Genetic dissection of ventral tegmental area glutamate and GABA neurons in reward and aversion
腹侧被盖区谷氨酸和 GABA 神经元奖励和厌恶的遗传解剖
基本信息
- 批准号:9886524
- 负责人:
- 金额:$ 33.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2025-01-31
- 项目状态:未结题
- 来源:
- 关键词:Aversive StimulusBehaviorBehavioralBiological AssayBrainCalciumCuesDataDiseaseDissectionDopamineDrug AddictionGeneticGlutamatesHabenulaImageIndividualInterventionLateralLearningLiteratureMapsMediatingModelingMotivationNeuromodulatorNeuronsNeurotransmittersNucleus AccumbensOutputPathway interactionsPatternPhenotypePopulationRabies virusResearchRewardsRoleSelf StimulationSpecificityStimulusTechniquesTestingTimeTransgenic OrganismsTyrosine 3-MonooxygenaseVentral Tegmental AreaViralViral Vectoraddictionbasecalcium indicatorcell typecellular targetingconditioned place preferencedesigndopaminergic neurondrug rewardgamma-Aminobutyric Acidinnovationmotivated behaviorneuronal cell bodynoveloptogeneticsprogramspublic health relevanceresponsesensortoolvesicular glutamate transporter 2
项目摘要
Project Summary / Abstract
The ventral tegmental area (VTA) controls the motivation to pursue rewards and avoid harmful stimuli. Within
the last decade it has been shown that the VTA is populated by neurons that release the neuromodulator
dopamine, neurons that release the inhibitory neurotransmitter GABA, and neurons that release the excitatory
neurotransmitter glutamate. Based on the use of optogenetic techniques to manipulate dopamine, GABA, or
glutamate neurons, current models of VTA function postulate that reward and aversion-based motivation is
mediated by heterogeneous types of VTA neurons and their discrete neuronal networks. However, we have
recently discovered an unanticipated type of neuron in the VTA, those that release both glutamate and GABA.
The discovery of the VTA glutamate-GABA neurons redefines the GABA-releasing and glutamate-releasing
VTA cell-types by multiple genetic features: release of glutamate without GABA (glutamate-only neurons),
release of GABA without glutamate (GABA-only neurons), or release of both (glutamate-GABA neurons). While
optogenetic studies have shown roles of glutamate-releasing or GABA-releasing neurons in motivated
behavior, the redefinition of VTA glutamate and GABA-releasing neurons into three subtypes indicates that our
understanding of the VTA cell-type specific roles in motivated behavior is incomplete. We will use novel
intersectional and subtractive genetic and viral tools to identify the neuronal networks and roles in reward- or
aversion-mediated behavior of VTA glutamate-GABA, glutamate-only, and GABA-only neurons and circuits. In
Aim 1, we will comprehensively map the brain-wide inputs and outputs of VTA glutamate-GABA, glutamate-
only, and GABA-only neurons using cell-type specific anterograde tracing and monosynaptic retrograde tracing
with a modified rabies virus. In Aim 2, using the genetically encoded calcium indicator GCaMP6 we will identify
the neuronal activity patterns of VTA glutamate-GABA, glutamate-only, and GABA-only neurons, as well as the
neuronal activity patterns of major afferents that target each genetically separate VTA cell-type, in response to
rewarding and aversive stimuli and their predictors. Finally, we will optogenetically stimulate or inhibit VTA
glutamate-GABA, glutamate-only, and GABA-only neurons and circuits to define their causal contributions
towards motivated behavior. Preliminary data support the hypothesis that VTA glutamate-GABA, glutamate-
only, and GABA-only neurons have distinct neuronal networks and motivational functions. Together, these
studies will comprehensively redefine the motivational functions of VTA neurons and their individual circuits.
Results will provide new directions to alleviate reward and aversion based disorders such as addiction.
项目概要/摘要
腹侧被盖区(VTA)控制着追求奖励和避免有害刺激的动机。之内
在过去的十年中,研究表明 VTA 中充满了释放神经调节剂的神经元
多巴胺、释放抑制性神经递质 GABA 的神经元以及释放兴奋性神经递质的神经元
神经递质谷氨酸。基于使用光遗传学技术来操纵多巴胺、GABA 或
谷氨酸神经元,当前的 VTA 功能模型假设基于奖励和厌恶的动机是
由不同类型的 VTA 神经元及其离散神经元网络介导。然而,我们有
最近在 VTA 中发现了一种意想不到的神经元类型,即释放谷氨酸和 GABA 的神经元。
VTA谷氨酸-GABA神经元的发现重新定义了GABA释放和谷氨酸释放
VTA 细胞类型具有多种遗传特征:释放谷氨酸,不含 GABA(仅谷氨酸神经元),
释放不含谷氨酸的 GABA(仅含 GABA 的神经元),或同时释放两者(谷氨酸-GABA 神经元)。尽管
光遗传学研究表明,释放谷氨酸或释放 GABA 的神经元在激励中发挥作用。
行为,将 VTA 谷氨酸和 GABA 释放神经元重新定义为三种亚型表明我们的
对 VTA 细胞类型在动机行为中特定作用的理解并不完整。我们将用小说
交叉和减法遗传和病毒工具来识别神经元网络和奖励或奖励中的作用
VTA 谷氨酸-GABA、纯谷氨酸和纯 GABA 神经元和回路的厌恶介导行为。在
目标1,我们将全面绘制VTA谷氨酸-GABA、谷氨酸-的全脑输入和输出图谱
使用细胞类型特异性顺行追踪和单突触逆行追踪的仅限 GABA 神经元
带有改良的狂犬病病毒。在目标 2 中,使用基因编码的钙指示剂 GCaMP6,我们将识别
VTA 谷氨酸-GABA、纯谷氨酸和纯 GABA 神经元的神经元活动模式,以及
针对每个基因上独立的 VTA 细胞类型的主要传入神经元活动模式,响应
奖励性和厌恶性刺激及其预测因素。最后,我们将通过光遗传学刺激或抑制 VTA
谷氨酸-GABA、纯谷氨酸和纯 GABA 神经元和电路来定义其因果贡献
朝向动机行为。初步数据支持以下假设:VTA 谷氨酸-GABA、谷氨酸-
仅和仅 GABA 神经元具有不同的神经元网络和激励功能。在一起,这些
研究将全面重新定义 VTA 神经元及其个体回路的激励功能。
研究结果将为缓解成瘾等基于奖赏和厌恶的疾病提供新的方向。
项目成果
期刊论文数量(0)
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{{ truncateString('David H Root', 18)}}的其他基金
Genetic dissection of ventral tegmental area glutamate and GABA neurons in reward and aversion
腹侧被盖区谷氨酸和 GABA 神经元奖励和厌恶的遗传解剖
- 批准号:
10554308 - 财政年份:2020
- 资助金额:
$ 33.6万 - 项目类别:
Genetic dissection of ventral tegmental area glutamate and GABA neurons in reward and aversion
腹侧被盖区谷氨酸和 GABA 神经元奖励和厌恶的遗传解剖
- 批准号:
10347366 - 财政年份:2020
- 资助金额:
$ 33.6万 - 项目类别:
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