Elucidating Ih Biophysical Epigenetic Modifications in VTA Dopaminergic Neurons after Contingent and Non-Contingent Cocaine Administration

摘要 腹侧被盖区（VTA）是中枢神经系统中参与奖赏和强化的关键区域 天然物质和毒品，如可卡因。超极化激活阳离子电流（Ih） 是多巴胺能（DA）神经元的基本内在特性的关键参与者， VTA。携带Ih的离子通道由HCN亚基组成，主要是HCN 2亚基。 VTA。可卡因致敏（CS）后，由于药物暴露，Ih发生了变化。 Ih的这种变化可能是中枢奖赏/强化的一种常见生理机制 导致成瘾的途径。表观遗传机制，如组蛋白去乙酰化， 负责慢性药物给药后发生的一些重要神经元变化。 本项目将研究CS发生发展过程中Ih功能的表观遗传调控 间歇性访问自我管理（IntA）模式。我们认为IntA更好 模拟人类吸毒具体目标包括：1）调查VTA CS、IntA和组蛋白脱乙酰酶抑制剂（HDACi）后的表观基因组谱; 2） 电生理检查CS、IntA和HDACi后VTA DA神经元中的Ih; 3）To 测量CS、IntA和HDACi后VTA中HCN 2亚基的变化; 4）为了研究是否 体内靶向HDAC 2的shRNA改变VTA DA的CS、IntA和Ih特性的发育 神经元检查可卡因引起的腹侧被盖区表观遗传学变化可以提供关键的 关于成瘾发展过程中发生的神经适应的信息。拨回 这些表观遗传修饰的组蛋白去乙酰化酶抑制可能提供了可能的 治疗性药理学干预的途径。

ABSTRACT The ventral tegmental area (VTA) is a key CNS region involved in the reward and reinforcement of natural substances and drugs, such as cocaine. Hyperpolarization-activated cation current (Ih) is a key participant in the fundamental intrinsic properties of dopaminergic (DA) neurons of the VTA. The ion channels that carry Ih are comprised of HCN subunits, predominantly the HCN2 in the VTA. Alteration of Ih due to drug exposure has been shown after cocaine sensitization (CS). This change in Ih may be a common physiological mechanism in central reward/reinforcement pathways that contributes to addiction. Epigenetic mechanisms like histone deacetylation are responsible for some crucial neuronal changes that occur following chronic drug administration. This project will study the epigenetic regulation of the Ih function during the development of CS and on the Intermittent access self-administration (IntA) model. The IntA in our opinion better simulates human drug consumption. The specific aims will include: 1) To investigate the VTA epigenomic profile after CS, IntA and Histone Deacetylase inhibitor (HDACi); 2) Electrophysiological examination of Ih in VTA DA neurons after CS, IntA and HDACi; 3) To measure changes in HCN2 subunits in the VTA after CS, IntA and HDACi; 4) To investigate if in vivo shRNA targeting HDAC2 alters the development of CS, IntA and Ih properties of VTA DA neurons. Examination of cocaine-induced epigenetic changes in the VTA can provide key information about neuroadaptations that occur during the development of addiction. The reversal of these epigenetic modifications by histone deacetylase inhibition might provide possible avenues for therapeutic pharmacological intervention.