Oriol Lucie, Chao Melody, Kollman Grace J, Dowlat Dina S, Singhal Sarthak M, Steinkellner Thomas, Hnasko Thomas S
Department of Neurosciences, University of California, San Diego, La Jolla, United States.
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Austria.
bioRxiv. 2025 Jan 17:2024.06.07.597996. doi: 10.1101/2024.06.07.597996.
The ventral tegmental area (VTA) contains projection neurons that release the neurotransmitters dopamine, GABA, and/or glutamate from distal synapses. VTA also contains GABA neurons that synapse locally on to dopamine neurons, synapses widely credited to a population of so-called VTA interneurons. Interneurons in cortex, striatum, and elsewhere have well-defined morphological features, physiological properties, and molecular markers, but such features have not been clearly described in VTA. Indeed, there is scant evidence that local and distal synapses originate from separate populations of VTA GABA neurons. In this study we tested whether several markers expressed in non-dopamine VTA neurons are selective markers of interneurons, defined as neurons that synapse locally but not distally. Challenging previous assumptions, we found that VTA neurons genetically defined by expression of parvalbumin, somatostatin, neurotensin, or mu-opioid receptor project to known VTA targets including nucleus accumbens, ventral pallidum, lateral habenula, and prefrontal cortex. Moreover, we provide evidence that VTA GABA and glutamate projection neurons make functional inhibitory or excitatory synapses locally within VTA. These findings suggest that local collaterals of VTA projection neurons could mediate functions prior attributed to VTA interneurons. This study underscores the need for a refined understanding of VTA connectivity to explain how heterogeneous VTA circuits mediate diverse functions related to reward, motivation, or addiction.
腹侧被盖区（VTA）包含投射神经元，这些神经元从远端突触释放神经递质多巴胺、γ-氨基丁酸（GABA）和/或谷氨酸。VTA还包含GABA神经元，它们在局部与多巴胺神经元形成突触，这种突触广泛归因于一群所谓的VTA中间神经元。皮质、纹状体和其他部位的中间神经元具有明确的形态特征、生理特性和分子标记，但VTA中的此类特征尚未得到清晰描述。事实上，几乎没有证据表明局部和远端突触起源于不同的VTA GABA神经元群体。在本研究中，我们测试了在非多巴胺能VTA神经元中表达的几种标记物是否是中间神经元的选择性标记物，中间神经元被定义为仅在局部而非远端形成突触的神经元。与之前的假设不同，我们发现由小白蛋白、生长抑素、神经降压素或μ-阿片受体的表达所遗传定义的VTA神经元投射到已知的VTA靶点，包括伏隔核、腹侧苍白球、外侧缰核和前额叶皮质。此外，我们提供证据表明，VTA的GABA和谷氨酸投射神经元在VTA内局部形成功能性抑制或兴奋性突触。这些发现表明，VTA投射神经元的局部侧支可能介导了先前归因于VTA中间神经元的功能。这项研究强调了需要更精确地理解VTA的连接性，以解释异质性的VTA回路如何介导与奖励、动机或成瘾相关的多种功能。
