Afferent Circuitry of Dopamine Dysregulation in Depression

 描述(由申请人提供)：预计到2030年，严重抑郁障碍(MDD)将成为全球最沉重的负担。改善对神经回路的了解，将有助于开发治疗MDD的新方法。对追求以前有益的刺激(快感缺乏)的兴趣降低是MDD的核心症状。在正常情况下，中脑边缘多巴胺(DA)系统对追求回报至关重要，临床神经成像研究表明，该系统在MDD中处于低活性状态。不可预测的慢性轻度应激(UCMS)动物模型是研究啮齿动物这一现象的有效手段。在UCMS后，动物的动机行为减少，这可以通过DA系统的兴奋来恢复。然而，一个重要的问题仍然没有得到回答，那就是为什么千年发展目标中的发展议程系统运行不正常。我们的实验室最近发现，在经历了UCMS(以及习得性无助)的动物中，由于腹侧被盖区(VTA)DA神经元的传入抑制增强，DA系统处于低活动状态。我们描述了一个回路，在UCMS后，腹侧苍白球(VP)的基底外侧杏仁核(BLA)驱动增加，导致VTA DA神经元群活动(活跃DA神经元的数量)显著减少，这似乎是UCMS降低DA系统张力的关键机制。然而，该回路目前忽略了两个被认为是人类MDD回路中重要节点的区域：亚膝扣带回(BA25)，其啮齿动物同源是边缘下前额叶皮质(ILPFC)和外侧缰核(LHb)。人类研究表明，BA25在MDD中过度活跃，BLA也是如此，因此已知的ILPFC到BLA的投射可能推动BLA过度激活，这是UCMS后DA活动减少的关键。另外，LHb对VTA DA神经元有更近的投射，因此该区域的过度激活可能通过旋转内侧被盖(RMTg)抑制VTA DA神经元。因此，我们将通过以下目的研究这两个区域在UCMS诱导的DA系统下调中的相对作用：1)利用电生理和行为读数来确定激活ILPFC；BLA和LHb；RMTg的传出投射对正常大鼠DA系统的影响；2)评估失活ILPFC；BLA或LHb；RMTg投射是否改善UCMS后表现出动机受损的动物的DA系统功能；3)确定潜在回路节点区域活动水平变化的时间进程，包括 ILPFC、BLA、LHb、RMTg、VP和VTA。随着对MDD中可能下调DA系统的传入结构的更多了解，新的治疗干预措施可能会专门针对这一神经回路中功能异常的节点。

 DESCRIPTION (provided by applicant): Major depressive disorder (MDD) is predicted to be the most burdensome disease worldwide by the year 2030. Improved understanding of the neural circuits mediating key psychological processes that go awry in the disorder will facilitate development of novel treatments for MDD. Reduced interest in pursuing previously rewarding stimuli (anhedonia) is a core symptom of MDD. The mesolimbic dopamine (DA) system is critical to the pursuit of rewards under normal conditions, and clinical neuroimaging studies suggest this system to be hypoactive in MDD. The unpredictable chronic mild stress (UCMS) animal model has been a useful means to study this phenomenon in rodents. Following UCMS, animals show decreased motivated behavior, which can be restored with DA system excitation. An important question that remains unanswered, however, is why the DA system is functioning improperly in MDD. Our lab has recently shown that the DA system is hypoactive in animals that have undergone UCMS (as well as learned helplessness), due to enhanced afferent inhibition of DA neurons located in the ventral tegmental area (VTA). We have delineated a circuit whereby increased basolateral amygdala (BLA) drive of the ventral pallidum (VP) following UCMS leads to a potent reduction in VTA DA neuron population activity (number of active DA neurons), and this appears to be critical to the mechanism whereby UCMS reduces DA system tone. However, this circuit presently omits two regions proposed to be important nodes in MDD circuitry in humans: the subgenual cingulate cortex (BA25), whose rodent homologue is the infralimbic prefrontal cortex (ILPFC), and the lateral habenula (LHb). Human studies have shown BA25 to be overactive in MDD, as is also seen for the BLA, and thus a known projection from the ILPFC to the BLA may be driving the BLA over-activation that is critical to diminished DA activity seen following UCMS. Alternatively, the LHb has a more proximal projection to the VTA DA neurons and therefore over- activation of this region may, via the rostromedial tegmentum (RMTg), inhibit VTA DA neurons. We will therefore investigate the relative roles of these two regions in UCMS-induced DA system down-regulation, via the following aims: 1) To determine the impact on the DA system of activating efferent projections from ILPFC- >BLA and LHb->RMTg in normal rats using electrophysiological and behavioral readouts, 2) To assess whether inactivating the ILPFC->BLA or LHb->RMTg projections improves DA system function in animals that exhibit impaired motivation after undergoing UCMS, 3) To define the time course for the development of alterations in regional activity level in potential circuit nodes, including the ILPFC, BLA, LHb, RMTg, VP, and VTA. With greater understanding of the afferent structures potentially down-regulating the DA system in MDD, novel therapeutic interventions could specifically target aberrantly functioning nodes in this neural circuit.