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

描述（由申请人提供）：药物滥用是一个重大的全球性问题，往往具有毁灭性的社会后果。虽然治疗药物成瘾的方法主要集中在药物干预和同时进行的行为治疗上，但在减少这一主要的社会和经济负担方面仍有待取得很大进展。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）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，而是由多个具有不同功能的亚型组成。这些VTA神经元的两个主要投射部位，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 -突出的种群与mpfc -突出的种群是独特的，但人们对这些种群的区别知之甚少；是什么大脑区域以不同的方式激活了这些不同的人群，这仍然是一个谜。迄今为止，由于多种神经元类型混杂在VTA内，并且现有技术不允许对特定亚型神经元进行遗传访问，因此很难研究VTA内的详细连接。使用一种新的基于狂犬病毒的跨突触追踪方法，我将构建一个详细的VTA DA神经元亚群的输入输出图。一旦建立了详细的连接，我将检查这些连接的一个子集的突触特性，并将它们与同一神经元的所有兴奋性输入进行比较。最后，我将研究这些突触在对有益或厌恶的刺激作出反应时发生改变的方式。这些数据将允许确定具体VTA DA神经元亚群上发生的可塑性的确切位点和机制。这些知识将允许高度有针对性地破坏这些突触变化，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。在未来，这些分析可以

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.