Diverse Roles of Adult Dentate Gyrus Neurogenesis

成人齿状回神经发生的多种作用

• 批准号: 8824981
• 负责人: Helen E Scharfman
• 金额: $ 36.11万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8824981
• 关键词: Ablation; Acute; Address; Adult; Affect; Animal Model; Animals; Area; Axon; Back; Brain; Chronic; Convulsants; Data; Diet; Disease; Dose; Electroencephalography; Epilepsy; Functional disorder; Generations; Genetic; Glial Fibrillary Acidic Protein; Glutamates; Halorhodopsins; Health; Hippocampus (Brain); Hour; Injection of therapeutic agent; Interneurons; Kainic Acid; Lead; Life; Light; Location; Methods; Modeling; Monitor; Moods; Motor Seizures; Mus; Neurons; Pathway interactions; Pattern; Physiologic pulse; Physiological; Play; Predisposition; Process; Pyramidal Cells; Recurrence; Regulation; Roentgen Rays; Role; Seizures; Simplexvirus; Site; Slice; Specificity; Stem cells; Synapses; Synaptic Transmission; Temporal Lobe Epilepsy; Testing; Thymidine Kinase; Valganciclovir; adult neurogenesis; base; cell type; cognitive function; dentate gyrus; entorhinal cortex; extracellular; feeding; granule cell; in vivo; interest; irradiation; killings; neurogenesis; newborn neuron; novel; optogenetics; postsynaptic; prevent; progenitor; reconstruction; subventricular zone; young adult

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.

描述（由申请人提供）：在哺乳动物成年大脑中，有两个区域，干细胞不断产生新的神经元，这一过程被称为成体神经发生：齿状回（DG）的室下区和颗粒下区。在 DG 中，成年神经元通常会变成颗粒细胞 (GC)，这是主要的细胞类型。有人认为，DG 中的成体神经发生是正常认知功能和稳定情绪所必需的。还有研究表明，成人神经发生在颞叶癫痫 (TLE) 中发挥着重要作用，其中癫痫发作涉及 DG。然而，目前尚不清楚成年颗粒细胞 (GC) 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，新生神经元通过年轻神经元与 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。具体而言，初步数据表明，在成年小鼠中进行局灶 X 射线照射或选择性消融前体后，缺乏成年神经发生的小鼠的抑制（通过细胞外场记录评估）减少。根据我们的初步结果，我们假设年轻的成年 GC 通过激活局部抑制性中间神经元来抑制成熟 GC 的活性。我们的初步数据还显着地表明，成年神经元会降低惊厥红藻氨酸的作用。这些效应非常重要，因为它们将允许成年神经元调节 DG 作为内嗅皮质输入“门”的作用，其中 DG 可以防止海马神经元的过度激活。这种皮质输入的门控似乎很重要，因此模式的细微差异 输入的数据可以被区分，这个功能称为模式分离。在 TLE 中，有人认为该门会减弱，初步数据表明成人神经发生会影响癫痫发作。然而，很难预测癫痫大脑中的癫痫发作将如何受到影响，因为在癫痫动物模型中产生的许多 GC 都是异常的，并且似乎会促进癫痫发作而不是抑制癫痫发作。为了解决这些问题，我们将 1) 使用海马切片中的生理方法确定内嗅皮层通过 DG (内嗅-DG-CA3) 激活海马的通路是否通常被成年出生的 GC 抑制，2) 测试选择性光遗传学激活或抑制年轻 GC 以确定是否对中间神经元的活动有优先影响，与初步数据一致，并且 3）检验以下假设：调节成年出生的 GC GC 会影响 TLE 动物模型的急性和慢性癫痫发作。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作用：在正常大脑中，成人出生的 DG 神经元具有抑制性和保护性，而在 TLE 中，成人出生的神经元中出现的异常神经元有助于疾病的病理生理学，并促进癫痫发作。