Investigating the mechanistic contribution of Cav1.2 channels in extinction of cocaine-associated memories

研究 Cav1.2 通道在可卡因相关记忆消退中的机制贡献

基本信息

批准号：
10366896
负责人：
Anjali M RAJADHYAKSHA
金额：
$ 53.17万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366896
关键词：
A kinase anchoring protein AMPA Receptors Address Affect Anatomy Behavior Behavior Therapy Binding Biochemical Brain Brain region C-terminal Calcineurin Cell Nucleus Cells Cocaine Cocaine Dependence Cocaine Users Complex Coupling Cues Cyclic AMP-Dependent Protein Kinases Development Dopamine Dopamine D1 Receptor Dorsal Electrophysiology (science)Event Extinction (Psychology)Fiber Gene Expression Genetic Genetic Transcription Heterodimerization Hippocampus (Brain)Human Image Imaging Techniques Impairment Individual Knock-out Knowledge Laboratories Learning Maintenance Maps Mediating Memory Modification Molecular Monitor Mus Mutant Strains Mice Neurons Nuclear Translocation Peptides Permeability Pharmaceutical Preparations Pharmacology Pharmacotherapy Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Photometry Pre-Clinical Model Process Property Protein Biosynthesis Proteins Regulation Relapse Resistance Rewards Rodent Role Scaffolding Protein Signal Transduction Signaling Molecule Site Slice Societies Study models Surface Synapses Synaptic plasticity Techniques Testing Training Variant Viral Work addiction behavior test brain reward regions cell type cocaine relapse prevention cocaine use conditioned place preference cost dentate gyrus drug of abuse experience gain of function granule cell hippocampal subregions improved in vivo in vivo calcium imaging knock-down learning extinction mutant neuromechanism novel prevent protein protein interaction recruit sensor small hairpin RNA transcription factor transcription factor NF-AT c3

项目摘要

Project Summary Cocaine addiction exerts a high cost on society and individuals and to date no pharmacotherapies exist. Behavioral therapies are not effective at preventing relapse; indeed, 70-80% of cocaine users will experience relapse following therapy. Preventing relapse to cocaine use represents the primary challenge that exists for the treatment of cocaine dependent individuals. One of the many factors that contribute to relapse is the exceptionally strong associations that drugs of abuse, such as cocaine make between environmental contexts and the rewarding properties of the drug. Thus, understanding the neural mechanisms that are responsible for these drug-context associations and ways in which we can override them, is critical for the development of improved treatment options. The dorsal hippocampus (dHPC), well known for its role in learning and memory, is an important anatomical region involved in cocaine-context associations. Despite this knowledge, the role of this brain region in cocaine addiction remains understudied. Work from our laboratory has identified a novel role for the Cav1.2 L-type Ca2+ channel (LTCC) in the dHPC in extinction of cocaine-associated contextual memories, consistent with their well-known role in hippocampal-dependent synaptic plasticity underlying certain forms of learning/memory. Extinction learning involves a new form of learning that is capable of overriding original memories, particularly maladaptive memories. Thus Cav1.2 channels serve as a promising candidate for overriding drug-context associations. Using the cocaine conditioned place preference (CPP), a preclinical model used to study cocaine-associated contextual memories, we find that extinction of cocaine CPP increases synaptic levels of Cav1.2 and its phosphorylated form in the dorsal dentate gyrus (dDG), a hippocampal subregion, in a dopamine D1 receptor cell type-dependent manner. This is consistent with growing evidence for a role of dHPC dopamine for learning/memory mechanisms including cocaine contextual memories. Our molecular studies have identified that extinction increases key signaling molecules in the dDG. These include AKAP150 anchoring protein, PKA, NFATc3 and the GluA1 subunit of AMPA receptors. Thus, in this application we aim to capitalize on this knowledge to further explore dDG Cav1.2 channel mechanisms in extinction of cocaine-associated memories. We will test the central hypothesis that contextual extinction learning recruits Cav1.2 channel mechanisms at dDG synapses via recruiting dopamine D1R signaling. We will use a combination of genetic, pharmacological, electrophysiological, and in vivo calcium imaging techniques with behavioral testing for the proposed studies. Aim 1 will test the involvement of AKAP-PKA-Cav1.2 signaling. Aim 2 will address the involvement of AKAP-CaN-NFAT signaling and Aim 3 will examine the contribution of D1R signaling, in cocaine CPP extinction and dDG cell activity.

项目摘要可卡因成瘾对社会和个人施加了很高的成本，迄今为止不存在任何药物治疗。行为疗法无效预防复发。实际上，有70-80％的可卡因用户会体验到治疗后复发。防止可卡因的复发代表了存在的主要挑战可卡因依赖人的治疗。导致复发的众多因素之一是滥用药物（例如可卡因）在环境环境之间产生的滥用药物非常强烈以及该药物的奖励特性。因此，了解负责的神经机制这些药物秘密关联以及我们可以覆盖它们的方式，对于发展至关重要改进的治疗选择。背侧海马（DHPC）以其在学习和记忆中的作用而闻名，是与可卡因秘密关联有关的重要解剖区域。尽管有这些知识，但可卡因成瘾中的这个大脑区域仍在研究中。我们实验室的工作已经确定了一个新颖的角色对于可卡因相关的上下文记忆中的DHPC中的Cav1.2 L型Ca2+通道（LTCC），与它们在海马依赖性突触可塑性中的众所周知的作用一致学习/记忆。灭绝学习涉及一种能够覆盖原始的新的学习形式记忆，尤其是适应不良的回忆。因此，CAV1.2通道是有前途的候选人覆盖毒品秘密关联。使用可卡因条件的位置偏好（CPP），临床前模型用于研究可卡因相关的上下文记忆，我们发现可卡因CPP的灭绝增加了 Cav1.2的突触水平及其磷酸化形式在背齿回（DDG）中，一种海马子区域，以多巴胺D1受体细胞类型依赖性方式。这与越来越多的证据一致 DHPC多巴胺在学习/记忆机制中的作用，包括可卡因上下文记忆。我们的分子研究已经确定，灭绝会增加DDG中的关键信号分子。这些包括 AKAP150锚定蛋白，PKA，NFATC3和AMPA受体的GLUA1亚基。因此，在此应用程序中我们旨在利用这些知识，以进一步探索DDG CAV1.2灭绝的渠道机制可卡因相关的记忆。我们将测试上下文灭绝学习新兵的中心假设 CAV1.2通过募集多巴胺D1R信号传导DDG突触的通道机制。我们将使用一个组合通过行为测试的遗传，药理，电生理和体内钙成像技术对于拟议的研究。 AIM 1将测试AKAP-PKA-CAV1.2信号传导的参与。 AIM 2将解决 AKAP-CAN-NFAT信号和AIM 3的参与将检查可卡因D1R信号的贡献 CPP灭绝和DDG细胞活性。