Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities
Brain-derived neurotrophic factor-deficient mice develop aggressiveness and hyperphagia in conjunction with brain serotonergic abnormalities
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DOI：
10.1073/pnas.96.26.15239
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发表时间：
1999-12-21
影响因子：
11.1
通讯作者：
Tessarollo, L
中科院分区：
文献类型：
--
作者：
Lyons, WE;Mamounas, LA;Tessarollo, L
脑源性神经营养因子（BDNF）对中枢神经系统的5-羟色胺能（5-HT）神经元具有营养作用。然而，内源性BDNF在这些神经元发育和功能中的作用尚未在体内确定，因为BDNF缺失小鼠出生后早期死亡。在本研究中，我们使用具有正常寿命的杂合子BDNF+/-小鼠，并表明这些动物在成年早期表现出增强的雄性间攻击性和嗜食，并伴有显著的体重增加；这些行为异常与5-羟色胺功能障碍有关。BDNF+/-小鼠的前脑5-HT水平和纤维密度在早期是正常的，但会出现过早的衰老相关的下降。然而，年轻的成年BDNF+/-小鼠在特定的5-羟色胺释放-摄取抑制剂右芬氟拉明的诱导下，c-fos的表达减弱，皮质、海马和下丘脑中几种5-HT受体的表达发生改变。选择性5 -羟色胺再摄取抑制剂氟西汀可改善侵袭性增强。我们的研究结果表明，内源性BDNF对于中枢5-HT神经元的正常发育和功能以及依赖于这些神经细胞的行为的细化至关重要。因此，BDNF+/-小鼠可能为研究5 -羟色胺能神经元功能障碍引起的人类精神疾病提供一个有用的模型。
Brain-derived neurotrophic factor (BDNF) has trophic effects on serotonergic (5-HT) neurons in the central nervous system. However, the role of endogenous BDNF in the development and function of these neurons has not been established in vivo because of the early postnatal lethality of BDNF null mice. In the present study, we use heterozygous BDNF+/- mice that have a normal life span and show that these animals develop enhanced intermale aggressiveness and hyperphagia accompanied by significant weight gain in early adulthood; these behavioral abnormalities are known to correlate with 5-HT dysfunction. Forebrain 5-HT levels and fiber density in BDNF+/- mice are normal at an early age but undergo premature age-associated decrements. However, young adult BDNF+/- mice show a blunted c-fos induction by the specific serotonin releaser-uptake inhibitor dexfenfluramine and alterations in the expression of several 5-HT receptors in the cortex, hippocampus, and hypothalamus. The heightened aggressiveness can be ameliorated by the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that endogenous BDNF is critical for the normal development and function of central 5-HT neurons and for the elaboration of behaviors that depend on these nerve cells. Therefore, BDNF+/- mice may provide a useful model to study human psychiatric disorders attributed to dysfunction of serotonergic neurons.