A highly opioid responsive VTA projection to the dorsal endopiriform nucleus.

摘要 虹膜背侧核(DEN)是哺乳动物大脑中发现的一种高度保守的结构，它是 在发育上与屏蔽门有关，并被认为与屏蔽门的作用有关 意识“。巢比屏状核连接更多的边缘区域，具有非常密集的投射。 至下缘皮质，并接受来自感觉皮质特别是嗅觉和味觉区域的强烈输入。 虽然除了导致癫痫发作之外，窝点在行为中的作用在很大程度上仍不清楚 长期以来，人们一直知道，它具有极高水平的Mu、Delta和kappa阿片受体(MOR， DOR和KOR)蛋白和mRNA。在初步研究中，我们发现大部分非多巴胺能腹侧 被盖区(VTA)投射到窝点；这些神经元表现出明显更强的超极化。 对MOR激动剂DAMGO的反应比我们研究过的任何其他VTA投射都要好。这是一个令人兴奋的 发现是因为阿片类奖赏，包括VTA内的阿片奖赏，在阿片类幼稚动物中是不依赖多巴胺的。 因此，这种非多巴胺能的、对吗啡敏感的投射可能有助于阿片类药物的奖赏。因为这个洞穴 从各种感觉皮质接受输入，这也是一个潜在的直接相互作用的部位 来自VTA和感觉线索信息的强化编码。在这里，我们建议解剖地绘制出 Vta对DEN的神经支配，表征VtaDEN的突触连接，包括其MOR敏感性， 并测试这种电路连接的选择性调制是否会产生奖励或促进学习或突出 发信号。总而言之，这些研究将为理解以前未被研究但高度重视的 VTA对阿片敏感输出到阿片受体丰富的大脑区域以整合信息 从整个大脑皮层。

SUMMARY The dorsal endopiriform nucleus (DEn) is a highly conserved structure found in mammalian brains that is developmentally related to the claustrum and has been linked to the claustrum's role as the “seat of consciousness”. The DEn is connected to more limbic regions than the claustrum, has a very dense projection to infralimbic cortex, and receives strong inputs from sensory cortices especially olfactory and gustatory regions. While the DEn's role in behavior remains largely unknown beyond contributing to the generation of seizure activity, it has long been known to have extremely high levels of mu, delta, and kappa opioid receptor (MOR, DOR, and KOR) protein and mRNA. In preliminary studies we discovered a mostly non-dopaminergic ventral tegmental area (VTA) projection to the DEn; these neurons show a significantly stronger hyperpolarization in response to the MOR agonist DAMGO than any other VTA projection we have investigated. This is an exciting find because opioid reward, including intra-VTA opioid reward, is dopamine independent in opioid naïve animals. Thus, this non-dopaminergic, MOR sensitive projection may contribute to this opioid reward. Since the DEn receives inputs from a variety of sensory cortices, this is also a potential site of direct interaction between reinforcement encoding from the VTA and sensory cue information. Here we propose to anatomically map the VTA innervation of the DEn, characterize the VTA  DEn synaptic connectivity including its MOR sensitivity, and test whether selective modulation of this circuit connection produces reward or promotes learning or salience signaling. Together these studies will lay the groundwork for understanding a previously unstudied but highly opioid sensitive output of the VTA to an opioid receptor enriched brain region situated to integrate information from across cerebral cortex.