Epigenetic mechanisms in the medial habenula governing drug-seeking behavior
Epigenetic mechanisms in the medial habenula governing drug-seeking behavior
批准号:
10210374
负责人:
GARY S LYNCH
金额:
$63.75万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-07-15 至 2025-04-30
关键词:
AbstinenceAdultAffectAnimalsBehaviorBindingBrainBrain regionCell physiologyChIP-seqCharacteristicsCholine O-AcetyltransferaseChromatin StructureChronicCocaineCuesDNA SequenceDataDeacetylaseDevelopmentDiseaseDominant-Negative MutationDopamineDrug ExposureDrug TargetingEpigenetic ProcessExposure toGene ExpressionGene Expression RegulationGenesHDAC3 geneHDAC4 geneHabenulaHistone AcetylationHumanKnowledgeLearningLightMedialMediatingMemoryMethodsMidbrain structureMolecularMusNR4A2 geneNatureNeuronal PlasticityNeuronsNicotine WithdrawalNicotinic ReceptorsNucleus AccumbensPathway interactionsPharmaceutical PreparationsPhysiological ProcessesPhysiologyPreparationPublishingRNA SplicingRelapseRewardsRoleSignal TransductionSliceSocial ImpactsSubstance Use DisorderSynapsesSynaptic TransmissionTestingUnited StatesVariantWorkaddictioncell typecholinergic neurondesigner receptors exclusively activated by designer drugsdrug of abusedrug seeking behaviordrug use behavioreconomic impactepigenetic regulationinterpeduncular nucleusmemory consolidationmemory processmutantneuropsychiatric disordernicotine seeking behaviornovelpromoterresponsereward circuitrysubstance use treatmenttargeted treatmenttranscription factortranscriptome sequencing
中文摘要
项目摘要
成瘾作为一种慢性神经精神疾病,与特定的分子和功能相关,
神经元可塑性变化是由反复药物暴露引发的,导致持续的变化,
神经元功能和最终的行为。一个强大的机制可能是这方面的基础,
坚持就是表观遗传学表观遗传学(即通过改变基因表达而发生的基因表达调节)
DNA序列本身没有根本变化的染色质结构)已被证明可以建立
细胞功能的稳定变化。细胞功能的这些稳定变化可以引起细胞内的显著变化,
许多层次的观察(例如神经元可塑性,行为)。目前,我们对这一现象仍知之甚少。
表观遗传机制,可以建立持久性特征的药物寻求行为,
这些机制是否也可能涉及复吸或其他类似复发的行为。这
这项提案的重点是研究可能涉及的分子和细胞机制,
复职更具体地说,我们将重点关注内侧缰核(MHb)在可卡因诱导的
恢复吸毒行为。大多数研究MHb的研究都集中在尼古丁上
寻找由于高浓度的烟碱乙酰胆碱受体发现整个中东
缰核-脚间核通路最近的研究已经开始暗示可卡因中含有MHb-
相关行为,但MHb在调节可卡因寻求行为恢复中的作用
仍然是未知的。事实上,MHb很少包含在奖励电路图中。我们最近
研究结果表明,MHb参与可卡因引发的恢复和胆碱的活性,
MHb中表达乙酰转移酶(ChAT)的神经元足以驱动恢复(洛佩斯等人,
2018年)。这些结果表明,MHb是复发样行为的有力调节因子,
这对理解与复发有关的大脑中的奖励途径具有重要意义。我们还将
研究组蛋白去乙酰化酶(HDAC 3)和关键的HDAC 3靶基因(Nr 4a 2)在
MHb依赖性药物寻求恢复。HDAC 3是记忆形成的关键负调节因子
以及通过抑制Nr 4a 2的表达而起作用的联合可塑性。NR 4A 2是一种转录物,
在发育过程中调节多巴胺信号的因子。HDAC 3和NR 4A 2都是
在ChAT表达神经元内的MHb中高度表达,表明这些重要的调节因子,
记忆过程在与MHb依赖性恢复相关的行为中具有中心作用。在这
建议,我们将测试中心假设,即MHb是可卡因恢复的关键调节器-
寻找行为,并以HDAC 3/NR 4A 2依赖的方式进行。成功完成这些
研究将证明MHb在恢复中的关键性质,确定恢复中的生理过程,
MHb对可卡因的反应,并确定MHb功能的关键表观遗传调节因子。
英文摘要
Project Summary
As a chronic neuropsychiatric disease, addiction is associated with specific molecular and functional
neuronal plasticity changes that are triggered by repeated drug exposure leading to persistent changes in
neuronal function and ultimately behavior. One powerful mechanism that may underlie aspects of this
persistence is epigenetics. Epigenetics (i.e. modulation of gene expression that occurs through altered
chromatin structure without fundamental changes to the DNA sequence itself) has been shown to establish
stable changes in cell function. These stable changes in cell function can give rise to remarkable changes at
many levels of observation (e.g. neuronal plasticity, behavior). Currently, we still know very little about the
epigenetic mechanisms that could establish the persistence characteristic of drug-seeking behavior and
whether such mechanisms may also be involved in reinstatement, or other relapse-like behaviors. This
proposal is focused on examining the molecular and cellular mechanisms that may be involved in
reinstatement. More specifically, we will focus on the role of the medial habenula (MHb) in cocaine-induced
reinstatement of drug-seeking behavior. Most studies investigating the MHb have focused on nicotine
seeking due to the high concentration of nicotinic acetylcholine receptors found throughout the medial
habenula-interpeduncular nucleus pathway. Recent studies have begun to implicate the MHb in cocaine-
associated behaviors, yet the role of the MHb in regulating reinstatement of cocaine-seeking behavior
remains largely unknown. In fact, the MHb is rarely included in reward circuitry diagrams. Our recent
findings demonstrate that the MHb is engaged by cocaine-primed reinstatement and the activity of choline
acetyltransferase (ChAT) expressing neurons in the MHb is sufficient to drive reinstatement (Lopez et al.,
2018). These results suggest that the MHb is a powerful regulator of relapse-like behaviors, which has
important implications for understanding the reward pathways in the brain related to relapse. We will also
examine the role of a histone deacetylase, called HDAC3, and a key HDAC3 target gene, called Nr4a2, in
MHb-dependent reinstatement of drug-seeking. HDAC3 is a key negative regulator of memory formation
and associative plasticity, which functions by repressing the expression of Nr4a2. NR4A2 is a transcription
factor that regulates aspects of dopamine signaling during development. Both HDAC3 and NR4A2 are
highly expressed in the MHb within ChAT expressing neurons, indicating these important regulators of
memory processes have a central role in behaviors associated with MHb-dependent reinstatement. In this
proposal, we will test the central hypothesis that the MHb is a key regulator of reinstatement of cocaine-
seeking behavior, and does so in an HDAC3/NR4A2-dependent manner. Successful completion of these
studies will demonstrate the key nature of the MHb in reinstatement, identify the physiological processes in
the MHb responding to cocaine, and identify key epigenetic regulators of MHb function.
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会议论文
Epigenetic mechanisms in the medial habenula governing drug-seeking behavior
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批准号:10612113
-
项目类别:
-
资助金额:$62.6万
-
财政年份:2020
-
负责人:GARY S LYNCH
-
依托单位:
Epigenetic mechanisms in the medial habenula governing drug-seeking behavior
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批准号:10382355
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项目类别:
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资助金额:$62.73万
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财政年份:2020
