Hippocampal Neurogenesis and Accutane Induced Depression

描述(由申请人提供)：许多临床报告都将痤疮药物Acutane(异维甲酸，1，3-顺式维甲酸，RA)的使用与抑郁症联系在一起。然而，RA的确切行为效应尚不清楚，因为很少有研究研究RA对神经系统的影响。RA进入中枢神经系统，是一种强有力的转录激活剂，因此RA极有可能影响大脑功能。在成人大脑中为数不多的研究类风湿蛋白功能的区域之一是海马体，学习和记忆需要类风湿因子。这些过程可能需要在海马区产生新的神经元，而RA可能通过其作为神经干细胞分化强大诱导剂的影响而联系在一起。关于人类抑郁的根本原因的一个新假说是，海马体中新神经元的诞生减少。预计长期暴露在RA中会持续诱导神经元分化，最终耗尽产生神经元的神经干细胞，从而导致这种情况。我们的目标是通过研究RA对海马区细胞分裂的影响来验证这一假设，通过将5-溴脱氧尿苷(BrdU)掺入神经元或神经胶质细胞标记物的双标记细胞中来测量。这将与这些动物的海马体依赖和独立行为变化相关。我们预测，RA治疗将导致小鼠海马神经发生减少，并将导致海马区依赖行为的退化。这些研究将导致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，以及最重要的3)Acutane治疗的神经学后果的研究。

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.