Homer Upregulation During Instrumental Learning in the Dorsomedial Striatum

描述（由申请人提供）：操作性学习的基本原理是在实验室中通过训练大鼠按下杠杆获得奖励来测试的。当老鼠学会用杠杆按压来获得蔗糖奖励时，皮质边缘回路中的突触可塑性立即发生。这种可塑性的一个例子是一个名为Homerla的立即早期基因的上调。Ann Kelley博士实验室的最新工作表明，Homerla在背内侧纹状体和前扣带皮层中的操作性学习的早期学习或获得过程中表达增加（埃尔南德斯等人，2006年）。目前尚不清楚的是，背内侧纹状体中的哪些细胞上调了Homerla的表达，以及这些细胞的传出和传入投射是什么。此外，前扣带皮层向背内侧纹状体发送一个神经元投射。到目前为止，这种皮质纹状体投射和突触后谷氨酸受体在操作性学习中的作用还没有被研究。据推测，前扣带回皮质投射到背内侧纹状体介导了蔗糖奖励的操作性反应，Homerla在表达脑啡肽（一种与食物摄入相关的神经肽）的皮质纹状体细胞中上调。为了研究这些假设，将谷氨酸受体拮抗剂显微注射到背内侧纹状体和前扣带皮层，以显示这些区域在操作性反应中的作用。此外，道跟踪研究将结合原位杂交，以确定回路连接的荷马拉表达细胞的蔗糖奖励的操作性响应过程中激活。从本提案的目的中获得的知识对于进一步理解在初始学习期间大脑不同区域发生的分子变化非常重要。这种与获得奖励有关的初始学习是成瘾期间启动的早期学习的一部分。成瘾是一种疾病，仅在美国每年就造成55万多人死亡，估计每年的经济损失为4320亿美元。了解成瘾的神经基础将有助于为这种毁灭性的疾病提供治疗。

DESCRIPTION (provided by applicant): The basic tenet of operant learning is tested in a laboratory by training rats to press a lever for a reward. When a rat learns to lever press for a sucrose reward, synaptic plasticity immediately occurs in the corticolimbic circuit. An example of this plasticity is the up regulation of an immediate early gene called Homerla. Recent work from Dr. Ann Kelley's laboratory has shown that Homerla has increased expression during the early learning, or acquisition, of operant learning in the dorsomedial striatum and the anterior cingulate cortex (Hernandez et al., 2006). What remains unknown is which cells in the dorsomedial striatum have upregulated Homerla expression, and what are the efferent and afferent projections of these cells. In addition, the anterior cingulate cortex sends a glutamatergic projection to the dorsomedial striatum. To date, the role of this corticostriatal projection and the postsynaptic glutamate receptors in operant learning has not been investigated. It is hypothesized that the .anterior cingulate cortical projection to the dorsomedial striatum mediates operant responding for a sucrose reward, and Homerla is upregulated in the corticostriatal cells that express enkephalin, a neuropeptide linked to food intake. To investigate these hypotheses, glutamate receptor antagonists will be microinjected into the dorsomedial striatum and anterior cingulate cortex to show the role of these areas in operant responding. In addition, tract tracing studies will be combined with in situ hybridization to determine the circuit connectivity of Homerla-expressing cells that are activated during operant responding for a sucrose reward. The knowledge gained from the aims of this proposal is important for furthering the understanding of the molecular changes that occur in different areas of the brain during initial learning. This initial learning that relates to procuring a reward is part of the early learning that initiates during addiction. Addiction is a disease that causes more than 550,000 deaths a year in the United States alone and has an estimated yearly economic cost of $432 billion. Understanding the neural substrates of addiction will help to produce treatments for this devastating disease.