DISTINCTIVE SPATIOTEMPORAL MAP OF TARGET ACTIVATION BY YOUNG NEURONS OF THE ADULT
成人年轻神经元目标激活的独特时空图
基本信息
- 批准号:8505342
- 负责人:
- 金额:$ 4.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-01-01 至 2015-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdultAnimalsAreaAstrocytesAwarenessAxonBiologicalBrainCationsCellsCharacteristicsCollaborationsCommunitiesDataDefectDevelopmentDevelopmental ProcessDiseaseDistalDyesFeedbackFemaleFrequenciesFutureGenerationsGlutamatesGoalsGrantGrowthHilarHippocampus (Brain)In VitroInfectionInstitutesInstitutionInstructionInternationalInterneuronsJointsKnowledgeLaboratoriesLearningLightLong-Term PotentiationMapsMediatingMemoryMental DepressionMolecularMorphologyMusNatural regenerationNerve DegenerationNeurodegenerative DisordersNeuronal DifferentiationNeuronsNewborn InfantOutcomeOutputPerinatalPhysiologic pulsePopulationPresynaptic TerminalsProcessPropertyProtein FamilyPyramidal CellsResearchResearch PersonnelRetroviral VectorRoleShapesSignal PathwaySignal TransductionSliceSocietiesSolidSourceStagingStimulusSynapsesTechnologyTestingTheoretical modelTimeTrainingTraumaUnited States National Institutes of HealthWhole-Cell Recordingsadult neurogenesisbrain repaircomputerized data processingdentate gyrusdesigndriving forceexpectationfeedinggamma-Aminobutyric Acidgranule cellhippocampal pyramidal neuronimprovedin vivoinformation processinglearned behaviorloss of functionmembermossy fibernerve stem cellneurogenesisneuron developmentnewborn neuronnovelparent grantpostsynapticpresynapticreconstructionregenerative therapyresponseretroviral transductionspatiotemporalsuccesssynaptogenesistooltransmission processyoung adult
项目摘要
The adult dentate gyrus continuously generates granule cells (DGCs) that are needed for specific
learning and memory tasks, but the precise contribution of new neurons to information processing in
the hippocampal circuitry remains unknown. In the past, we have demonstrated that key
developmental processes occurring in the perinatal brain such as maturation of excitability, afferent
synaptogenesis and function are all recapitulated during adult neurogenesis. We now propose the
central hypothesis that newly born cells establish functional outputs as they develop, and the
population of postsynaptic target cells contacted by young neurons is predominantly inhibitory,
therefore different from the mixed excitatory/inhibitory network activated by mature granule cells.
Thus, there would be a time window in which young DGCs primarily activate feedforward and/or
feedback inhibitory circuits without exciting pyramidal cells, exerting a tight inhibitory control over
the dentate gyrus output. In Aim 1 we will build a spatio-temporal map of target activation by young
developing neurons of the adult dentate gyrus. We will use retroviral transduction to express the light-
activated cation channel Channelrhodopsin-2 in newborn DGCs of young-adult female mice
(C57Bl6/J). We will sacrifice the animals at different times and prepare acute brain slices to carry out
electrophysiological recordings. By stimulating the whole hippocampal slice with brief light pulses, all
retrovirally transduced neurons will spike. We will search randomly for active postsynaptic target cells
throughout the hilus and CA3 regions, and identify and characterize responsive neurons by combining
loose patch and whole-cell recordings. In Aim 2 we will investigate the functional maturation of new
mossy fiber synapses made onto GABAergic and glutamatergic targets. We plan to utilize whole-cell
recordings to test whether synapses forming onto GABAergic interneuron targets mature faster than
those made onto pyramidal cells, as suggested by our previous structural studies. We will also study
presynaptic mechanisms of short- and long-term plasticity that will shape both activity-dependent
competition and activation of postsynaptic circuits. This project will address fundamental questions
about connectivity and activation (spiking) of newborn cells that will contribute to understanding the
precise impact of adult neurogenesis in the preexisting hippocampal network and the rules of neuronal
connectivity in the adult brain. Identifying the rules by which neurons integrate in the existing
network in a manner that is both safe and functionally relevant is also crucial for developing future
brain repair therapies.
