striatal neurons as well as how discrete sets of cortical inputs produce adaptations within the direct and indirect striatal pathways will be critical for unraveling the circuitry underlying reward and motivated behavior. Thus, the overall goal of this proposal is to develop novel molecular targeting approaches to assess the phenotype of cortical neurons that target direct and indirect pathway striatal neurons as well as to define the role of sets of cortical afferents that target these two striatal pathwaysin one form of drug-induced behavioral plasticity, psychomotor sensitization. Through modeling how loss of top-down control from cortical inputs into the basal ganglia contribute to behaviors that are related to addiction, we will gain a better understanding of the intricacies of this circutry, which is likely to have a big impact on the development and application of treatments for addicts.