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:10591507
- 负责人:
- 金额:$ 53.17万
- 依托单位:
- 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:
- 关键词:A kinase anchoring proteinAMPA ReceptorsAffectBehaviorBehavior TherapyBindingBiochemicalBrainBrain regionC-terminalCalcineurinCell NucleusCellsCocaineCocaine DependenceCocaine UsersComplexCouplingCuesCyclic AMP-Dependent Protein KinasesDevelopmentDopamineDopamine D1 ReceptorDorsalElectrophysiology (science)EventExtinctionFiberGene ExpressionGeneticGenetic TranscriptionHeterodimerizationHippocampusHumanImageImaging TechniquesImpairmentIndividualKnock-outKnowledgeLaboratoriesLearningMaintenanceMapsMediatingMemoryModificationMolecularMonitorMusMutant Strains MiceNeuronsNuclear TranslocationPeptidesPermeabilityPharmaceutical PreparationsPharmacotherapyPhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPhotometryPre-Clinical ModelProcessPropertyProtein BiosynthesisProtein DeficiencyProteinsRegional AnatomyRegulationRelapseResistanceRewardsRodentRoleScaffolding ProteinSignal TransductionSignaling MoleculeSiteSliceSocietiesStudy modelsSurfaceSynapsesSynaptic plasticityTechniquesTestingTrainingVariantViralWorkaddictionbehavior testbrain reward regionscell typecocaine relapse preventioncocaine seekingcocaine useconditioned place preferencecostdentate gyrusdrug of abuseexperiencegain of functiongranule cellhippocampal subregionsimprovedin vivoin vivo calcium imagingknock-downlearning extinctionmutantneuromechanismnovelnuclear factors of activated T-cellspharmacologicprotein protein interactionrecruitrelapse preventionsensorsmall hairpin RNAtranscription factortranscription 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
可卡因成瘾给社会和个人带来了高昂的代价,迄今为止还没有药物治疗。
行为疗法无法有效预防复发;事实上,70-80%的可卡因使用者会经历
治疗后复发。预防可卡因复吸是毒品和犯罪问题办公室面临的主要挑战,
可卡因依赖者的治疗。导致复发的众多因素之一是
可卡因等药物滥用与环境背景之间的联系异常强烈
和药物的有益特性。因此,了解负责
这些药物背景的关联以及我们可以克服它们的方法,对于开发
改善治疗选择。背侧海马(dHPC),众所周知其在学习和记忆中的作用,
是可卡因相关的重要解剖区域。尽管有这些知识,
可卡因成瘾的大脑区域仍然研究不足。我们实验室的工作已经确定了一个新的角色
对于可卡因相关背景记忆消退中dHPC中的Cav1.2 L型Ca 2+通道(LTCC),
这与它们在某些形式的突触可塑性基础上的突触依赖性中的众所周知的作用一致。
学习/记忆灭绝学习涉及到一种新的学习形式,这种学习形式能够超越原始的学习形式。
记忆,特别是适应不良的记忆。因此,Cav1.2通道作为一个有前途的候选者,
排除毒品关联使用可卡因条件性位置偏爱(CPP),一个临床前模型
用于研究可卡因相关的上下文记忆,我们发现,可卡因CPP的消退增加,
Cav1.2及其磷酸化形式在背侧齿状回(dDG),海马
亚区,多巴胺D1受体细胞类型依赖性的方式。这与越来越多的证据相一致,
dHPC多巴胺对学习/记忆机制的作用,包括可卡因背景记忆。我们
分子研究已经确定,消光增加了dDG中的关键信号分子。这些包括
AKAP 150锚定蛋白、PKA、NFATc 3和AMPA受体的GluA 1亚基。因此,在本申请中,
我们的目标是利用这些知识,进一步探索dDG Cav1.2通道机制在灭绝的,
可卡因相关的记忆我们将测试中心假设,即情境消退学习招募
Cav1.2通道机制在dDG突触通过招募多巴胺D1 R信号。我们将使用一个组合
遗传学、药理学、电生理学和体内钙成像技术与行为测试
对于拟议的研究。目的1将测试AKAP-PKA-Cav1.2信号传导的参与。目标2将解决
AKAP-CaN-NFAT信号传导和Aim 3的参与将检查D1 R信号传导在可卡因中的作用。
CPP消退和dDG细胞活性。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Anjali M RAJADHYAKSHA其他文献
Anjali M RAJADHYAKSHA的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Anjali M RAJADHYAKSHA', 18)}}的其他基金
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
- 批准号:
10366896 - 财政年份:2022
- 资助金额:
$ 53.17万 - 项目类别:
The Role of Cav1.2 L-type Ca2+ Channels in Cocaine-Induced Reinstatement
Cav1.2 L 型 Ca2 通道在可卡因诱导恢复中的作用
- 批准号:
8373332 - 财政年份:2012
