Effect of chronic ethanol exposure on synaptic organization in the rostromedial tegmental nucleus

项目总结 2009年，两个实验室独立发现了人头内侧被盖核(RMTg)--一种小的 GABA能核通过对中脑施加抑制控制来编码负奖赏预测错误 多巴胺神经元。以及随后的研究，证明了RMTG在应对 厌恶刺激，这项工作引发了新的研究，调查该区域在神经生物学中的参与。 酒精使用障碍的潜在机制。内侧前额叶皮质(MPFC)在大脑中起着重要的调节作用 寻酒和饮酒行为。有趣的是，我们最近的工作揭示了来自 MPFC到RMTG，跨越前缘(PL)和下缘(IL)亚区。研究操纵 分区域水平上的PL和IL活性表明，这两个区域对酒精施加相反的控制 寻找。然而，电路专用方法的应用开始显示出一幅更复杂的图景 在不同的皮质-皮质下投射中具有不同的作用。结合起来只是一个非常肤浅的 对于RMTg神经元的异质性/一致性的理解，这些相互矛盾的数据使得很难 提出关于RMTG中的电路基序以及RMTG的潜在协同或二分功能的假设 投射RMTg的PL和IL-mPFC神经元。考虑到最近的数据表明之前 腹侧被盖区不为人知的异质性影响了对该区域的功能理解， 有必要对RMTG进行严格调查。目前提案中描述的目标将结合电路- 用最先进的连接组学方法进行特异性标记以表征慢性酒精的影响 以纳米分辨率照射RMTG及其皮质传入神经。收购RMTg连接件 将提供对细胞结构和突触模式的重要洞察以及密集的 RMTg的皮质输入被认为在自上而下控制酒精寻求方面发挥着关键作用。由此产生的电路 数据将为未来研究依赖的功能后果提供基础- 通过将亚细胞解剖学发现与生理和行为相结合来诱导突触重组。

PROJECT SUMMARY In 2009 two laboratories independently discovered the rostromedial tegmental nucleus (RMTg) – a small GABAergic nucleus that encodes negative reward prediction error via the inhibitory control it exerts over midbrain dopamine neurons. Together with subsequent studies demonstrating a role for the RMTg in responding to aversive stimuli, this work sparked new research investigating involvement of this region in the neurobiological mechanisms underlying alcohol use disorder. The medial prefrontal cortex (mPFC) plays a key role in regulating alcohol seeking and taking behavior. Interestingly, our recent work revealed the presence of dense input from the mPFC to the RMTg that spans both the prelimbic (PL) and infralimbic (IL) subregions. Studies manipulating PL and IL activity at the subregional level suggest that these two regions exert opposing control over alcohol seeking. However, the application of circuit-specific approaches is beginning to suggest a more complex picture with differing roles across discrete cortico-subcortical projections. Combined with only a very superficial understanding of the heterogeneity / uniformity of RMTg neurons, these conflicting data make it difficult to develop hypotheses regarding circuit motifs in RMTg and the potential synergistic or dichotomous functions of RMTg-projecting PL and IL mPFC neurons. Given the impact that recent data demonstrating the previously unappreciated heterogeneity of the ventral tegmental area has had on functional understanding of this region, a rigorous investigation of the RMTg is warranted. The aims described in the current proposal will combine circuit- specific labeling with state-of-the-art connectomics approaches to characterize the effects of chronic ethanol exposure on the RMTg and its cortical afferents at nanometer resolution. Acquisition of an RMTg connectome will provide crucial insight into cell structure and synaptic patterns as well as a precise neuronal map of dense cortical input to RMTg thought to play a critical role in top-down control over alcohol seeking. The resulting circuit data will provide a foundation for future studies investigating the functional consequences of dependence- induced synaptic reorganization by integrating subcellular anatomical findings with physiology and behavior.