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

基本信息

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
项目类别：
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

项目摘要

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问题，常常造成毁灭性的社会后果。虽然旨在治疗毒瘾的疗法主要集中于药物干预和行为疗法，但在减轻这一重大社会和经济负担方面仍有很大进展。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) 的神经元激活，其部分功能是发出奖励信号。然而，DA 神经元并不是同质群体，而是由具有不同功能的多种亚型组成。这些 VTA 神经元的两个主要投射位点，即伏隔核 (NAc) 和内侧前额叶皮层 (mPFC)，也是与成瘾密切相关的大脑区域。虽然现有数据表明 NAc 预测群体与 mPFC 预测群体是独特的，但人们对这些群体如何不同知之甚少。哪些大脑区域差异性地激活这些不同的群体仍然是一个谜。迄今为止，研究 VTA 内的详细连接性一直很困难，因为 VTA 内混合了多种神经元类型，并且现有技术不允许对神经元的特定亚型进行遗传访问。使用一种新的基于狂犬病病毒的突触追踪方法，我将构建 VTA 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的所有兴奋性输入进行比较。最后，我将研究这些突触响应奖励或厌恶刺激而改变的方式。这些数据将允许识别特定 VTA DA 神经元亚群上发生的可塑性的确切位点和机制。这些知识将允许对这些突触变化进行高度有针对性的破坏，最终使我们能够评估输入特异性突触可塑性对药物相关行为的贡献。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毒瘾和复发中的作用。

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）

Amygdala-Midbrain Connections Modulate Appetitive and Aversive Learning.

杏仁核-中脑连接调节食欲和厌恶学习。

DOI：
发表时间：
2020
期刊：
影响因子：
16.2
作者：
Steinberg, Elizabeth E;Gore, Felicity;Heifets, Boris D;Taylor, Madison D;Norville, Zane C;Beier, Kevin T;Földy, Csaba;Lerner, Talia N;Luo, Liqun;Deisseroth, Karl;Malenka, Robert C
通讯作者：
Malenka, Robert C

Control of REM sleep by ventral medulla GABAergic neurons.

腹侧延髓 GABA 能神经元对 REM 睡眠的控制。

DOI：
发表时间：
2015-10-15
期刊：
影响因子：
64.8
作者：
Weber, Franz;Chung, Shinjae;Beier, Kevin T;Xu, Min;Luo, Liqun;Dan, Yang
通讯作者：
Dan, Yang

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

腹侧被盖区催产素对社会奖励的门控。

DOI：
发表时间：
2017-09-29
期刊：
影响因子：
0
作者：
Hung, Lin W;Neuner, Sophie;Polepalli, Jai S;Beier, Kevin T;Wright, Matthew;Walsh, Jessica J;Lewis, Eastman M;Luo, Liqun;Deisseroth, Karl;Dölen, Gül;Malenka, Robert C
通讯作者：
Malenka, Robert C