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

消退由边缘下皮层和蛋白激酶 C epsilon 介导

• 批准号: 7902115
• 负责人: Philip M. Newton
• 金额: $ 4.13万
• 依托单位: ERNEST GALLO CLINIC AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7902115
• 关键词: Addictive Behavior; Amphetamines; Amygdaloid structure; Animals; Association Learning; Attention; Behavior Control; Behavioral; Biological; Biology; Brain; Brain region; Characteristics; Cocaine; Data; Department of Defense; Discrimination; Disease; Drug Addiction; Drug Delivery Systems; Enzymes; Epidemiology; Ethanol; Exhibits; Extinction (Psychology); Foundations; Functional Imaging; Funding; Knockout Mice; Lead; Lesion; Location; Measures; Medial; Mediating; Memory; Modeling; Molecular; Morphine; Motivation; Mus; Onset of illness; Patients; Pharmaceutical Preparations; Post-Traumatic Stress Disorders; Prefrontal Cortex; Process; RNA Interference; Signal Transduction; Site; Testing; addiction; base; classical conditioning; conditioned fear; conditioning; disorder prevention; drug of abuse; flexibility; forgetting; mouse model; preference; protein kinase C epsilon; public health relevance

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.

描述（由申请人提供）：成瘾和创伤后应激障碍（PTSD）被认为有共同的机制基础。这两种疾病的一个基本特征是前额叶皮层的活动受损，这可能存在于疾病发作之前，并导致巴甫洛夫条件反射的消退延迟。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。我们有数据显示，缺乏细胞内信号传导酶蛋白激酶C-κ B（PKC 5）的小鼠在创伤后应激障碍、成瘾和行为灵活性模型中表现出前额叶皮质功能受损的行为体征。这些数据表明，通过PKC 5的信号传导对于前额叶皮层的正常功能是必要的。在另一个由美国国防部资助的项目中，我们正在使用RNA干扰来确定PKC 5在条件恐惧消退中的解剖学作用部位，并测试PKC 5激活剂以确定它们是否可以加速条件恐惧的消退。目前，对介导条件性药物寻求消退的解剖学底物知之甚少。在这个建议中，我们将确定的神经解剖区域，调解灭绝的条件药物寻求使用病变的研究。我们还将确定增强获取过程是否会导致灭绝延迟。具体目的1药物条件性位置偏爱的消退是由边缘下皮层介导的我们将损伤小鼠的边缘下皮层或整个内侧前额叶皮层，然后检查可卡因、吗啡和乙醇条件性位置偏爱的消退。特异性目的两个PKC 5基因敲除小鼠表现出对可卡因和苯丙胺的条件性位置偏好延迟消退。我们目前的数据表明，PKC 5穆尔小鼠表现出延迟灭绝的条件位置偏好吗啡和乙醇。为了证实这种消退延迟也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性位置偏好的消退。特异性目的三PKC 5基因敲除小鼠表现出增强的条件性辨别能力。我们已经证明，PKC 5基因敲除小鼠表现出延迟巴甫洛夫条件反射的消退。这种延迟可能是通过“增强的获取”过程产生的，由此PKC 5缺失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大的注意力。我们将测量巴甫洛夫条件辨别任务的获得。 公共卫生关系：药物成瘾和创伤后应激障碍（PTSD）是经常一起发生的使人衰弱的疾病，这表明它们有着共同的生物学基础。流行病学、行为学和功能成像研究支持这一假设。这些研究的一个共同主题是，患者大脑中被称为前额叶皮层的部分功能受损。这个大脑区域控制动机和驱动力，以及促进忘记学习关联的能力（例如，可怕的记忆或药物与服用地点之间的关联）。我们有数据显示，缺乏细胞内信号传导酶蛋白激酶C-κ B（PKC 5）的小鼠在创伤后应激障碍、成瘾和行为灵活性模型中表现出前额叶皮质功能受损的行为体征。我们目前由美国国防部资助，以确定PKCe在大脑中的何处起作用，以控制PTSD小鼠模型的行为。在目前的提案中，我们将为确定PKC 5控制成瘾行为的大脑区域奠定基础。

项目成果

The biology of protein kinase C.

• DOI: 10.1007/978-94-007-2888-2_28
• 发表时间: 2012
• 期刊: Advances in experimental medicine and biology
• 作者: Lily Zeng;S. Webster;P. M. Newton