Role of neurotransmitters and environmental enrichment in the critical period of brain development

哺乳动物海马结构的齿状回(DG)在整个成年期产生新的神经元。在成年DG中，已经确定了几种实验状态和调节神经发生的因素。例如，暴露在丰富的环境中会增强DG中的神经发生，并改善依赖海马体的空间学习。此外，已知5-羟色胺会影响成人的神经发生、学习和记忆。然而，5-羟色胺在发育期的长期枯竭对神经发生的影响还没有被研究。因此，我们研究了长期5-羟色胺缺乏对环境富集性诱导的神经发生和空间记忆表现的影响。正如以前报道的那样，环境的丰富显著增加了DG中的新神经元。然而，在标准和环境富集室中，成年大鼠的空间学习测试没有改善。出生后第3天脑室注射5-羟色胺能神经毒素5，7-二羟色胺(5，7-DHT)明显降低成年大鼠海马中5-羟色胺的含量，而不能再生。在丰富的环境中，这种实验性的大鼠海马区5-羟色胺的耗竭对空间记忆能力没有影响，但导致DG中溴脱氧尿苷(BrdU)标记的新细胞的数量显著减少。这些发现表明，由环境丰富刺激的新产生的细胞对改善海马体依赖学习并不关键。此外，注射5，7-二羟色胺的大鼠DG内BrdU标记细胞的数量在注射BrdU后1d和4周之间没有差异。这些数据表明，在长期5-羟色胺耗竭的情况下，新生DG细胞的存活率保持相对稳定。

ABSTRACTThe dentate gyrus(DG) of the hippocampal formation produces new neurons throughout adulthood in mammalian species. Several experimental statuses and factors regulating neurogenesis have been identified in the adult DG. For example, exposure to an enriched environment enhances neurogenesis in the DG and improves hippocampus-dependent spatial learning. Furthermore, serotonin is known to influence adult neurogenesis, and learning and memory. However, the effects of long-lasting depletion of serotonin over the developing period on the neurogenesis have not been investigated. Thus, we examined the influence of long-lasting serotonin depletion on the environmental enrichment-induced neurogenesis and spatial memory performance. As reported previously, environmental enrichment significantly increased new neurons in the DG. However, there was no improvement of spatial learning test in adult rats in standard and in environmental enrichment housings.Intracisternal administration of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), on postnatal day 3 apparently reduced serotonin content in the adult hippocampus without regeneration. This experimental depletion of serotonin in the hippocampus of rats housed in an enriched environment had no effect on spatial memory performance, but produced significant decreases in the number of bromodeoxyuridine (BrdU)-labeled new cells in the DG. These findings indicate that newly generated cells stimulated by environmental enrichment are not critical for improvements in hippocampus-dependent learning. Furthermore, numbers of BrdU-labeled cells in the DG of 5,7-DHT-injected rats did not differ between 1 day and 4 weeks after BrdU injection. These data suggest that survival of newly generated DG cells remains relatively constant under long-lasting serotonin depletion.