Neuropeptide driven cholinergic activity underlying learning and reward in the Nucleus Accumbens

伏隔核D2-MSN活动被认为驱动奖励或封锁厌恶。然而，最近的研究表明，d2 - msn在编码信息方面发挥着更复杂的作用，并可以驱动对自然刺激的奖励。此外，D1-MSN和D2-MSN的活性是不同的，往往是相反的，由于多巴胺受体的表达和侧抑制机制。我们的研究表明D1-MSNs通过肽释放和ChI激发增强D2-MSNs的兴奋。这种增强是子区域特异性的，我们预测这种特异性是由于这些区域的不同输入。利用全细胞切片生理学和光遗传学，我们首先通过检查多个输入（腹侧海马、室旁丘脑核和颗粒岛）的增强来确定特定输入是否对P物质有不同的反应。我们假设多种输入可以整合和促进肽释放。因此，我们正在使用双光遗传学方法和红移视蛋白来探测NAc核心的msn的兴奋性输入，以确定这些输入的强刺激是否能引起d2 - msn的肽释放和兴奋性增强。此外，我们将使用双光遗传学和钙成像方法来检查胆碱能中间神经元和d2 - msn的单细胞活性。

Nucleus Accumbens D2-MSN activity is thought to drive reward or block aversion. However, recent work indicates D2-MSNs play a more complicated role in encoding information and can drive reward to natural stimuli. Additionally, D1-MSN and D2-MSN activity is differential and often opposing due to dopamine receptor expression and lateral inhibition mechanisms. Our work shows D1-MSNs enhance excitation on D2-MSNs through peptide release and ChI firing. This potentiation is sub-region specific and we predict this specificity is due to differential input to these regions. Using whole-cell slice physiology and combined optogenetics, we are first determining if specific inputs respond to substance P differentially by examining potentiation of multiple inputs (ventral hippocampus, paraventricular thalamic nucleus, and the agranular insula). We hypothesize that multiple inputs can integrate and promote peptide release. Therefore, we are probing excitatory inputs to MSNs in the NAc core using a dual optogenetic approach with red-shifted opsins to determine if strong stimulation of these inputs can evoke peptide release and excitatory potentiation on D2-MSNs. Additionally, we will be using a dual optogenetics and calcium imaging approach to examine single cell activity of both cholinergic interneurons and D2-MSNs using a miniscope implantation. Cholinergic activity is necessary for reward responding but it is unknown what long-lasting increases in ChI activity does to behavior. To activate ChIs, we will inject a bi-stable opsin that has long kinetics and mimics the response of substance P activation. We will use a conditioned food aversion task in which aversive shocks are paired with a novel palatable food distinct from animals home chow. We predict lasting ChI activation and D2-MSN potentiation will enhance associated learning of food and an aversive stimulus. Finally, using stimulation paradigms developed as discussed previously and the behavioral task described, we will examine how naturalistic in vivo activation of NAc ChI cells by excitatory inputs drive aversive behavioral responding.