Ectopic Granule Cells in the Dentate Gyrus

齿状回异位颗粒细胞

• 批准号: 8197857
• 负责人: Helen E Scharfman
• 金额: $ 18.8万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197857
• 关键词: Address; Adult; Affect; Alcoholism; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein Precursor; Animal Experiments; Animal Model; Animals; Area; Autopsy; BAX gene; Behavior; Behavioral; Cell Count; Cells; Cognition; Cognitive; Complex; Computer Simulation; Cues; Data; Defect; Development; Diagnosis; Diagnostic; Disease; Electrophysiology (science); Epilepsy; Exhibits; Foundations; Functional disorder; Goals; Hilar; Hippocampus (Brain); Human; Image; Impaired cognition; Impairment; In Vitro; Laboratories; Lead; Learning; Life; Memory; Mental disorders; Modeling; Molecular; Molecular Target; Moods; Mus; Mutate; Neurons; Normal Range; Pathology; Patients; Pattern; Physiology; Pilot Projects; Recurrence; Reporting; Research; Schizophrenia; Seizures; Simulate; Slice; Specimen; Temporal Lobe Epilepsy; Tg2576; Therapeutic; Transgenic Mice; Transgenic Organisms; adult neurogenesis; base; behavior test; behavioral impairment; cognitive function; conditioned fear; dentate gyrus; granule cell; improved; in vivo; insight; migration; mood regulation; nervous system disorder; neurogenesis; novel diagnostics; novel therapeutics; overexpression; postnatal; prevent; public health relevance; research study; tool

DESCRIPTION (provided by applicant): It has been suggested that postnatal neurogenesis of granule cells (GCs) in the adult dentate gyrus serves important functions related to cognition and mood regulation, and that impairments in postnatal neurogenesis may occur in many diseases. In contrast to most research about adult neurogenesis, which focuses on the normal area where GCs are located, the granule cell layer, in this proposal we suggest a different area is important, the adjacent hilus. We propose that, in a variety of pathological conditions, adult-born GCs mismigrate into the hilus, and these ectopic GCs (EGCs) cause dysfunction. This hypothesis is based on studies of EGCs in an animal model of epilepsy, where it was found that hilar EGCs develop, and display abnormal excitability and circuitry. Surprisingly, we have now found evidence for hilar EGCs in animal models of psychiatric illness, such as Alzheimer's disease (AD). In parallel, other laboratories have reported that mismigration of adult-born GCs occurs in schizophrenia and alcoholism. In our pilot studies from transgenic mice that simulate AD, EGCs appear to develop abnormal excitability and circuitry, so we hypothesize that they will disrupt circuit function like they do in animal models of epilepsy. We also have preliminary data suggesting that EGCs are present in postmortem specimens from patients with psychiatric illness. Therefore, in this proposal we will attempt to show that hilar EGCs are not only relevant to epilepsy, but psychiatric disease. We hypothesize that EGCs develop in psychiatric disorders because the molecular mechanisms that are responsible for these conditions also disrupt the normal cues that control migration of GCs. The experiments that are proposed will use 1) anatomical approaches to prove that EGCs exist in animal models of psychiatric diseases, 2) slice electrophysiology to prove the EGCs have abnormal excitability and circuitry in these animal models, 3) behavioral experiments to prove the EGCs are accompanied by dysfunction in vivo, and 4) computational modeling to show that EGCs will disrupt specific functions of the dentate gyrus in a computational model of the normal dentate gyrus network. The results would be significant because they would provide evidence for a common pathology across many diseases that affect cognition and behavior: EGCs in the hilus of the dentate gyrus. This insight could lead to the development of new therapeutics to target the molecular mechanisms of migration. Imaging EGCs could become a new diagnostic strategy. Improved therapeutics and diagnostics are both important because many psychiatric disorders are complex, presenting difficulties both in diagnosis as well as treatment. PUBLIC HEALTH RELEVANCE: It is often assumed that postnatal neurogenesis in the dentate gyrus improves cognitive function and mood, so increasing the rate of neurogenesis is beneficial. However, we suggest that this positive effect may not occur when pathological conditions exist, because these conditions disrupt the cues that control normal migration. Therefore, ectopic neurons can develop and disrupt function, and therapeutic strategies that support normal migration would prevent dysfunction.

