Extinction is mediated by the infralimbic cortex and protein kinase C epsilon

描述(由申请人提供)：成瘾和创伤后应激障碍(PTSD)被认为具有共同的机制基础。这两种疾病的一个基本特征是前额叶皮质的活动受损，这可能在疾病发作之前就存在，并导致巴甫洛夫条件反射消退的延迟。了解前额叶皮质功能的分子基础可能会发现治疗和预防这些疾病的药物靶点。我们有数据表明，缺乏细胞内信号酶蛋白激酶C-epsilon(PKC5)的小鼠，在创伤后应激障碍、成瘾和行为灵活性的模型中，表现出前额叶皮质功能受损的行为迹象。这些数据表明，通过PKC5发出的信号对于前额叶皮质的正常功能是必要的。在由美国国防部资助的另一个项目中，我们正在使用RNA干扰来确定PKC5在消退条件性恐惧中的作用部位，并测试PKC5激活剂，以确定它们是否可以加速消退条件性恐惧。目前，调节条件性药物寻求消亡的解剖学基础还知之甚少。在这项建议中，我们将利用病变研究来确定调节条件性药物寻求消亡的神经解剖学区域。我们还将确定加强收购过程是否会导致物种灭绝的延迟。特定目的1药物条件性位置偏爱的消退是由下缘皮质介导的。我们将损毁小鼠的下缘或整个前额叶皮质，然后观察对可卡因、吗啡和乙醇的条件性位置偏爱的消退。目的两只PKC5缺失的小鼠表现出对可卡因和苯丙胺的条件性偏爱的延迟灭绝。我们目前的数据表明，PKC5MULL小鼠表现出对吗啡和乙醇的条件性偏爱的条件消退延迟。为了证实这种消亡延迟适用于其他滥用药物，我们将研究可卡因和安非他明的条件地偏好的消亡。目的3只PKC5基因缺失小鼠表现出条件性辨别的增强习得。我们已经证明，PKC5缺失的小鼠表现出巴甫洛夫条件反射消失的延迟。这种延迟可能是由于“增强习得”过程而产生的，在这个过程中，PKC5缺失的动物能够更好地区分正确和不正确的选择，或者对正确的选择表现出更多的关注。我们将测量巴甫洛夫条件性辨别任务的习得。 公共卫生相关性：吸毒和创伤后应激障碍(PTSD)是经常同时发生的衰弱疾病，这表明它们具有共同的生物学基础。这一假说得到了流行病学、行为和功能成像研究的支持。这些研究的一个共同主题是，患者大脑中名为前额叶皮质的部分功能受损。这一大脑区域控制着动机和驱动力，并有助于忘记习得的联系(例如，可怕的记忆或毒品与服用地点之间的联系)。我们有数据表明，缺乏细胞内信号酶蛋白激酶C-epsilon(PKC5)的小鼠，在创伤后应激障碍、成瘾和行为灵活性的模型中，表现出前额叶皮质功能受损的行为迹象。我们目前由美国国防部资助，以确定PKCE在大脑的哪里控制创伤后应激障碍小鼠模型的行为。在目前的提案中，我们将为确定PKC5控制成瘾行为的大脑区域的提案奠定基础。

DESCRIPTION (provided by applicant): Addiction and posttraumatic stress disorder (PTSD) have been proposed to share a common mechanistic basis. A fundamental characteristic of both disorders is impaired activity of the prefrontal cortex, which may exist prior to disease onset and lead to a delay in the extinction of Pavlovian conditioning. Understanding the molecular basis of prefrontal cortex function may uncover drug targets for the treatment and prevention of these disorders. We have data showing that mice lacking an intracellular signaling enzyme, protein kinase C-epsilon (PKC5), exhibit behavioral signs of impaired prefrontal cortex function in models of PTSD, addiction and behavioral flexibility. These data suggest that signaling through PKC5 is necessary for normal functioning of the prefrontal cortex. In a separate project, funded by the US Department of Defense, we are using RNA-interference to identify the anatomical site of action for PKC5 in the extinction of conditioned fear as well as testing PKC5 activators to determine if they can accelerate the extinction of conditioned fear. Currently the anatomical substrates that mediate the extinction of conditioned drug seeking are poorly understood. In this proposal we will identify the neuroanatomical regions that mediate the extinction of conditioned drug seeking using lesion studies. We will also determine whether enhancing the acquisition process leads to a delay in extinction. SPECIFIC AIM ONE Extinction of a drug conditioned place preference is mediated by the infralimbic cortex We will lesion the infralimbic or entire medial prefrontal cortex of mice and then examine the extinction of a conditioned place preference for cocaine, morphine and ethanol. SPECIFIC AIM TWO PKC5 null mice show delayed extinction of a conditioned place preference for cocaine and amphetamine. Our current data demonstrate that PKC5 mull mice exhibit delayed extinction to a conditioned place preference for morphine and ethanol. To confirm that this extinction delay generalizes to other drugs of abuse, we will examine the extinction of a conditioned place preference for both cocaine and amphetamine. SPECIFIC AIM THREE PKC5 null mice show enhanced acquisition of conditioned discrimination. We have shown that PKC5 null mice exhibit a delay in the extinction of Pavlovian conditioning. It is possible that this delay arises through an "enhanced acquisition" process, whereby PKC5 null animals are better able to discriminate between correct and incorrect choices, or display greater attention to the correct choice. We will measure the acquisition of a Pavlovian conditioned discrimination task. PUBLIC HEALTH RELEVANCE: Drug addiction and posttraumatic stress disorder (PTSD) are debilitating conditions that often occur together, suggesting that they share a common biological basis. This hypothesis is supported by epidemiological, behavioral and functional imaging studies. A common theme of these studies is that patients have impaired function of a part of their brain called the prefrontal cortex. This brain region controls motivation and drive, as well as facilitating the ability to forget learned associations (for example, fearful memories or associations between drugs and the location in which they were taken). We have data showing that mice lacking an intracellular signaling enzyme, protein kinase C-epsilon (PKC5), exhibit behavioral signs of impaired prefrontal cortex function in models of PTSD, addiction and behavioral flexibility. We are currently funded by the US Department of Defense to determine where in the brain PKCe acts to control behavior in a mouse model of PTSD. In the current proposal, we will lay the foundations for proposals to determine the brain regions in which PKC5 acts to control addictive behavior.