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负责人:GARY S LYNCH
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依托单位:
Epigenetic mechanisms in the medial habenula governing drug-seeking behavior
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批准号:10754682
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项目类别:
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资助金额:$6.46万
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财政年份:2020
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Role of Neuron-Specific Nucleosome Remodeling in Intellectual Disability
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批准号:9082570
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财政年份:2015
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依托单位:
Role of neuron-specific nucleosome remodeling in intellectual disability
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批准号:9272441
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依托单位:
Role of neuron-specific nucleosome remodeling in intellectual disability
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批准号:8560955
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项目类别:
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资助金额:$50.73万
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依托单位:
Role of neuron-specific nucleosome remodeling in intellectual disability
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批准号:8694099
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项目类别:
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资助金额:$43.67万
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财政年份:2013
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负责人:GARY S LYNCH
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依托单位:
Role of neuron-specific nucleosome remodeling in intellectual disability
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批准号:9069518
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项目类别:
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财政年份:2013
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Kinase Inhibitors against Neurodegeneration
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批准号:6736607
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财政年份:2004
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The Spine Cytoskeleton and Memory Disorders
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批准号:8723899
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项目类别:
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资助金额:$20.84万
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财政年份:2003
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负责人:GARY S LYNCH
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依托单位:
The Spine Cytoskeleton and Memory Disorders
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批准号:8533013
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项目类别:
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财政年份:2003
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Effects of Elevating Brain Derived Neurotrophic Factor on Hippocampal Physiology
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财政年份:2003
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依托单位:
The Spine Cytoskeleton and Memory Disorders
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批准号:8376695
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项目类别:
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资助金额:$21.52万
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财政年份:2003
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负责人:GARY S LYNCH
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依托单位:
The Spine Cytoskeleton and Memory Disorders
-
批准号:8121195
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项目类别:
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资助金额:$22.96万
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财政年份:2003
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负责人:GARY S LYNCH
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依托单位:
Integrin and LTP Consolidation
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批准号:6528653
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项目类别:
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资助金额:$20.9万
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财政年份:2001
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负责人:GARY S LYNCH
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依托单位:
Integrin and LTP Consolidation
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批准号:6400515
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项目类别:
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资助金额:$22.16万
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财政年份:2001
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负责人:GARY S LYNCH
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依托单位:
Integrin and LTP Consolidation
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批准号:6646452
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项目类别:
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资助金额:$20.9万
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财政年份:2001
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负责人:GARY S LYNCH
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依托单位:
LINKS BETWEEN PROTEOLYTIC PROCESSING AND BRAIN AGING
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项目类别:
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资助金额:$14.4万
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财政年份:1999
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负责人:GARY S LYNCH
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依托单位:
Integrins and LTP consolidation
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批准号:6985725
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项目类别:
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资助金额:$28.15万
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财政年份:1999
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依托单位:
Integrins and LTP consolidation
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项目类别:
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依托单位:
海外基金