日前，中科院心理所林文娟和亓晓丽等研究者前期的研究结果表明抑郁大鼠海马和前额叶皮质这两个脑区的ERK信号通路活性水平显著降低，而抗抑郁药物氟西汀能够逆转ERK信号通路的损伤，并显著的缓解抑郁行为。这些结果提示ERK信号通路可能参与了抑郁行为的调节，但并不能得出ERK信号通路损伤是导致抑郁行为产生的原因的结论。
为了进一步揭示ERK信号通路在抑郁行为中的可能作用，林文娟和亓晓丽等研究者利用脑立体定位技术对海马和前额叶皮质的ERK信号通路分别进行阻断，然后观察大鼠的抑郁行为反应。结果表明海马ERK信号通路阻断大鼠表现了抑郁症的核心症状缺乏和明显的焦虑行为；前额叶皮质ERK信号通路阻断大鼠表现为缺乏和活动水平的降低。该研究结果表明无论海马或前额叶皮质的ERK信号通路都参与了抑郁行为的调节，海马或前额叶皮质的ERK信号通路损伤都可导致明显的抑郁行为反应。但值得提出的是两个脑区ERK通路在对具体的抑郁行为表现的调节上存在一定的差异，如海马ERK信号阻断引起显著的焦虑行为反应而无活力水平的降低，而前额叶皮质ERK通路阻断则表现了活力降低而无焦虑行为，从而表现了一定的脑区特异性。她们的研究同时考查了ERK调节抑郁行为的可能的下游目标分子，结果发现ERK阻断后核转录因子CREB的活性水平也显著降低，提示CREB可能是ERK调节抑郁行为的中间环节
Behavioural Brain Research Volume 199, Issue 2, 16 May 2009,
A role for the extracellular signal-regulated kinase signal pathway in depressive-like behavior
Xiaoli Qia, Wenjuan Lin, a, , Donglin Wanga, Yuqin Pana, Weiwen Wanga and Meng Suna
aKey Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Science, 4A Datun Road, Chaoyang District, Beijing 100101, China
Abstract
Our recent research demonstrates that the extracellular signal-regulated kinase (ERK) signal pathway is impaired in depressed animals, and such disruption is effectively reversed following antidepressant treatment. These results indicate that the ERK pathway may participate in the molecular mechani of depression. To provide direct evidence for the potential role of the ERK pathway in depression, the present study using a sub-chronic regimen of ERK inhibition investigated the disparate role for the ERK cascade in two specific brain areas, the dorsal hippocampus (dHP) and the medial prefrontal cortex (mPFC), in the pathophysiology of depressive-like behavior. Rats were bilaterally implanted with cannulas in the dHP or mPFC and were microinjected with U0126, a specific inhibitor of ERK upstream activator, or vehicle for 7 consecutive days. The behavioral effects of the ERK pathway inhibition were examined in the open field, elevated plus maze, and saccharin preference test. The results showed that the inhibition of the ERK pathway in dHP resulted in anhedonia and anxiety-like behavior, and the ERK pathway inhibition in the mPFC induced anhedonia and locomotor impairment in rats. The phosphorylation of the cyclic AMP-responsive-element-binding protein (CREB) was decreased following the ERK pathway inhibition either in dHP or mPFC. These findings demonstrate that the ERK pathway in either the dHP or mPFC participates in the pathophysiology of the depressive-like behavior, and may have pivotal role in human depression
