Diverse Roles of Adult Dentate Gyrus Neurogenesis

描述(申请人提供)：在哺乳动物的成年大脑中，干细胞有两个区域不断地产生新的神经元，这一过程被称为成人神经发生：脑室下区和齿状回颗粒下区(DG)。在DG中，成年出生的神经元通常成为颗粒细胞(GC)，这是主要的细胞类型。已有研究表明，正常认知功能和稳定情绪需要DG中的成体神经发生。也有研究表明，成人神经发生在颞叶癫痫(TLE)中起作用，癫痫发作涉及DG。然而，目前尚不清楚成人出生的颗粒细胞(GC)如何影响DG的功能，以及这可能如何影响TLE的癫痫发作。我们的初步结果表明，新生神经元通过年轻神经元与GABA能中间神经元的联系来调节局部网络抑制，从而影响DG的活动。具体地说，初步数据显示，在局部X射线照射或选择性切除成年小鼠的前体细胞后，缺乏成年神经发生的小鼠的抑制(通过细胞外场记录进行评估)减少。根据我们的初步结果，我们假设年轻的成年出生的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，成年出生的神经元减少了惊厥红藻氨酸的影响。这些影响是重要的，因为它们将允许成年出生的神经元调节DG作为内嗅皮层输入的“门”的作用，其中DG被认为防止海马神经元的过度激活。这种大脑皮层输入的门控似乎很重要，因此模式中的细微差异 可以区分输入，这是一种称为模式分离的功能。在TLE中，这个门被认为是减弱的，初步数据表明成人神经发生影响癫痫发作。然而，很难预测癫痫发作将如何在癫痫脑中受到影响，因为许多出生在癫痫动物模型中的GC是异常的，似乎促进而不是抑制癫痫发作。为了解决这些问题，我们将1)确定通过DG(内嗅皮层-DG-CA3)激活海马区的内嗅皮层通路通常是否被成年出生的GCs使用海马片中的生理学方法抑制，2)测试年轻GCs的选择性光遗传激活或抑制，以确定是否有优先影响中间神经元的活动，与初步数据一致，以及3)在TLE动物模型中测试成人出生的GCs的调节将影响急性和慢性癫痫发作的假设。我们预测，这些结果将导致范式转变，因为它们将表明成人神经发生具有不同的角色：在正常大脑中，成年出生的DG神经元是抑制和保护的，而在TLE中，成年出生的神经元出现的异常有助于疾病的病理生理，并促进癫痫发作。

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.