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）：滥用药物是一个主要的全球问题，经常造成毁灭性的社会后果。虽然旨在治疗药物成瘾的治疗剂将重点放在同时进行的行为疗法的药物干预上，但在减轻这种主要的社会和经济负担方面仍将取得很多进展。许多滥用药物在大脑的多巴胺（DA）途径上起作用，该途径通常被腹侧段盖区域（VTA）中的神经元激活，部分作用以表达奖励。但是，DA神经元不是同质种群，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影位点，伏隔核（NAC）和内侧前额叶皮层（MPFC）也与成瘾有关。尽管现有数据表明，NAC项目中的种群是MPFC项目的独特之处，但对这些人群的不同知之甚少。哪些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，由于多种神经元类型在VTA中混合在一起，因此很难研究VTA内的详细连接性，并且现有技术不允许遗传进入神经元的特定亚型。使用新的基于狂犬病病毒的经透射性跟踪方法，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性，我将检查这些连接子集的突触特性，并将这些连接的突触性质与所有兴奋性输入进行比较。最后，我将研究这些突触因有意义或厌恶刺激而改变的方式。这些数据将允许鉴定在特定的VTA DA神经元亚群上发生的确切基因座和可塑性机制。这些知识将允许对这些突触变化的高度针对性破坏，最终使我们能够评估投入特异性突触可塑性对药物相关行为的贡献。将来，这些分析可以与行为研究结合使用，以分析这些特定突触在药物成瘾和复发中的作用。

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）

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.)
影响因子：
0
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