描述（申请人提供）：有人提出，成人齿状回中颗粒细胞（GC）的出生后神经发生具有与认知和情绪调节相关的重要功能，并且出生后神经发生损伤可能在许多疾病中发生。大多数关于成体神经发生的研究都集中在 GC 所在的正常区域（颗粒细胞层），与此相反，在本提案中，我们建议另一个重要的区域，即相邻的门。我们认为，在各种病理条件下，成年出生的 GC 会错误迁移到肺门，而这些异位 GC (EGC) 会导致功能障碍。 这一假设基于对癫痫动物模型中 EGC 的研究，研究发现肺门 EGC 发育并表现出异常的兴奋性和电路。令人惊讶的是，我们现在在阿尔茨海默病（AD）等精神疾病动物模型中发现了肺门 EGC 的证据。与此同时，其他实验室也报告称，在精神分裂症和酗酒中，成年出生的 GC 会发生错误迁移。在我们对模拟 AD 的转基因小鼠进行的初步研究中，EGC 似乎出现了异常的兴奋性和回路，因此我们假设它们会像在癫痫动物模型中那样破坏回路功能。我们还有初步数据表明，精神疾病患者的尸检标本中存在 EGC。因此，在本提案中，我们将尝试证明肺门 EGC 不仅与癫痫相关，而且与精神疾病相关。我们假设 EGC 在精神疾病中发展，因为导致这些疾病的分子机制也会破坏控制 GC 迁移的正常线索。所提出的实验将使用1）解剖学方法来证明EGCs存在于精神疾病的动物模型中，2）切片电生理学来证明EGCs在这些动物模型中具有异常的兴奋性和电路，3）行为实验来证明EGCs伴随体内功能障碍，以及4）计算模型来证明EGCs将 破坏正常齿状回网络计算模型中齿状回的特定功能。 这些结果意义重大，因为它们将为影响认知和行为的许多疾病的共同病理学提供证据：齿状回门中的 EGC。这一见解可能会导致针对迁移分子机制的新疗法的开发。 EGC 成像可能成为一种新的诊断策略。改进的治疗和诊断都很重要，因为许多精神疾病很复杂，给诊断和治疗带来困难。 公众健康相关性：人们通常认为出生后齿状回的神经发生可以改善认知功能和情绪，因此提高神经发生率是有益的。然而，我们认为，当存在病理条件时，这种积极作用可能不会发生，因为这些条件破坏了控制正常迁移的线索。因此，异位神经元可以发育并破坏功能，支持正常迁移的治疗策略可以防止功能障碍。

项目成果

Corruption of the dentate gyrus by "dominant" granule cells: Implications for dentate gyrus function in health and disease.

“主导”颗粒细胞对齿状回的破坏：对健康和疾病中齿状回功能的影响。

• DOI: 10.1016/j.nlm.2015.09.005
• 发表时间: 2016
• 期刊: Neurobiology of learning and memory
• 影响因子: 2.7
• 作者: Scharfman,HelenE;Myers,CatherineE
• 通讯作者: Myers,CatherineE

The influence of ectopic migration of granule cells into the hilus on dentate gyrus-CA3 function.

颗粒细胞异位迁移到Hilus对齿状回-CA3功能的影响。

• DOI: 10.1371/journal.pone.0068208
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Myers CE;Bermudez-Hernandez K;Scharfman HE
• 通讯作者: Scharfman HE

Hilar mossy cells of the dentate gyrus: a historical perspective.

• DOI: 10.3389/fncir.2012.00106
• 发表时间: 2012
• 期刊: Frontiers in neural circuits
• 影响因子: 3.5
• 作者: Scharfman HE;Myers CE
• 通讯作者: Myers CE

Hilar granule cells of the mouse dentate gyrus: effects of age, septotemporal location, strain, and selective deletion of the proapoptotic gene BAX.

• DOI: 10.1007/s00429-017-1391-5
• 发表时间: 2017-09
• 期刊: Brain structure & function
• 影响因子: 3.1
• 作者: Bermudez-Hernandez K;Lu YL;Moretto J;Jain S;LaFrancois JJ;Duffy AM;Scharfman HE
• 通讯作者: Scharfman HE