Role of lateral habenula in methamphetamine TAAR1-mediated synaptic plasticity and aversion
外侧缰核在甲基苯丙胺 TAAR1 介导的突触可塑性和厌恶中的作用
基本信息
- 批准号:10733665
- 负责人:
- 金额:$ 56.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-30 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAgonistAminesBehaviorBehavioralBilateralBrainBreedingCell NucleusCellsClustered Regularly Interspaced Short Palindromic RepeatsConsumptionDataDependenceDiseaseDopamineDorsalDoseDrug Use DisorderElectrophysiology (science)G-Protein-Coupled ReceptorsGeneticGenotypeGlutamate ReceptorGlutamate TransporterGlutamatesGoalsHabenulaInjectionsIntakeKnock-inKnock-in MouseLabelLaboratoriesLateralLesionMediatingMediationMembraneMembrane Transport ProteinsMethamphetamineMethamphetamine dependenceMotivationMusNeuronsPathway interactionsPatternPharmaceutical PreparationsPhysiologicalPresynaptic TerminalsPropertyPublishingRegulationResearchRewardsRisk ReductionRoleSerotoninSerotonin AgonistsSignal TransductionSliceSynapsesSynaptic plasticityTestingTherapeuticTracerVentral Tegmental AreaWild Type MouseWith lateralitybehavioral studydopamine transporterdopaminergic neuroneffective therapyexcitatory amino acid transporter 3experienceextracellularin vivomethamphetamine actionmethamphetamine effectmethamphetamine usemonoamineneural circuitneurotransmitter releaseoptogeneticspatch clamppresynapticreceptorretrograde transportserotonin transportertool
项目摘要
PROJECT SUMMARY
Considerable research has focused on drug use disorders as motivational disorders involving inherent or drug-
induced reward pathway function. However, the focus of this application is on opposing aversive effects of
methamphetamine (MA) that may curb its use, which have been little studied. The Richards (Phillips)
laboratory identified the trace amine associated receptor 1 (TAAR1) as a critical target impacting MA-induced
aversion. TAAR1 is an intracellularly located G protein-coupled receptor. MA gains access to TAAR1 only if it
is transported into the cell. This occurs via extracellular membrane transporters, such as dopamine and
serotonin transporters, DAT and SERT, respectively. We propose that TAAR1 activation by MA in dopamine
and serotonin neurons is responsible for MA-induced aversion and that monoaminergic circuit interactions with
the lateral habenula (LHb) are of particular importance. The overarching goal of the studies proposed in this
application is to understand the monoaminergic neuron-LHb interactions responsible for the experience of MA-
induced aversion via TAAR1 that may reduce risk for MA use. Our preliminary data show that MA activates
lateral habenula (LHb) neurons, specifically in mice with functional TAAR1. The studies in Aim 1 will use slice
electrophysiology to examine the TAAR1-dependent effects of MA in ventral tegmental area dopamine and
dorsal raphe serotonin neurons, comparing slices from wildtype and CRISPRed knock-in mice, mice that have
functional vs. nonfunctional TAAR1, respectively. Aim 1 studies will also use optogenetic stimulation to
examine the effects of MA on glutamatergic synapses from the LHb. Based on our published findings,
functional behavioral studies in this aim will examine the role of a glutamate receptor subunit, GluN2B, on MA
aversion and intake. Aim 2 will perform behavioral studies focused on the LHb, which has been shown to
mediate other types of aversion, has not been studied for MA aversion. We will ablate the LHb in mice with
and without functional TAAR1 and study the impact on MA aversion and intake. Finally, Aim 3 studies will use
a retrograde tracer to identify the LHb neurons that project to either the ventral tegmentum or dorsal raphe.
Electrophysiological studies will determine whether dopamine or serotonin modulate MA activation of LHb
neurons and determine whether MA activation of TAAR1 in presynaptic terminals of ventral tegmental area
dopamine neurons or dorsal raphe serotonin neurons regulate the effects of MA using slices from mice with
and without functional TAAR1. Thus, this proposal utilizes genetic tools, circuit analysis via electrophysiology
and behavioral analysis to identify how MA engages LHb neurons in a TAAR1-dependent manner, whether
LHb circuits are necessary for MA-induced aversion behaviors, and whether they inhibit MA intake. This
strategy could be used to study effects of MA on TAAR1 signaling in other regions. The study of mechanisms
underlying sensitivity to MA-induced aversion could lead to the identification of a new class of therapeutics.
