Elucidating input-output relations of rewarding and aversive VTA dopamine neurons

阐明奖励性和厌恶性 VTA 多巴胺神经元的输入输出关系

• 批准号: 8832974
• 负责人: KEVIN T BEIER
• 金额: $ 5.42万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-02 至 2016-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832974
• 关键词: Address; Affect; Animal Behavior; Area; Aversive Stimulus; Behavior; Behavior Therapy; Behavioral; Brain; Brain Diseases; Brain region; Cell Nucleus; Combination Drug Therapy; Controlled Study; Data; Development; Dopamine; Drug Addiction; Drug abuse; Economic Burden; Electric Stimulation; Electrophysiology (science); Excitatory Synapse; Foundations; Functional disorder; Future; Genetic; Hypothalamic structure; Intervention; Knowledge; Lateral; Lead; Learning; Link; Maps; Measures; Medial; Mental disorders; Modification; Molecular Profiling; Neurons; Nucleus Accumbens; Output; Pathway interactions; Pattern; Pharmaceutical Preparations; Physiologic pulse; Physiological; Physiology; Population; Positioning Attribute; Prefrontal Cortex; Property; Prosencephalon; Rabies virus; Recurrence; Relapse; Research; Rewards; Role; Signal Transduction; Site; Slice; Specificity; Stimulus; Stress; Structure; Substance abuse problem; Synapses; Synaptic plasticity; Techniques; Technology; Therapeutic; Therapeutic Intervention; Training; Ventral Tegmental Area; Work; addiction; base; behavioral study; design; dopaminergic neuron; drug abuse prevention; drug of abuse; drug relapse; experience; in vivo; motivated behavior; nerve supply; neuronal circuitry; optogenetics; prevent; public health relevance; research study; response; reward circuitry; reward processing; social; success

DESCRIPTION (provided by applicant): Drug abuse is a major global problem with often devastating societal consequences. While therapeutics designed to treat drug addiction have focused on medicinal intervention with concurrent behavioral therapy, much progress remains to be made in reducing this major social and economic burden. Many drugs of abuse work on the dopamine (DA) pathway in the brain, which is normally activated by neurons in the ventral tegmental area (VTA) that function, in part, to signal reward. However, DA neurons are not a homogenous population, but rather are composed of multiple subtypes with distinct functions. Two of the major projection sites of these VTA neurons, the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC), are also brain regions strongly implicated in addiction. While existing data suggest that the NAc-projecting population is unique from the mPFC-projecting population, little is known about how these populations are distinct; what brain areas differentially activate these distinct populations remains a mystery. To date, it has been difficul to study the detailed connectivity within the VTA, as multiple neuron types are intermingled within the VTA, and existing technologies do not permit genetic access to specific subtypes of neurons. Using a new rabies virus- based transsynaptic tracing approach, I will construct a detailed input-output map of VTA DA neuron subpopulations. Once the detailed connectivity has been established, I will examine the synaptic properties of a subset of these connections, and will compare these against all excitatory inputs onto the same neurons. Lastly, I will examine the ways in which these synapses are altered in response to a rewarding or aversive stimulus. These data will allow for the identification of the exact loci and mechanisms of plasticity occurring on specific VTA DA neuron subpopulations. This knowledge would permit highly targeted disruptions of these synaptic changes, ultimately allowing us to assess the contribution of input-specific synaptic plasticity to drug- related behaviors. In the future, these analyses can be combined with behavioral studies to analyze the role of these specific synapses in drug addiction and relapse.

描述（由申请人提供）：药物滥用是一个重大的全球性问题，往往具有破坏性的社会后果。虽然旨在治疗药物成瘾的治疗方法主要集中在药物干预和同时进行的行为治疗，但在减少这一重大社会和经济负担方面仍需取得很大进展。许多滥用药物作用于大脑中的多巴胺（DA）通路，该通路通常由腹侧被盖区（VTA）中的神经元激活，其部分功能是发出奖励信号。然而，DA神经元不是一个同质的群体，而是由具有不同功能的多个亚型组成。这些腹侧被盖区神经元的两个主要投射部位，即内侧前额叶皮层（mPFC）和脑桥核（NAc），也是与成瘾密切相关的大脑区域。虽然现有的数据表明，NAC投射人群是独特的mPFC投射人群，很少有人知道这些人群是如何不同的;什么大脑区域差异激活这些不同的人群仍然是一个谜。迄今为止，研究VTA内的详细连接性一直很困难，因为多种神经元类型混合在VTA内，并且现有技术不允许遗传访问特定亚型的神经元。使用一种新的基于狂犬病病毒的跨突触追踪方法，我将构建腹侧被盖区DA神经元亚群的详细输入输出图。一旦建立了详细的连接，我将检查这些连接的子集的突触特性，并将它们与相同神经元上的所有兴奋性输入进行比较。最后，我将研究这些突触在对奖励或厌恶刺激做出反应时发生改变的方式。这些数据将允许识别特定腹侧被盖区DA神经元亚群上发生的可塑性的确切位点和机制。这种知识将允许高度靶向地破坏这些突触变化，最终允许我们评估输入特异性突触可塑性对药物相关行为的贡献。在未来，这些分析可以 与行为研究相结合，分析这些特定突触在药物成瘾和复发中的作用。

项目成果

Control of REM sleep by ventral medulla GABAergic neurons.

• DOI: 10.1038/nature14979
• 发表时间: 2015-10-15
• 期刊: Nature
• 影响因子: 64.8
• 作者: Weber F;Chung S;Beier KT;Xu M;Luo L;Dan Y
• 通讯作者: Dan Y

Amygdala-Midbrain Connections Modulate Appetitive and Aversive Learning

• DOI: 10.1016/j.neuron.2020.03.016
• 发表时间: 2020-06-17
• 期刊: NEURON
• 影响因子: 16.2
• 作者: Steinberg, Elizabeth E.;Gore, Felicity;Malenka, Robert C.
• 通讯作者: Malenka, Robert C.

Gating of social reward by oxytocin in the ventral tegmental area.

• DOI: 10.1126/science.aan4994
• 发表时间: 2017-09-29
• 期刊: Science (New York, N.Y.)
• 作者: Hung LW;Neuner S;Polepalli JS;Beier KT;Wright M;Walsh JJ;Lewis EM;Luo L;Deisseroth K;Dölen G;Malenka RC
• 通讯作者: Malenka RC