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

高度阿片类药物反应的 VTA 投射到背内核状核。

• 批准号: 10739039
• 负责人: Elyssa Margolis
• 金额: $ 24.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739039
• 关键词: Acceleration; Agonist; Alcohol consumption; Anatomy; Animals; Attention; Behavior; Brain; Brain region; Cell Nucleus; Cerebral cortex; Claustral structure; Conscious; Cues; Development; Disease; Dopamine; Dorsal; G-Protein-Coupled Receptors; Generations; Genetic; Health; Investigation; Label; Learning; Light; Link; Maps; Medial; Messenger RNA; Modality; Motivation; Neurons; Neurotransmitters; Nucleus Accumbens; Opioid; Opioid Peptide; Opioid Receptor; Optics; Outcome; Output; Performance; Phenotype; Play; Prefrontal Cortex; Prosencephalon; Proteins; Psychological reinforcement; Receptor Activation; Resolution; Rewards; Role; Seizures; Sensory; Signal Transduction; Site; Stress; Structure; Synapses; Techniques; Testing; Thinness; Time; Tracer; Ventral Tegmental Area; Viral Vector; Whole-Cell Recordings; delta opioid receptor; design; endogenous opioids; experimental study; food consumption; kappa opioid receptors; motivated behavior; mu opioid receptors; nerve supply; neural; neurochemistry; neurotransmitter release; postsynaptic; preference; receptor expression; receptor function; response; sensory cortex; sensory input; sensory integration; tool

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.

总结 背侧虹膜状核（DEn）是在哺乳动物脑中发现的高度保守的结构， 与屏状体的发育有关，并与屏状体作为“座位”的作用有关。 意识”。与屏状核相比，DEn连接到更多的边缘系统区域，具有非常密集的投射 到边缘下皮层，并从感觉皮层特别是嗅觉和味觉区域接收强烈的输入。 虽然DEn在行为中的作用除了导致癫痫发作外， 活性，长期以来已知其具有极高水平的μ、δ和κ阿片样受体（莫尔， DOR和KOR）蛋白和mRNA。在初步研究中，我们发现了一个主要是非多巴胺能腹侧 被盖区（VTA）投射到DEn;这些神经元显示出显着更强的超极化， 对莫尔激动剂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 这是因为阿片奖励，包括VTA内阿片奖励，在阿片类药物幼稚动物中是多巴胺独立的。 因此，这种非多巴胺能的、莫尔敏感的投射可能有助于这种阿片样物质奖赏。由于DEn 接受来自各种感觉皮层的输入，这也是一个潜在的直接相互作用的网站， 来自VTA和感觉线索信息的强化编码。在这里，我们建议解剖地图， DEn的VTA神经支配，表征包括其莫尔敏感性的VTA神经支配DEn突触连接， 并测试这种回路连接的选择性调制是否产生奖励或促进学习或突出 发信号。这些研究将共同为理解一个以前未研究但高度 腹侧被盖区的阿片样物质敏感输出到阿片样物质受体富集的脑区，该脑区位于整合信息的位置 从大脑皮层传来。