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

描述(由申请人提供)：药物滥用是一个主要的全球性问题，往往具有破坏性的社会后果。虽然治疗药物成瘾的治疗方法侧重于药物干预和同时进行行为治疗，但在减少这一主要的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)的神经元激活，部分功能是发出奖赏信号。然而，DA神经元并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。伏隔核(NAC)和内侧前额叶皮质(MPFC)是这些VTA神经元的两个主要投射部位，也是与成瘾密切相关的脑区。虽然现有数据表明，NAC-投射人群与mPFC-投射人群是独一无二的，但人们对这些人群是如何不同的知之甚少；哪些大脑区域以不同的方式激活这些不同的人群仍然是一个谜。到目前为止，研究VTA内的详细连接一直是困难的，因为VTA内混合了多种神经元类型，而且现有技术不允许特定亚型神经元的遗传访问。使用一种新的基于狂犬病病毒的跨突触追踪方法，我将构建一张详细的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子集的突触属性，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，我将研究这些突触如何在受到奖赏或厌恶的刺激时发生改变。这些数据将有助于识别发生在特定VTA DA神经元亚群上的确切可塑性位点和机制。这一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 结合行为学研究，分析这些特定突触在药物成瘾和复发中的作用。

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.