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작성일 : 18-04-17 13:28
2018-04-21 저널 발표 고범진
 글쓴이 : 관리자
조회 : 185  
 2018 May;24(4):438-449.

Dentate granule cell recruitment of feedforward inhibition governs engram maintenance and remote memory generalization.

Guo N1,2,3Soden ME4,5Herber C1,2Kim MT1,2,3Besnard A1,2,3Lin P1,2,3Ma X6,7Cepko CL6,7Zweifel LS4,5Sahay A1,2,3,8.


Abstract

Memories become less precise and generalized over time as memory traces reorganize in hippocampal-cortical networks. Increased time-dependent loss of memory precision is characterized by an overgeneralization of fear in individuals with post-traumatic stress disorder (PTSD) or age-related cognitive impairments. In the hippocampal dentate gyrus (DG), memories are thought to be encoded by so-called 'engram-bearing' dentate granule cells (eDGCs). Here we show, using rodents, that contextual fear conditioning increases connectivity between eDGCs and inhibitory interneurons (INs) in the downstream hippocampal CA3 region. We identify actin-binding LIM protein 3 (ABLIM3) as a mossy-fiber-terminal-localized cytoskeletal factor whose levels decrease after learning. Downregulation of ABLIM3 expression in DGCs was sufficient to increase connectivity with CA3 stratum lucidum INs (SLINs), promote parvalbumin (PV)-expressing SLIN activation, enhance feedforward inhibition onto CA3 and maintain a fear memory engram in the DG over time. Furthermore, downregulation of ABLIM3 expression in DGCs conferred conditioned context-specific reactivation of memory traces in hippocampal-cortical and amygdalar networks and decreased fear memory generalization at remote (i.e., distal) time points. Consistent with the observation of age-related hyperactivity of CA3, learning failed to increase DGC-SLIN connectivity in 17-month-old mice, whereas downregulation of ABLIM3 expression was sufficient to restore DGC-SLIN connectivity, increase PV+ SLIN activation and improve the precision of remote memories. These studies exemplify a connectivity-based strategy that targets a molecular brake of feedforward inhibition in DG-CA3 and may be harnessed to decrease time-dependent memory generalization in individuals with PTSD and improve memory precision in aging individuals.


https://www.nature.com/articles/nm.4491




 
 

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