Diverse Roles of Adult Dentate Gyrus Neurogenesis

描述（由申请人提供）：在哺乳动物成年脑中，有两个区域干细胞不断产生新的神经元，这一过程称为成年神经发生：齿状回（DG）的脑室下区和颗粒下区。在DG中，成年出生的神经元通常会变成颗粒细胞（GC），这是主要的细胞类型。已经表明，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）中发挥作用，其中癫痫发作涉及DG。然而，目前尚不清楚成年出生的颗粒细胞（GC）如何影响DG的功能，以及如何影响TLE的癫痫发作。 我们的初步结果表明，新生神经元的影响活动的DG通过调制本地网络抑制通过连接年轻的神经元与GABA能中间神经元。具体而言，初步数据显示，抑制（通过胞外场记录评估）减少缺乏成年神经发生的小鼠后，局灶性X射线照射或选择性消融的前体在成年小鼠。基于我们的初步结果，我们假设年轻的成年人出生的GC抑制成熟GC的活性，通过激活本地抑制性中间神经元。我们的初步数据还表明，值得注意的是，成人出生的神经元减少了惊厥性红藻氨酸的影响。这些影响是显着的，因为它们将允许成年出生的神经元调节DG的作用作为一个“门”，内嗅皮质输入，其中有人提出，DG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， 可以区分输入，这一功能称为模式分离。在TLE中，已经表明这个门变弱，初步数据表明成年神经发生影响癫痫发作。然而，很难预测癫痫发作将如何影响癫痫患者的大脑，因为许多在癫痫动物模型中出生的GC是异常的，并且似乎促进癫痫发作而不是抑制它们。为了解决这些问题，我们将1）确定是否从内嗅皮层通过DG激活海马的通路2）测试年轻GC的选择性光遗传学激活或抑制以确定是否存在对中间神经元活性的优先效应，与初步数据一致，和3）在TLE的动物模型中检验成人出生的GC的调节将影响急性和慢性癫痫发作的假设。我们预测，结果将导致一个范式转变，因为他们将表明，成人神经发生有不同的角色：在正常的大脑中，成年出生的DG神经元是抑制和保护，而在TLE中，出现在成年出生的神经元异常有助于疾病的病理生理学，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.