Role of Striatopallidal Neurons in Drug-Induced Neural Plasticity and Behavior

描述(申请人提供)：纹状体主要由GABA能中棘投射神经元(MSN)组成，它们的神经肽表达不同，形成两条主要的传出通路。含有神经肽强啡肽和P物质的MSN是纹状体黑质或“直接”通路的一部分，而含有神经肽脑啡肽的MSN是纹状体苍白球或“间接”通路的一部分。精神刺激剂诱导的纹状体改变被认为在药物成瘾的发展和维持中起关键作用；然而，特定的纹状体细胞群的作用尚不清楚。尽管如此，最近的证据表明，纹状体苍白球神经元可能对药物引起的大脑和行为的长期变化特别重要。例如，使用即刻早期基因表达作为神经元活动指标的研究发现，虽然仅仅精神刺激剂暴露就足以增加纹状体黑质神经元的活动，但只有在导致药物诱导的行为可塑性形式的条件下暴露药物，如精神运动敏化，才会激活纹状体苍白质神经元。该实验的总体目标是使用新的分子和遗传靶向方法来直接检测纹状体蛋白在药物诱导的分子变化和行为可塑性中的作用。推测纹状体丘脑神经元的募集对于精神刺激剂诱导的纹状体基因表达的长期变化、精神运动敏化的发展和药物自我给药行为的升级是至关重要的。这项工作将有助于阐明纹状体苍白质中棘神经元在成瘾过程中的作用。此外，准确识别调控成瘾转变的神经回路，应该有助于指导未来成瘾者治疗方法的发展。 与公共卫生相关：吸毒成瘾已成为一种世界性流行病，给社会带来了重大的社会和经济负担。组成这一提议的研究旨在更好地了解大脑区域以及这些区域中的特定细胞是如何促进成瘾的发展的。通过这样做，这项研究可能会为治疗干预的新路线提供途径，以缓解这一严重的公共卫生问题。

DESCRIPTION (provided by applicant): The striatum is mostly comprised of GABAergic medium spiny projection neurons (MSNs) that differ in their neuropeptide expression and form two major efferent pathways. MSNs that contain the neuropeptides dynorphin and substance P are part of the striatonigral, or 'direct', pathway whereas MSNs that contain the neuropeptide enkephalin are part of the striatopallidal, or 'indirect', pathway. Psychostimulant-induced alterations in the striatum are thought to be critical in the development and maintenance of drug addiction; however, the role of specific striatal cell populations is not clear. Nonetheless, recent evidence suggests that striatopallidal neurons may be especially important for the long-term changes in brain and behavior produced by drugs. For example, studies using immediate early gene expression as an indicator of neuronalactivity found that while mere psychostimulant exposure is sufficient to increase activity in striatonigral neurons, only drug exposure under conditions that lead to forms of drug-induced behavioral plasticity, such as psychomotor sensitization, also activates striatopallidal neurons. The overall aim of the proposed experiments is to use novel molecular and genetic targeting approaches to directly examine the involvement of striatopallidal MSNs in drug-induced molecular changes and behavioral plasticity. It is hypothesized that recruitment of striatopallidal neurons is critical for the long-term changes in striatal gene expression induced by psychostimulants, as well as in the development of psychomotor sensitization and the escalation of drug self-administration behavior. This work will help to elucidate the contribution of striatopallidal medium spiny neurons in the processes that underlie addiction. In addition, precise identification of the neural circuits that regulate the transition to addiction should be useful for guiding the development of future treatments for addicts. PUBLIC HEALTH RELEVANCE: Drug addiction has become a worldwide epidemic with major social and economic burdens on society. The research that comprises this proposal aims to better understand how brain regions, and specific cells within those regions, contribute to the development of addiction. In so doing, this research may provide avenues for novel lines of therapeutic interventions in order to mitigate this serious public health issue.