Hippocampal Neurogenesis and Accutane Induced Depression

描述（由申请人提供）：大量临床报告将痤疮药物Accutane（异维甲酸，1 - 3-顺式维甲酸，RA）的使用与抑郁症相关联。然而，RA的确切行为影响是未知的，因为很少有研究调查了RA的神经影响。RA进入中枢神经系统，是一种有效的转录激活因子，因此RA极有可能影响脑功能。研究RA功能的成人大脑的少数区域之一是海马体，其中RA是学习和记忆所必需的。这些过程可能需要新的神经元出生在海马和RA可能通过其作为一个强大的诱导神经干细胞分化的影响。一个关于人类抑郁症潜在原因的新假设是海马体中新神经元的出生减少。长期暴露于RA预计将导致正是通过持续诱导神经元分化，并最终耗尽神经干细胞产生神经元。我们的目标是通过研究RA对海马细胞分裂的影响来检验这一假设，所述海马细胞分裂是通过将5-溴脱氧尿苷（BrdU）掺入双标记的神经元或神经胶质细胞标志物的细胞中来测量的。这将与这些动物的海马依赖性和独立性行为变化相关。我们预测用RA治疗将导致小鼠海马神经发生的减少，并将导致海马依赖性行为的退化。这些研究将导致未来的研究：1）RA在海马神经发生中的正常功能，2）神经发生在行为变化中的作用，最重要的是3）维甲酸治疗的神经学后果。

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.