Novel retroviral tools will be developed in collaboration with the Gage lab to enhance
Channelrhodopsin-2 expression, thus improving the capability of light activation of newborn cells. In
turn, experimental data obtained here will be used to feed into the theoretical model being developed
by the Gage lab on the role of immature neurons in signal processing. The success of the proposed
project relies on strengthening the close interaction between the Schinder laboratory at the Leloir
Institute (Buenos Aires) and the Gage laboratory at the Salk Institute of La Jolla. Members of the
Schinder lab will have the opportunity to train at Salk on the generation and characterization of novel
retroviral vectors, improving the capabilities to develop advanced molecular tools at the foreign
institution. We anticipate that capacity building leading to the design, generation and
use of novel retroviral tools at the Leloir Institute will have an enormous impact on the
local scientific community. This collaborative effort will therefore serve as a driving
force to increase the critical mass of Argentine investigators that incorporate
competitive technologies for the study of neurodegenerative disorders within their
research focus. An increase in the number of laboratories carrying out regeneration-
related projects will certainly enhance awareness to these and related problems to our
community.
成年齿状回持续产生颗粒细胞(DGCs),这些颗粒细胞是特定的
学习和记忆任务,但新的神经元对信息处理的精确贡献,
海马体的电路仍然未知。在过去,我们已经证明,
发生在围产期大脑的发育过程,如兴奋性的成熟,传入
突触发生和功能都在成年神经发生过程中重演。我们现在建议
中心假设,即新生细胞在发育过程中建立功能输出,
与年轻神经元接触的突触后靶细胞群主要是抑制性的,
因此不同于成熟颗粒细胞激活的混合兴奋/抑制网络。
因此,将存在年轻的DGC主要激活前馈和/或反馈的时间窗。
反馈抑制回路,不刺激锥体细胞,对
齿状回输出在目标1中,我们将建立一个年轻人目标激活的时空图。
发育中的成年齿状回神经元。我们将用逆转录病毒转导来表达光-
阳离子通道激活的视紫红质-2在未成年雌性小鼠新生DGC中的作用
(C57B16/J)。我们将在不同的时间处死动物,并准备急性脑切片进行
电生理记录。通过用短暂的光脉冲刺激整个海马切片,
逆转录病毒转导的神经元将出现尖峰。我们将随机寻找活跃的突触后靶细胞
在整个门和CA 3区,并确定和表征反应神经元,
散斑和全细胞记录。在目标2中,我们将研究新的
苔藓纤维突触形成的GABA能和谷氨酸能靶点。我们计划利用全细胞
记录,以测试形成GABA能中间神经元靶点的突触是否比
这些细胞形成于锥体细胞上,正如我们之前的结构研究所表明的那样。我们还将研究
突触前机制的短期和长期的可塑性,将塑造活动依赖
竞争和激活突触后回路。这个项目将解决一些基本问题,
关于新生细胞的连接和激活(尖峰),这将有助于理解
成年人神经发生在预先存在的海马网络中的精确影响和神经元的规则
成人大脑中的连通性识别神经元整合到现有神经元中的规则
以一种既安全又功能相关的方式建立网络对于开发未来也至关重要。
大脑修复疗法
将与Gage实验室合作开发新型逆转录病毒工具,
表达视紫红质-2,从而提高新生细胞的光激活能力。在
反过来,这里获得的实验数据将被用来输入正在开发的理论模型
研究未成熟神经元在信号处理中的作用。建议的成功
该项目依赖于加强Leloir的Schinder实验室之间的密切互动
研究所(布宜诺斯艾利斯)和拉霍亚索尔克研究所的盖奇实验室。成员
辛德实验室将有机会在索尔克培训的产生和小说的特点
逆转录病毒载体,提高在国外开发先进分子工具的能力,
机构。我们预计能力建设将导致设计、生产和
在Leloir研究所使用新的逆转录病毒工具将对
当地科学界。因此,这种合作努力将成为一种推动力,
努力增加阿根廷调查人员的临界质量,
竞争性技术,用于研究神经退行性疾病,
研究重点。进行再生的实验室数量增加-
相关的项目肯定会提高人们对这些问题和相关问题的认识,
社区
项目成果
期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Unique processing during a period of high excitation/inhibition balance in adult-born neurons.