项目概要
大量研究集中在药物使用障碍作为涉及固有或药物的动机障碍。
诱导奖赏通路功能。然而,本申请的重点是反对
甲基苯丙胺(MA)可能会限制其使用,但对此的研究很少。理查兹 (菲利普斯)
实验室确定微量胺相关受体 1 (TAAR1) 是影响 MA 诱导的关键靶点
厌恶。 TAAR1 是一种位于细胞内的 G 蛋白偶联受体。仅当 MA 获得对 TAAR1 的访问权时,
被输送到细胞内。这是通过细胞外膜转运蛋白发生的,例如多巴胺和
血清素转运蛋白分别为 DAT 和 SERT。我们认为多巴胺中的 MA 可以激活 TAAR1
血清素神经元负责 MA 诱导的厌恶以及单胺能回路与
外侧缰核 (LHb) 特别重要。本研究提出的总体目标
应用程序是为了了解单胺能神经元 - LHb 相互作用,负责 MA- 的体验
通过 TAAR1 诱导厌恶,可能会降低使用 MA 的风险。我们的初步数据显示 MA 激活
外侧缰核 (LHb) 神经元,特别是在具有功能性 TAAR1 的小鼠中。目标 1 中的研究将使用切片
电生理学检查 MA 对腹侧被盖区多巴胺和 TAAR1 依赖性的影响
中缝背侧血清素神经元,比较野生型和 CRISPR 敲入小鼠的切片,
分别是功能性 TAAR1 和非功能性 TAAR1。目标 1 研究还将利用光遗传学刺激
检查 MA 对 LHb 谷氨酸能突触的影响。根据我们发表的调查结果,
此目的的功能行为研究将检查谷氨酸受体亚基 GluN2B 对 MA 的作用
厌恶和摄入。目标 2 将进行针对 LHb 的行为研究,该研究已被证明可以
调解其他类型的厌恶,尚未针对 MA 厌恶进行研究。我们将用以下方法消融小鼠的 LHb:
以及没有功能性 TAAR1 并研究对 MA 厌恶和摄入的影响。最后,Aim 3 研究将使用
一种逆行示踪剂,用于识别投射到腹侧被盖或中缝背侧的 LHb 神经元。
电生理学研究将确定多巴胺或血清素是否调节 LHb 的 MA 激活
神经元并确定腹侧被盖区突触前末梢 TAAR1 的 MA 激活是否
多巴胺神经元或中缝背侧血清素神经元使用小鼠切片调节 MA 的作用
并且没有功能性 TAAR1。因此,该提案利用遗传工具,通过电生理学进行电路分析
和行为分析以确定 MA 如何以 TAAR1 依赖性方式参与 LHb 神经元,是否
LHb 回路对于 MA 引起的厌恶行为以及它们是否抑制 MA 的摄入是必需的。这
策略可用于研究 MA 对其他区域 TAAR1 信号传导的影响。机制研究
对 MA 引起的厌恶的潜在敏感性可能会导致一类新疗法的鉴定。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Susan L Ingram其他文献
Susan L Ingram的其他文献
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{{ truncateString('Susan L Ingram', 18)}}的其他基金
Role of pre- and postsynaptic mu opioid receptors in antinociception and tolerance
突触前和突触后μ阿片受体在镇痛和耐受中的作用
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9107437 - 财政年份:2015
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使用荧光生物传感器监测树突状 DAT 活性
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Dendritic DAT activity monitored with fluorescent biosensors
使用荧光生物传感器监测树突状 DAT 活性
- 批准号:
7524822 - 财政年份:2008
- 资助金额:
$ 56.56万 - 项目类别:
Dendritic DAT activity monitored with fluorescent biosensors
使用荧光生物传感器监测树突状 DAT 活性
- 批准号:
8044143 - 财政年份:2008
- 资助金额:
$ 56.56万 - 项目类别:
Dendritic DAT activity monitored with fluorescent biosensors
使用荧光生物传感器监测树突状 DAT 活性
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7628408 - 财政年份:2008
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Dendritic DAT activity monitored with fluorescent biosensors
使用荧光生物传感器监测树突状 DAT 活性
- 批准号:
8302583 - 财政年份:2008
- 资助金额:
$ 56.56万 - 项目类别:
Dendritic DAT activity monitored with fluorescent biosensors
使用荧光生物传感器监测树突状 DAT 活性
- 批准号:
8245828 - 财政年份:2008
- 资助金额:
$ 56.56万 - 项目类别:
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6955074 - 财政年份:2005
- 资助金额:
$ 56.56万 - 项目类别:
Dendritic DAT Conductances in Psychostimulant Addiction
精神兴奋剂成瘾中的树突 DAT 电导
- 批准号:
7082969 - 财政年份:2005
- 资助金额:
$ 56.56万 - 项目类别:
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