ProBDNF Signaling Regulates Depression-Like Behaviors in Rodents under Chronic Stress
ProBDNF Signaling Regulates Depression-Like Behaviors in Rodents under Chronic Stress
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DOI：
10.1038/npp.2016.100
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发表时间：
2016-11-01
影响因子：
7.6
通讯作者：
Zhou, Xin-Fu
中科院分区：
文献类型：
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作者：
Bai, Yin-Yin;Ruan, Chun-Sheng;Zhou, Xin-Fu
长期暴露在有压力的环境中是导致抑郁症发展的关键风险因素。然而，这一过程涉及的机制仍不清楚。脑源性神经营养因子(BDNF)在情绪调节中的积极作用一直被研究，尽管其前体ProBDNF在情绪调节中的作用尚不清楚。在这项研究中，使用不可预测的慢性温和应激(UCMS)范式，我们发现应激小鼠新皮质和海马区proBDNF的蛋白水平增加，这种由UCMS诱导的proBDNF上调可被长期给予氟西汀取消。然后我们建立了UCMS的大鼠模型，发现在慢性应激大鼠的大脑皮层和海马区，proBDNF/p75(NTR)/sortilin的表达上调，而成熟的BDNF和TrkB的表达下调。最后，我们发现经侧脑室注射抗ProBDNF抗体(i.c.v.)和腹膜腔(I.P.)入路UCMS大鼠可明显逆转应激诱导的抑郁样行为，恢复探索活动和脊柱生长。肌肉注射AAV-proBDNF不能加重UCMS诱导的大鼠情绪相关行为或病理异常，i.c.v。注射AAV-proBDNF可增加幼年大鼠的抑郁样行为。我们的研究结果表明，proBDNF在慢性应激诱导的啮齿动物情绪障碍的发展中起着作用。中环(I.C.V.)或外围设备(IP)通过注射特异性的抗ProBDNF抗体抑制proBDNF，可能为应激相关情绪障碍的治疗提供一种新的治疗方法。
Chronic exposure to stressful environment is a key risk factor contributing to the development of depression. However, the mechanisms involved in this process are still unclear. Brain-derived neurotropic factor (BDNF) has long been investigated for its positive role in regulation of mood, although the role of its precursor, proBDNF, in regulation of mood is not known. In this study, using an unpredictable chronic mild stress (UCMS) paradigm we found that the protein levels of proBDNF were increased in the neocortex and hippocampus of stressed mice and this UCMS-induced upregulation of proBDNF was abolished by chronic administration of fluoxetine. We then established a rat model of UCMS and found that the expression of proBDNF/p75(NTR)/sortilin was upregulated, whereas the expression of mature BDNF and TrkB was downregulated in both neocortex and hippocampus of chronically stressed rats. Finally, we found that the injection of anti-proBDNF antibody via intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) approaches into the UCMS rats significantly reversed the stress-induced depression-like behavior and restored the exploratory activity and spine growth. Although intramuscular injection of AAV-proBDNF did not exacerbate the UCMS-elicited rat mood-related behavioral or pathological abnormalities, i.c.v. injection of AAV-proBDNF increased the depression-like behavior in naive rats. Our findings suggest that proBDNF plays a role in the development of chronic stress-induced mood disturbances in rodents. Central (i.c.v.) or peripheral (i.p.) inhibition of proBDNF by injecting specific anti-proBDNF antibodies may provide a novel therapeutic approach for the treatment of stress-related mood disorders.