Clerke Joseph, Preston-Ferrer Patricia, Zouridis Ioannis S, Tissot Audrey, Batti Laura, Voigt Fabian F, Pagès Stephane, Burgalossi Andrea, Mameli Manuel
The Department of Fundamental Neuroscience, The University of Lausanne, Lausanne, Switzerland.
Institute of Neurobiology, University of Tübingen, Tübingen, Germany.
Front Synaptic Neurosci. 2021 Mar 31;13:643138. doi: 10.3389/fnsyn.2021.643138. eCollection 2021.
Projections from the lateral habenula (LHb) control ventral tegmental area (VTA) neuronal populations' activity and both nuclei shape the pathological behaviors emerging during cocaine withdrawal. However, it is unknown whether cocaine withdrawal modulates LHb neurotransmission onto subsets of VTA neurons that are part of distinct neuronal circuits. Here we show that, in mice, cocaine withdrawal, drives discrete and opposing synaptic adaptations at LHb inputs onto VTA neurons defined by their output synaptic connectivity. LHb axons innervate the medial aspect of VTA, release glutamate and synapse on to dopamine and non-dopamine neuronal populations. VTA neurons receiving LHb inputs project their axons to medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and lateral hypothalamus (LH). While cocaine withdrawal increases glutamate release from LHb onto VTA-mPFC projectors, it reduces presynaptic release onto VTA-NAc projectors, leaving LHb synapses onto VTA-to-LH unaffected. Altogether, cocaine withdrawal promotes distinct adaptations at identified LHb-to-VTA circuits, which provide a framework for understanding the circuit basis of the negative states emerging during abstinence of drug intake.
外侧缰核（LHb）的投射控制腹侧被盖区（VTA）神经元群体的活动，并且这两个核团都塑造了可卡因戒断期间出现的病理行为。然而，尚不清楚可卡因戒断是否会调节LHb对VTA神经元亚群的神经传递，这些神经元亚群是不同神经回路的一部分。在这里，我们表明，在小鼠中，可卡因戒断会在LHb输入到由其输出突触连接定义的VTA神经元上驱动离散且相反的突触适应性变化。LHb轴突支配VTA的内侧部分，释放谷氨酸并与多巴胺能和非多巴胺能神经元群体形成突触。接受LHb输入的VTA神经元将其轴突投射到内侧前额叶皮质（mPFC）、伏隔核（NAc）和外侧下丘脑（LH）。虽然可卡因戒断会增加LHb向VTA - mPFC投射神经元的谷氨酸释放，但会减少其向VTA - NAc投射神经元的突触前释放，而LHb到VTA至LH的突触则不受影响。总之，可卡因戒断促进了在已确定的LHb到VTA回路中的不同适应性变化，这为理解药物摄入戒断期间出现的消极状态的回路基础提供了一个框架。
