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

伏核D2-MSN活动被认为是驱动奖励或阻止厌恶。然而，最近的研究表明，D2-MSNs在编码信息方面发挥着更复杂的作用，并且可以驱动对自然刺激的奖励。此外，D1-MSN和D2-MSN活性是不同的，并且由于多巴胺受体表达和侧抑制机制而常常相反。我们的工作表明D1-MSNs通过肽释放和ChI放电增强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差分输入。使用全细胞切片生理学和组合的光遗传学，我们首先确定特定的输入是否响应P物质的差异，通过检查多个输入（腹侧海马，丘脑室旁核，和无颗粒核）的增强。我们假设多个输入可以整合并促进肽释放。因此，我们使用具有红移视蛋白的双重光遗传学方法来探测NAc核心中MSN的兴奋性输入，以确定这些输入的强刺激是否可以引起D2-MSN上的肽释放和兴奋性增强。此外，我们将使用双重光遗传学和钙成像方法，使用微型显微镜植入来检查胆碱能中间神经元和D2-MSNs的单细胞活性。 胆碱能活动是奖励反应所必需的，但ChI活动的长期增加对行为有何影响尚不清楚。为了激活ChIs，我们将注射具有长动力学并模拟P物质激活反应的双稳态视蛋白。我们将使用条件性食物厌恶任务，其中厌恶性电击与不同于动物家庭食物的新颖可口食物配对。我们预测持久的ChI激活和D2-MSN增强将增强相关的学习的食物和厌恶刺激。最后，使用刺激范式开发如前所述的行为任务，我们将研究如何自然在体内激活NAc ChI细胞的兴奋性输入驱动厌恶的行为反应。

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.