Hippocampal Neurogenesis and Accutane Induced Depression

描述（由申请人提供）：许多临床报告将痤疮药物维甲酸（异维甲酸，1 3-顺式维甲酸，RA）与抑郁症的使用联系起来。然而，由于很少有研究调查类风湿关节炎的神经效应，类风湿关节炎的确切行为效应尚不清楚。RA进入中枢神经系统，是一种有效的转录激活剂，因此RA极有可能影响大脑功能。成人大脑中少数几个被研究类风湿关节炎功能的区域之一是海马体，类风湿关节炎是学习和记忆所必需的。这些过程可能需要海马中新的神经元生成，RA可能通过其作为神经干细胞分化的强大诱导剂的影响而联系在一起。一个关于人类抑郁的潜在原因的新假设是海马中新神经元的生成减少。长期暴露于类风湿关节炎会通过持续诱导神经元分化并最终消耗产生神经元的神经干细胞而导致这种情况。目的是通过研究RA对海马细胞分裂的影响来验证这一假设，通过将5-溴脱氧尿苷（BrdU）掺入双标记神经元或胶质细胞标记的细胞来测量。这将与这些动物的海马依赖性和独立行为变化有关。我们预测，RA治疗将导致小鼠海马神经发生减少，并导致海马依赖行为的退化。这些研究将引导未来的研究：1)RA在海马神经发生中的正常功能，2)神经发生在行为改变中的作用，最重要的是3)acutane治疗的神经学后果。

DESCRIPTION (provided by applicant): Numerous clinical reports have associated the use of the acne drug Accutane (Isotretinoin, 1 3-cis retinoic acid, RA) with depression. However, the precise behavioral effects of RA are unknown because few studies have investigated the neurological effects of RA. RA enters the CNS and is a potent transcriptional activator and thus it is highly likely that RA will influence brain function. One of the few areas of the adult brain in which RA function has been investigated is the hippocampus where RA is required for learning and memory. These processes probably require new neuronal birth in the hippocampus and RA may be linked via its influence as a powerful inducer of neural stem cell differentiation. A new hypothesis for the underlying cause of human depression is a decline in the birth of new neurons in the hippocampus. Chronic exposure to RA would be expected to cause exactly that by persistently inducing neuronal differentiation and eventually depleting the neural stem cells that generate neurons. The goal will be to test this hypothesis by investigating the influence of RA on cell division in the hippocampus as measured by 5-bromo deoxy-uridine (BrdU) incorporation into cells double labeled for either neuronal or glial cell markers. This will be correlated with hippocampal dependant and independent behavioral changes in these animals. We predict that treatment with RA will result in a decrease in hippocampal neurogensis in mice and will result in degradation of hippocampal dependant behavior. These studies will lead to future studies on 1) the normal function of RA in hippocampal neurogenesis, 2) the role of neurogenesis in behavior changes and, most importantly 3) the neurological consequences of Accutane treatment.