Sert Expression and Survival of Serotonin Neurons

描述（由申请方提供）：已充分记录了前脑多巴胺能神经支配的年龄依赖性下降，并可能导致人类迟发性神经退行性疾病、抑郁症发生率增加或认知功能丧失（随年龄增长）。这项建议将调查突触5-羟色胺和年龄的长期升高之间的关系，以及它们对神经元神经支配的影响与5-羟色胺转运蛋白基因的遗传失活的小鼠。我们最近的研究表明，降低5-羟色胺转运蛋白的表达，结果在逆转或预防正常的年龄相关性退化的肾上腺素能轴突。我们推测，细胞外5-羟色胺的增加可能是作为一种营养因子，以促进前脑神经元轴突的生存。与野生型小鼠相比，缺乏5-羟色胺转运蛋白的小鼠显示细胞外5-羟色胺增加5倍。在5-羟色胺转运蛋白表达减少50%的小鼠中，已检测到细胞外5-羟色胺增加5倍。事实上，70%的正常人群表达的血清素转运蛋白减少了约30%，因此这些发现将直接适用于人类的衰老。我们将通过免疫细胞化学研究5-羟色胺转运体表达减少对前脑多巴胺能、儿茶酚胺能和胆碱能轴突的存活和完整性的影响。此外，我们还将评估5-羟色胺转运蛋白表达减少对局部5-羟色胺、多巴胺、去甲肾上腺素和乙酰胆碱神经递质水平的年龄相关影响。这些研究旨在整合解剖学和神经化学数据，以评估由于5-羟色胺转运蛋白表达降低而导致的整个生命周期中轴突神经支配的年龄相关变化。

DESCRIPTION (provided by applicant): An age-dependent decline in serotonergic innervation of the forebrain has been well documented and may contribute to late onset neurodegenerative disorders, increased incidence of depression or loss of cognitive function that occur with age in humans. This proposal will investigate the relationship between long-term elevations in synaptic serotonin and age and their effects on neuronal innervation in mice with a genetic inactivation of the serotonin transporter gene. Our recent studies indicate that decreased serotonin transporter expression results in a reversal or prevention of normal age-related degeneration of serotonergic axons. We hypothesize that increased extracellular serotonin may be functioning as a trophic factor to promote the survival of serotonergic axons in the forebrain. Mice that lack the serotonin transporter display a 5-fold increase in extracellular serotonin compared to wild type mice. In mice with a 50% reduction in serotonin transporter expression, a 5-fold increase in extracellular serotonin has been detected. In fact, 70% of the normal human population expresses approximately 30% less serotonin transporter, so these findings will have direct applicability to aging in humans. We will investigate the effect decreased serotonin transporter expression on the survival and integrity of forebrain serotonergic, catecholaminergic and cholinergic axons by immunocytochemistry. In addition, we will evaluate the age-related effects of reduced serotonin transporter expression on regional serotonin, dopamine, norepinephrine and acetylcholine neurotransmitter levels. These studies have been designed to integrate anatomical and neurochemical data to assess age-related changes in axonal innervation across the lifespan resulting from decreased of the serotonin transporter expression.