Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice
Increased vulnerability to psychosocial stress in heterozygous serotonin transporter knockout mice
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DOI：
10.1242/dmm.004614
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发表时间：
2010-07-01
影响因子：
4.3
通讯作者：
Gross, Cornelius
中科院分区：
文献类型：
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作者：
Bartolomucci, Alessandro;Carola, Valeria;Gross, Cornelius
流行病学证据将暴露于压力性生活事件与精神疾病风险增加联系起来。然而，对环境风险因素的脆弱性存在显着的个体差异，遗传变异被认为在决定谁会生病方面发挥主要作用。例如，一些研究表明，携带5-羟色胺转运体（5-HTT）基因连锁多态性区域（5-HTTLPR）S（短）等位基因的个体在成年后暴露于压力后患重度抑郁症的风险增加。确定这种基因-环境风险因素的分子机制可以帮助我们理解压力恢复力的个体差异。在这里，我们提出了一个小鼠模型的5-HT的压力风险因素。野生型和杂合5-HTT敲除雄性小鼠经受三周的慢性心理社会应激。5-HTT基因型并没有影响应激的生理后果，测量体温，体重增加和血浆皮质酮的变化。然而，当与野生型同窝出生的小鼠相比，杂合5-HTT基因敲除小鼠经历高水平的应激性生活事件，表现出显着抑郁的运动活动和增加社会回避对一个陌生的男性在一个新的环境。暴露于高压力下的杂合5-HTT敲除小鼠也显示出比野生型同窝仔明显更低的5-羟色胺周转水平，选择性地在额叶皮质中，这是一种已知控制恐惧和回避反应的结构，并且与抑郁症的易感性有关。这些数据可以作为一个有用的动物模型，更好地了解增加的脆弱性，以压力报告携带5-HTTLPR S等位基因的个人，并建议，社会回避代表5-HTT和压力之间的相互作用的行为内表型。
Epidemiological evidence links exposure to stressful life events with increased risk for mental illness. However, there is significant individual variability in vulnerability to environmental risk factors, and genetic variation is thought to play a major role in determining who will become ill. Several studies have shown, for example, that individuals carrying the S (short) allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) have an increased risk for major depression following exposure to stress in adulthood. Identifying the molecular mechanisms underlying this gene-by-environment risk factor could help our understanding of the individual differences in resilience to stress. Here, we present a mouse model of the 5-HTT-by-stress risk factor. Wild-type and heterozygous 5-HTT knockout male mice were subjected to three weeks of chronic psychosocial stress. The 5-HTT genotype did not affect the physiological consequences of stress as measured by changes in body temperature, body weight gain and plasma corticosterone. However, when compared with wild-type littermates, heterozygous 5-HTT knockout mice experiencing high levels of stressful life events showed significantly depressed locomotor activity and increased social avoidance toward an unfamiliar male in a novel environment. Heterozygous 5-HTT knockout mice exposed to high stress also showed significantly lower levels of serotonin turnover than wild-type littermates, selectively in the frontal cortex, which is a structure that is known to control fear and avoidance responses, and that is implicated in susceptibility to depression. These data may serve as a useful animal model for better understanding the increased vulnerability to stress reported in individuals carrying the 5-HTTLPR S allele, and suggest that social avoidance represents a behavioral endophenotype of the interaction between 5-HTT and stress.