- 资助金额:
$ 53.17万 - 项目类别:
The Role of Cav1.2 L-type Ca2+ Channels in Cocaine-Induced Reinstatement
Cav1.2 L 型 Ca2 通道在可卡因诱导恢复中的作用
- 批准号:
9109107 - 财政年份:2012
- 资助金额:
$ 53.17万 - 项目类别:
The Role of Cav1.2 L-type Ca2+ Channels in Cocaine-Induced Reinstatement
Cav1.2 L 型 Ca2 通道在可卡因诱导恢复中的作用
- 批准号:
8471683 - 财政年份:2012
- 资助金额:
$ 53.17万 - 项目类别:
The Role of Cav1.2 L-type Ca2+ Channels in Cocaine-Induced Reinstatement
Cav1.2 L 型 Ca2 通道在可卡因诱导恢复中的作用
- 批准号:
9059913 - 财政年份:2012
- 资助金额:
$ 53.17万 - 项目类别:
The Role of Cav1.2 L-type Ca2+ Channels in Cocaine-Induced Reinstatement
Cav1.2 L 型 Ca2 通道在可卡因诱导恢复中的作用
- 批准号:
8657167 - 财政年份:2012
- 资助金额:
$ 53.17万 - 项目类别:
The Role of Cav1.2 L-type Ca2+ Channels in Cocaine-Induced Reinstatement
Cav1.2 L 型 Ca2 通道在可卡因诱导恢复中的作用
- 批准号:
8657425 - 财政年份:2012
- 资助金额:
$ 53.17万 - 项目类别:
The Role of Cav1.2 L-type Ca2+ Channels in Cocaine-Induced Reinstatement
Cav1.2 L 型 Ca2 通道在可卡因诱导恢复中的作用
- 批准号:
8835085 - 财政年份:2012
- 资助金额:
$ 53.17万 - 项目类别:
The Role of Cav1.2 L-type Ca2+ Channels in Cocaine-Induced Reinstatement
Cav1.2 L 型 Ca2 通道在可卡因诱导恢复中的作用
- 批准号:
9058007 - 财政年份:2012
- 资助金额:
$ 53.17万 - 项目类别:
相似海外基金
Role of PSD-95-linked PDE4A5 in Regulation of AMPA Receptors
PSD-95 连接的 PDE4A5 在 AMPA 受体调节中的作用
- 批准号:
10829146 - 财政年份:2023
- 资助金额:
$ 53.17万 - 项目类别:
The role of AMPA receptors in critical period plasticity in the auditory cortex
AMPA 受体在听觉皮层关键期可塑性中的作用
- 批准号:
RGPIN-2018-06552 - 财政年份:2022
- 资助金额:
$ 53.17万 - 项目类别:
Discovery Grants Program - Individual
In vivo Probe for ionotropic glutamate signaling system: AMPA receptors
离子型谷氨酸信号系统体内探针:AMPA 受体
- 批准号:
10584340 - 财政年份:2022
- 资助金额:
$ 53.17万 - 项目类别:
The role of AMPA receptors in critical period plasticity in the auditory cortex
AMPA 受体在听觉皮层关键期可塑性中的作用
- 批准号:
RGPIN-2018-06552 - 财政年份:2021
- 资助金额:
$ 53.17万 - 项目类别:
Discovery Grants Program - Individual
The role of AMPA receptors in critical period plasticity in the auditory cortex
AMPA 受体在听觉皮层关键期可塑性中的作用
- 批准号:
RGPIN-2018-06552 - 财政年份:2020
- 资助金额:
$ 53.17万 - 项目类别:
Discovery Grants Program - Individual
Binding of Endophilin Endocytic Proteins to AMPA Receptors and Neuronal Voltage-gated Potassium (Kv) Channels: Regulation of Synaptic Plasticity
内亲素内吞蛋白与 AMPA 受体和神经元电压门控钾 (Kv) 通道的结合:突触可塑性的调节
- 批准号:
RGPIN-2015-03850 - 财政年份:2019
- 资助金额:
$ 53.17万 - 项目类别:
Discovery Grants Program - Individual
The missing link: Opioid modulation of AMPA receptors
缺失的环节:阿片类药物对 AMPA 受体的调节
- 批准号:
2253144 - 财政年份:2019
- 资助金额:
$ 53.17万 - 项目类别:
Studentship
Calcium-permeable AMPA receptors and their auxiliary subunits: pharmacological and molecular intervention in health and disease
钙渗透性 AMPA 受体及其辅助亚基:健康和疾病的药理学和分子干预
- 批准号:
MR/T002506/1 - 财政年份:2019
- 资助金额:
$ 53.17万 - 项目类别:
Research Grant
The role of AMPA receptors in critical period plasticity in the auditory cortex
AMPA 受体在听觉皮层关键期可塑性中的作用
- 批准号:
RGPIN-2018-06552 - 财政年份:2019
- 资助金额:
$ 53.17万 - 项目类别:
Discovery Grants Program - Individual
Life cycle of AMPA receptors under acute metabolic stress
急性代谢应激下 AMPA 受体的生命周期
- 批准号:
411538084 - 财政年份:2018
- 资助金额:
$ 53.17万 - 项目类别:
Research Units