The Effects Of Environmental Factors On Adult Mouse Hippocampal Neurogenesis And Learning And Memory

In most mammals, active neurogenesis occurs throughout life. Active neurogenesis occurs in two discrete regions: the subventricular zone of the lateral ventricle, from where newborn neurons migrate to the olfactory bulb or striatum and differentiate mostly into interneurons, and the dentate gyrus of the hippocampus, where newborn granule cells are integrated into the local circuitry The generation of newborn cells is maintained throughout life in the hippocampus of the mammalian brain by the proliferation, differentiation and migration of adult neural progenitor cells(NPCs), and their eventual integration into neural networks. Originally thought to occur only during embryonic development, active adult neurogenesis has now been shown in almost all mammalian species examined so far. Failing adult hippocampal neurogenesis has thus been brought into connection with the pathogenesis and course of dementias, age-related cognitive decline, major depression, and schizophrenia. Conversely, supporting or even enhancing adult neurogenesis might become a useful target to address these diseases. In many pathological conditions, adult neurogenesis responds to the damaging stimulus, presumably in a rather nonspecific way. Hypoxia, ischemia, trauma, infection, etc., all initially stimulate neurogenesis. Learning and memory is the advanced brain functions, which is the mostly studied field in biology sciences. It has been identified that the adult neurogenesis is closed related with learning and memory. Individual molecules with regulatory effects on adult neurogenesis are numerous, ranging from transcription factors over paracrine signaling molecules, extracellular matrix, and cell–cell contacts, to neurotransmitters, growth factors, hormones, and cytokines. The most notorious negative regulator of adult neurogenesis, again only extensively studied in the hippocampus, is stress, while physical activity promotes the proliferation of the precursor cells, the more cognitive stimuli, for example, the experience of so-called enriched environments or concrete learning stimuli, enhance the recruitment and survival of newborn neurons.How did the neural stem cells generated and integrated in the local networks, what is the mechanisms underling the process. What were the coutributions of adult neurogenesis for brain function. To investigate how environmental factor work on adult neurogenesis, we chose several neural compounds, including swainsonine, lead, lithium and nitrite. Firstly, we are try to study what effects of these compound on adult neurogenesis. Secondly, we want to illustrate the relation between adult neurogenesis and cognitions through these drugs. Furthermore, what is the mechanisms underling the process.This work were conducted based on animal model, we will investigate the effects of drugs on adult neurogenesis and learning and memory with following advanced techniques: Intraperitoneal injection of BrdU(a marker for cell proliferation), multiple fluorescent immunohistochemistry, laser confocal microscope, Western-blot and Morris Water Maze test. The main findings are as follows:1. Swainsonine(SW) is an indolizidine triol plant alkaloid isolated from the species Astragalus, colloquially termed locoweed. Ingestion induces severe neurological symptoms of livestock and wildlife, including ataxia, trembling, exaggerated fright reactions. Toxicity to the central and peripheral nervous system is caused by inhibition of lysosomal a-mannosidase(AMA) and accumulation of intracellular oligosaccharide. Our results showed that SW reduced proliferation and survival of neural progenitor cells(NPCs) in culture, and in the hippocampus of adult mice. In addition, exposure to SW led to down-regulation of doublecortin(DCX) and synaptophysin(SYP) in the hippocampus. However, caspase3 and glial fibrillary acidic protein(GFAP) levels were significantly increased in SW-treated mice. Finally, SW-treated mice exhibited deficits in hippocampus-dependent spatial learning and memory. Our findings suggest that SW affects adult neurogenesis and cognitive function.2. Occupational and environmental exposures to lead(Pb), one of the toxic metal pollutants, is of global concern. The present study aims to investigate the protective effects of lithium(Li) against Pb-induced damages in vivo and in vitro. Treatment of mice with Pb induced remarkable morphological damages in multiple organs, such as swelling and necrosis in liver, kidney and spleen. Immunohistochemistry demonstrated that the number of newly generated cells and immature neurons in hippocampus was significantly decreased in mice exposed to Pb when compared with those that received saline for control or Li. Furthermore, in mice exposed to Pb a higher percentage of newly generated cells differentiated to glial cells and fewer to neurons, and less newborn cells survived compared to those in controls and Li-treated mice. In mice exposed to Pb cognitive tests were impaired. Interestingly, pre-administration of Li markedly decreased Pb-induced pathological and neurological lesions in vivo and in vitro. Specifically, the reduction of hippocampal neurogenesis resulting from Pb exposure was prevented by administration of Li. In addition, we found that pretreatment with Li effectively prevented cognitive impairment in mice exposed to Pb. Furthermore, Li pretreatment significantly improved Pb-induced depletion in p-GSK-3β(Ser9) and microRNA-34 c levels in hippocampus. Collectively our findings point to a capacity of Li to attenuate Pb-induced damage.3. To investigate the influence of nitrite poisoning on the proliferation, differentiation and survival of adult neural stem cells in mouse dentate gyrus. Our results showed that both the number of BrdU-positive cells and the survival rate of new born cells in experimentally poisoning mice were remarkably decreased compared with the control group, indicating that the differentiation and survival of adult neural stem cells were significantly influenced by the nitrite poisoning. The BrdU/NeuN double labeled cells in experimentally poisoning group were significantly lower than that in control group. But the migration direction of new born cells was not influenced by nitrite. These results suggest that nitrite poisoning suppressed the proliferation of adult neural stem cells and reduced the survival rate of newly generated cells in the SGZ of the dentate gyrus in mice.