Moreines Jared L, Owrutsky Zoe L, Grace Anthony A
Departments of Neuroscience, Psychology, and Psychiatry, Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
Medical Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Neuropsychopharmacology. 2017 Mar;42(4):904-913. doi: 10.1038/npp.2016.249. Epub 2016 Nov 4.
Emerging evidence supports a role for dopamine in major depressive disorder (MDD). We recently reported fewer spontaneously active ventral tegmental area (VTA) dopamine neurons (ie, reduced dopamine neuron population activity) in the chronic mild stress (CMS) rodent model of MDD. In this study, we examined the role of two brain regions that have been implicated in MDD in humans, the infralimbic prefrontal cortex (ILPFC)-that is, rodent homolog of Brodmann area 25 (BA25), and the lateral habenula (LHb) in the CMS-induced attenuation of dopamine neuron activity. The impact of activating the ILPFC or LHb was evaluated using single-unit extracellular recordings of identified VTA dopamine neurons. The involvement of each region in dopamine neuron attenuation following 5-7 weeks of CMS was then evaluated by selective inactivation. Activation of either ILPFC or LHb in normal rats potently suppressed dopamine neuron population activity, but in unique patterns. ILPFC activation selectively inhibited dopamine neurons in medial VTA, which were most impacted by CMS. Conversely, LHb activation selectively inhibited dopamine neurons in lateral VTA, which were unaffected by CMS. Moreover, only ILPFC inactivation restored dopamine neuron population activity to normal levels following CMS; LHb inactivation had no restorative effect. These data suggest that, in the CMS model of MDD, the ILPFC is the primary driver of diminished dopamine neuron responses. These findings support a neural substrate for ILPFC/BA25 linking affective and motivational circuitry dysfunction in MDD.
新出现的证据支持多巴胺在重度抑郁症（MDD）中发挥作用。我们最近报道，在MDD的慢性轻度应激（CMS）啮齿动物模型中，腹侧被盖区（VTA）的自发活动多巴胺神经元较少（即多巴胺神经元群体活动减少）。在本研究中，我们研究了在人类MDD中涉及的两个脑区，即边缘下前额叶皮质（ILPFC）（即啮齿动物的布罗德曼25区（BA25）同源物）和外侧缰核（LHb）在CMS诱导的多巴胺神经元活动减弱中的作用。使用已鉴定的VTA多巴胺神经元的单单位细胞外记录来评估激活ILPFC或LHb的影响。然后通过选择性失活来评估每个区域在CMS 5-7周后对多巴胺神经元衰减的参与情况。在正常大鼠中激活ILPFC或LHb均能有效抑制多巴胺神经元群体活动，但方式独特。激活ILPFC选择性抑制内侧VTA中的多巴胺神经元，这些神经元受CMS影响最大。相反，激活LHb选择性抑制外侧VTA中的多巴胺神经元，这些神经元不受CMS影响。此外，只有ILPFC失活能使CMS后多巴胺神经元群体活动恢复到正常水平；LHb失活没有恢复作用。这些数据表明，在MDD的CMS模型中，ILPFC是多巴胺神经元反应减弱的主要驱动因素。这些发现支持了ILPFC/BA25在MDD中连接情感和动机回路功能障碍的神经基础。
