Afferent Circuitry of Dopamine Dysregulation in Depression

 描述（由申请人提供）：到2030年，重度抑郁症（MDD）预计将成为全球最沉重的疾病。更好地理解神经回路介导的关键心理过程，在疾病中出错，将促进新的治疗MDD的发展。对追求先前奖励刺激的兴趣降低（快感缺乏）是MDD的核心症状。中脑边缘多巴胺（DA）系统是在正常条件下追求奖励的关键，临床神经影像学研究表明，该系统在MDD中是功能减退的。不可预知的慢性轻度应激（UCMS）动物模型是研究这一现象的有效手段。在UCMS之后，动物表现出动机行为减少，这可以通过DA系统兴奋来恢复。然而，一个重要的问题仍然没有得到回答，那就是为什么DA系统在MDD中运行不正常。我们的实验室最近表明，DA系统在经历UCMS（以及习得性无助）的动物中活动减退，这是由于位于腹侧被盖区（VTA）的DA神经元的传入抑制增强。我们已经描绘了一个电路，其中腹侧苍白球（VP）的基底外侧杏仁核（BLA）驱动增加UCMS导致腹侧被盖区DA神经元群体活性（活跃DA神经元的数量）的有效减少，这似乎是关键的机制，UCMS降低DA系统的张力。然而，该电路目前省略了两个区域，被认为是人类MDD电路中的重要节点：膝下扣带皮层（BA 25），其啮齿动物同源物是边缘下前额叶皮层（ILPFC）和外侧缰（LHb）。人体研究表明，BA 25在MDD中过度活跃，BLA也是如此，因此ILPFC到BLA的已知投射可能导致BLA过度激活，这对UCMS后观察到的DA活性降低至关重要。或者，LHb具有到VTA DA神经元的更近端的投射，因此该区域的过度激活可以通过嘴内侧被盖（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）采用电生理和行为学方法研究正常大鼠ILPFC- >BLA和LHb->RMTg激活传出投射对DA系统的影响，2）为了评估在经历UCMS后表现出动机受损的动物中，使ILPFC->BLA或LHb->RMTg投射失活是否改善DA系统功能，3）确定潜在电路节点区域活动水平变化的发展时间进程，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深入了解，新的治疗干预措施可以专门针对该神经回路中的异常功能节点。

 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.