Epigenetic Mechanisms in Motor Habits Stability

描述（由申请人提供）：虽然运动习惯对运动技能的发展很重要，但异常的运动习惯与药物成瘾有关。运动习惯与其他类型的记忆截然不同。它们需要很长时间才能形成，并且很难被修改。我们假设，这种独特的功能使得很难扭转药物成瘾的异常运动习惯。是什么让运动习惯不同于其他类型的记忆？答案可能在于纹状体中棘神经元（MSN）的独特信号通路。从皮质中的多巴胺能神经元和中脑中的多巴胺神经元到MSN的会聚输入涉及皮质纹状体突触可塑性和习惯学习。基于已发表的研究和在我们实验室进行的研究，我们假设腺苷酸环化酶V型（ACS），这是选择性和高度表达在成年纹状体是一个关键的决定因素的稳定性皮质纹状体突触和稳定的运动习惯。然而，在出生后的早期发育，腺苷酸环化酶I型（AC 1），而不是ACS是高度表达在纹状体。与ACS促进突触稳定性相反，AC 1促进突触可塑性。因此，AC 1表达的沉默在出生后的发展和出现ACS的优势亚型可能是一个重大的事件，在神经发育，有相应的行为后果。AC 1启动子序列富含GC并含有CpG岛，使其成为表观遗传调控的潜在靶点。拟议的研究旨在：1）检查发育过程中关闭纹状体AC 1表达的表观遗传机制; 2）测试以下假设：成年纹状体中重新唤醒AC 1表达将使运动习惯更容易改变。这些研究将指出未来潜在的表观遗传干预，可能能够通过逆转运动习惯来治疗药物添加。

DESCRIPTION (provided by applicant): While motor habits are important for the development of motor skills, aberrant motor habits are implicated in drug addiction. Motor habits are uniquely different from other types of memory. They take a long time to form and are hard to be modified. We hypothesize that this unique feature makes it hard to reverse aberrant motor habits in drug addiction. What makes motor habits different from other types of memory? The answer may lie in the unique signaling pathways in striatal medium spiny neurons (MSNs). The converged inputs to the MSNs from glutamatergic neurons in the cortex and from dopamine neurons in the midbrain are implicated in corticostriatal synaptic plasticity and habit learning. Based on published studies and studies done in our lab, we hypothesize that adenylyl cyclase type V (ACS) which is selectively and highly expressed in adult striatum is a key determinant of stability of corticostriatal synapses and stability of motor habits. However, during early postnatal development, adenylyl cyclase type I (AC1) rather than ACS is highly expressed in the striatum. In contrast to ACS which promotes synaptic stability, AC1 promotes synaptic plasticity. Therefore, the silencing of AC1 expression during postnatal development and emergence of ACS as the dominant isoform may be a major event in neural development that has corresponding behavioral consequences. The AC1 promoter sequence is GC rich and contains CpG islands, making it potential targets for epigenetic regulation. The proposed studies aim to 1) examine epigenetic mechanisms in turning off AC1 expression in striatum during development; 2) test the hypothesis that reawaking AC1 expression in adult striatum will make motor habits more susceptible for modifications. These studies will point to potential epigenetic interventions in the future that may be able to treat drug addition by reversing motor habits.