Diverse Roles of Adult Dentate Gyrus Neurogenesis

描述（由申请人提供）：在哺乳动物成年大脑中，有两个区域的干细胞不断产生新的神经元，这一过程被称为成人神经发生：脑室下区和齿状回（DG）的亚颗粒区。在DG中，成年出生的神经元通常变成颗粒细胞（GCs），这是主要的细胞类型。有研究表明，DG中的成人神经发生是正常认知功能和稳定情绪所必需的。也有人认为，成人神经发生在颞叶癫痫（TLE）中起作用，其中癫痫发作涉及DG。然而，目前尚不清楚成人颗粒细胞（GCs）如何影响DG的功能，以及这如何影响TLE的癫痫发作。我们的初步结果表明，新生神经元通过与gaba能中间神经元的连接来调节局部网络抑制，从而影响DG的活动。具体来说，初步数据显示，在局部x射线照射或选择性消融成年小鼠的前体后，缺乏成年神经发生的小鼠的抑制作用（通过细胞外场记录评估）降低。基于我们的初步结果，我们假设年轻成年出生的GCs通过激活局部抑制性中间神经元来抑制成熟GCs的活性。我们的初步数据还表明，值得注意的是，成年的神经元减少了惊厥酸的作用。这些影响是重要的，因为它们允许成年神经元调节DG作为内嗅皮层输入的“门”的作用，在那里，DG被认为可以防止海马神经元的过度激活。这种皮层输入的门控似乎很重要，因此模式上的细微差异

DESCRIPTION (provided by applicant): In the mammalian adult brain, there are two regions where stem cells continuously give rise to new neurons, a process termed adult neurogenesis: the subventricular zone and the subgranular zone of the dentate gyrus (DG). In the DG, adult-born neurons normally become granule cells (GCs), the principal cell type. It has been suggested that adult neurogenesis in the DG is required for normal cognitive functions, and to stabilize mood. It also has been suggested that adult neurogenesis plays a role in temporal lobe epilepsy (TLE) where seizures involve the DG. However, it is not yet clear how adult-born granule cells (GCs) influence the function of the DG and how this might influence seizures in TLE. Our preliminary results indicate that newborn neurons influence activity in the DG by modulating local network inhibition via the connections young neurons make with GABAergic interneurons. Specifically, preliminary data show that inhibition (assessed by extracellular field recordings) is reduced in mice lacking adult neurogenesis following focal X-ray irradiation or selective ablation of precursors in an adult mouse. Based on our preliminary results, we hypothesize that young adult-born GCs inhibit the activity of mature GCs via the activation of local inhibitory interneurons. Our preliminary data also suggest, remarkably, that adult-born neurons reduce the effects of the convulsant kainic acid. These effects are significant because they would allow adult-born neurons to regulate the role of the DG as a "gate" to entorhinal cortical input, where it is proposed that the DG prevents excessive activation of hippocampal neurons. This gating of cortical input appears to be important so that fine differences in patterns of input can be discriminated, a function called pattern separation. In TLE, where it has been suggested that this gate weakens, the preliminary data suggest that adult neurogenesis influences seizures. However, it is hard to predict how seizures will be influenced in the epilepti brain because many GCs that are born in animal models of epilepsy are abnormal and appear to facilitate seizures rather than inhibit them. To address these questions we will 1) determine whether the pathway from the entorhinal cortex that activates hippocampus via the DG (entorhinal-DG-CA3) is normally inhibited by adult-born GCs using physiological methods in hippocampal slices, 2) test selective optogenetic activation or inhibition of young GCs to determine if there is a preferential effect on the activity of interneurons, consistent with preliminary data, and 3) test the hypothesis that modulation of adult-born GCs will affect acute and chronic seizures in an animal model of TLE. We predict that the results will lead to a paradigm shift because they will show that adult neurogenesis has diverse roles: in the normal brain, adult-born neurons of the DG are inhibitory and protective, whereas in TLE, abnormalities that arise in adult-born neurons contribute to the pathophysiology of the disease, and facilitate seizures.