- DOI:10.1126/science.1214956
- 发表时间:2012-03-09
- 期刊:
- 影响因子:0
- 作者:Marín-Burgin A;Mongiat LA;Pardi MB;Schinder AF
- 通讯作者:Schinder AF
Delayed dendritic development in newly generated dentate granule cells by cell-autonomous expression of the amyloid precursor protein.
- DOI:10.1016/j.mcn.2013.07.003
- 发表时间:2013-09
- 期刊:
- 影响因子:3.5
- 作者:Morgenstern, Nicolas A.;Giacomini, Damiana;Lombardi, Gabriela;Castano, Eduardo M.;Schinder, Alejandro F.
- 通讯作者:Schinder, Alejandro F.
The timing for neuronal maturation in the adult hippocampus is modulated by local network activity.
- DOI:10.1523/jneurosci.1380-11.2011
- 发表时间:2011-05-25
- 期刊:
- 影响因子:0
- 作者:Piatti VC;Davies-Sala MG;Espósito MS;Mongiat LA;Trinchero MF;Schinder AF
- 通讯作者:Schinder AF
Delayed coupling to feedback inhibition during a critical period for the integration of adult-born granule cells.
- DOI:10.1016/j.neuron.2014.11.023
- 发表时间:2015-01-07
- 期刊:
- 影响因子:16.2
- 作者:Temprana, Silvio G.;Mongiat, Lucas A.;Yang, Sung M.;Trinchero, Mariela F.;Alvarez, Diego D.;Kropff, Emilio;Giacomini, Damiana;Beltramone, Natalia;Lanuza, Guillermo M.;Schinder, Alejandro F.
- 通讯作者:Schinder, Alejandro F.
Dynamic role of adult-born dentate granule cells in memory processing.
- DOI:10.1016/j.conb.2015.06.002
- 发表时间:2015-12
- 期刊:
- 影响因子:5.7
- 作者:Kropff E;Yang SM;Schinder AF
- 通讯作者:Schinder AF
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{{ truncateString('FRED H GAGE', 18)}}的其他基金
Neuronal senescence and inflammation in Alzheimer's disease
阿尔茨海默病的神经元衰老和炎症
- 批准号:
10213563 - 财政年份:2021
- 资助金额:
$ 4.98万 - 项目类别:
Neuronal senescence and inflammation in Alzheimer's disease
阿尔茨海默病的神经元衰老和炎症
- 批准号:
10633023 - 财政年份:2021
- 资助金额:
$ 4.98万 - 项目类别:
Combinatorial Actions of Genetic Variants and Gender Bias of Alzherimer's Disease
阿尔茨海默病的遗传变异和性别偏见的组合作用
- 批准号:
9431031 - 财政年份:2017
- 资助金额:
$ 4.98万 - 项目类别:
Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients
评估阿尔茨海默病患者衰老和恢复活力的神经元的细胞老化
- 批准号:
10522910 - 财政年份:2017
- 资助金额:
$ 4.98万 - 项目类别:
Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients
评估阿尔茨海默病患者衰老和恢复活力的神经元的细胞老化
- 批准号:
10835760 - 财政年份:2017
- 资助金额:
$ 4.98万 - 项目类别:
Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients
评估阿尔茨海默病患者衰老和恢复活力的神经元的细胞衰老情况
- 批准号:
10153611 - 财政年份:2017
- 资助金额:
$ 4.98万 - 项目类别:
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