Jayatissa Magdalena N, Bisgaard Christina, Tingström Anders, Papp Mariusz, Wiborg Ove
Centre for Basic Psychiatric Research, Aarhus Psychiatric University Hospital, Aarhus, Denmark.
Neuropsychopharmacology. 2006 Nov;31(11):2395-404. doi: 10.1038/sj.npp.1301041. Epub 2006 Feb 8.
From clinical studies it is known that recurrent depressive episodes associate with a reduced hippocampal volume. Conversely, preclinical studies have shown that chronic antidepressant treatment increases hippocampal neurogenesis. Consequently, it has been suggested that a deficit in hippocampal neurogenesis is implicated in the pathophysiology of depression. To study a potential correlation between recovery and hippocampal cytogenesis, we established the chronic mild stress (CMS) rat model of depression. When rats are subjected to CMS, several depressive symptoms develop, including the major symptom anhedonia. Rats were exposed to stress for 2 weeks and subsequently to stress in combination with antidepressant treatment for 4 consecutive weeks. The behavioral deficit measured in anhedonic animals is a reduced intake of a sucrose solution. Prior to perfusion animals were injected with bromodeoxyuridine (BrdU), a marker of proliferating cells. Brains were sectioned horizontally and newborn cells positive for BrdU were counted in the dentate gyrus and tracked in a dorsoventral direction.CMS significantly decreased sucrose consumption and cytogenesis in the ventral part of the hippocampal formation. During exposure to the antidepressant escitalopram, given as intraperitoneally dosages of either 5 or 10 mg/kg/day, animals distributed in a bimodal fashion into a group, which recovered (increase in sucrose consumption), and a subgroup, which refracted treatment (no increase in sucrose consumption). Chronic treatment with escitalopram reversed the CMS-induced decrease in cytogenesis in the dentate gyrus of the ventral hippocampal formation, but in recovered animals only. Our data show a correlation between recovery from anhedonia, as measured by cessation of behavioral deficits in the CMS model, and an increase in cytogenesis in the dentate gyrus of the ventral hippocampal formation.
从临床研究可知，复发性抑郁发作与海马体体积减小有关。相反，临床前研究表明，慢性抗抑郁治疗可增加海马体神经发生。因此，有人提出海马体神经发生缺陷与抑郁症的病理生理学有关。为了研究恢复与海马体细胞生成之间的潜在相关性，我们建立了慢性轻度应激（CMS）大鼠抑郁症模型。当大鼠受到CMS刺激时，会出现多种抑郁症状，包括主要症状快感缺失。大鼠先接受2周的应激，随后连续4周接受应激并结合抗抑郁治疗。在快感缺失的动物中测量的行为缺陷是蔗糖溶液摄入量减少。在灌注前，给动物注射溴脱氧尿苷（BrdU），这是一种增殖细胞的标记物。将大脑水平切片，对齿状回中BrdU阳性的新生细胞进行计数，并沿背腹方向追踪。CMS显著降低了海马结构腹侧部分的蔗糖消耗和细胞生成。在腹腔注射剂量为5或10mg/kg/天的抗抑郁药艾司西酞普兰期间，动物以双峰方式分为一组恢复（蔗糖消耗增加）的动物和一组对治疗无反应（蔗糖消耗无增加）的亚组。艾司西酞普兰的慢性治疗逆转了CMS诱导的腹侧海马结构齿状回细胞生成减少，但仅在恢复的动物中出现这种情况。我们的数据表明，通过CMS模型中行为缺陷的停止来衡量的快感缺失恢复与腹侧海马结构齿状回细胞生成增加之间存在相关性。
