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

项目摘要 2009年，两个实验室独立地发现了头内侧被盖核（RMTg）-一个小的 GABA能核，通过对中脑施加抑制控制来编码负性奖励预测错误 多巴胺神经元以及随后的研究表明，RMTg在应对 令人厌恶的刺激，这项工作引发了新的研究调查参与该地区的神经生物学 酒精使用障碍的潜在机制内侧前额叶皮层（mPFC）在调节 酒精寻求和服用行为。有趣的是，我们最近的工作揭示了存在密集的输入， mPFC到RMTg跨越边缘前（PL）和边缘下（IL）亚区。研究操纵 PL和IL活动在次区域一级表明，这两个地区施加相反的控制酒精 寻找然而，特定于电路的方法的应用开始显示出更复杂的情况 在离散的皮质-皮质下投射中具有不同的作用。再加上一个非常肤浅的 由于对RMTg神经元的异质性/均匀性的理解，这些相互矛盾的数据使得难以 发展关于RMTg中电路基序的假设，以及RMTg的潜在协同或二分功能， RMTg投射PL和IL mPFC神经元。考虑到最近的数据显示， 腹侧被盖区的未被重视的异质性已经对该区域的功能理解产生了影响， 对RMTg的严格调查是必要的。当前提案中描述的目标将联合收割机电路- 使用最先进的连接组学方法进行特异性标记，以表征慢性乙醇的影响 暴露在RMTg及其皮质传入在纳米分辨率。获得RMTg连接体 将提供对细胞结构和突触模式的重要见解以及致密神经元的精确神经元地图 RMTg的皮层输入被认为在自上而下控制酒精寻求中起着关键作用。所得电路 这些数据将为未来研究依赖的功能后果提供基础- 通过整合亚细胞解剖学发现与生理和行为诱导突触重组。

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.