Homer Upregulation During Instrumental Learning in the Dorsomedial Striatum

描述(由申请人提供)：操作式学习的基本原理是在实验室里通过训练大鼠按下杠杆来获得奖励来测试的。当一只大鼠学会用杠杆施加压力以获得蔗糖奖励时，皮质边缘回路中的突触立即发生可塑性。这种可塑性的一个例子是一种称为Hmer la的即刻早期基因的上调。Ann Kelley博士的实验室最近的研究表明，在操纵性学习的早期学习或习得过程中，Hmer la在背内侧纹状体和前扣带皮质中的表达增加(Hernandez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Hmer的表达，以及这些细胞的传出和传出投射是什么。此外，前扣带回皮质向背内侧纹状体发出谷氨酸能投射。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过。据推测，前扣带回皮质到背内侧纹状体的投射介导了对蔗糖奖赏的操控反应，而Hmer在表达脑啡肽的皮质纹状体细胞中上调，脑啡肽是一种与食物摄取有关的神经肽。为了研究这些假说，谷氨酸受体拮抗剂将被微量注射到背内侧纹状体和前扣带回皮质，以显示这些区域在操作反应中的作用。此外，轨迹追踪研究将与原位杂交相结合，以确定在对蔗糖奖励的操作反应中激活的表达Hmer la的细胞的电路连通性。从这一提议的目的中获得的知识对于进一步了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。这种最初的学习与获得奖励有关，是在上瘾期间开始的早期学习的一部分。上瘾是一种疾病，仅在美国每年就导致超过55万人死亡，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方法。

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.