Identifying Mechanisms of Normal Cognitive Aging Using a Novel Mouse Genetic Reference Panel.
Identifying Mechanisms of Normal Cognitive Aging Using a Novel Mouse Genetic Reference Panel.
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DOI：
10.3389/fcell.2020.562662
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发表时间：
2020
影响因子：
5.5
通讯作者：
Kaczorowski CC
中科院分区：
文献类型：
--
作者：
Dunn AR;Hadad N;Neuner SM;Zhang JG;Philip VM;Dumitrescu L;Hohman TJ;Herskowitz JH;O'Connell KMS;Kaczorowski CC
制定策略以保持认知健康对老龄化期间的生活质量至关重要。健康认知老化的基础知之甚少;因此，很难预测谁在以后的生活中会有正常的认知。个人可能具有更高的基线功能（认知储备），而其他人可能会随着年龄的增长而保持甚至改善（认知弹性）。了解认知储备和弹性的机制可能是维持认知健康的新治疗策略的关键。然而，储备和恢复力在人类研究中的定义并不一致。此外，我们对这些现象的分子和细胞基础的理解很差，由于缺乏纵向分子和认知数据，无法充分捕捉认知老化的动态轨迹。在这里，我们使用了一个遗传多样性的小鼠种群（B6-BXDs）来表征成年期认知能力的个体差异，并研究了中年小鼠认知储备和/或弹性的证据。我们测试了两个年龄（6个月和14个月）的认知功能，使用Y-迷宫和上下文恐惧条件反射。我们观察到这些性状的遗传变异（h2 RIx ε = 0.51-0.74），表明中度到强烈的遗传控制取决于认知领域。由于认知功能的多基因性质，我们没有发现与Y-迷宫，情境恐惧获得（CFA）或记忆，或在全基因组水平上认知功能下降显着相关的QTL。为了更精确地询问这些性状变异的分子调控，我们采用了RNA-seq并鉴定了与转录/翻译，细胞代谢和神经元功能相关的基因网络，这些基因网络与工作记忆，背景恐惧记忆和认知衰退相关。使用这种方法，我们提名Trio基因作为工作记忆能力的调节剂。最后，我们提出了一个概念框架，用于识别表现出认知储备和/或弹性的菌株，以评估这些特征是否可以在中年B6-BXD中观察到。虽然我们发现，在生命早期明显的早期认知储备可以防止生命后期的认知障碍，但认知表现和年龄相关的下降沿着一个连续体下降，没有明确的基因型出现作为异常储备或弹性的范例-导致建议未来使用老龄小鼠群体来了解认知储备和弹性的性质。
Developing strategies to maintain cognitive health is critical to quality of life during aging. The basis of healthy cognitive aging is poorly understood; thus, it is difficult to predict who will have normal cognition later in life. Individuals may have higher baseline functioning (cognitive reserve) and others may maintain or even improve with age (cognitive resilience). Understanding the mechanisms underlying cognitive reserve and resilience may hold the key to new therapeutic strategies for maintaining cognitive health. However, reserve and resilience have been inconsistently defined in human studies. Additionally, our understanding of the molecular and cellular bases of these phenomena is poor, compounded by a lack of longitudinal molecular and cognitive data that fully capture the dynamic trajectories of cognitive aging. Here, we used a genetically diverse mouse population (B6-BXDs) to characterize individual differences in cognitive abilities in adulthood and investigate evidence of cognitive reserve and/or resilience in middle-aged mice. We tested cognitive function at two ages (6 months and 14 months) using y-maze and contextual fear conditioning. We observed heritable variation in performance on these traits (h2RIx̄ = 0.51–0.74), suggesting moderate to strong genetic control depending on the cognitive domain. Due to the polygenetic nature of cognitive function, we did not find QTLs significantly associated with y-maze, contextual fear acquisition (CFA) or memory, or decline in cognitive function at the genome-wide level. To more precisely interrogate the molecular regulation of variation in these traits, we employed RNA-seq and identified gene networks related to transcription/translation, cellular metabolism, and neuronal function that were associated with working memory, contextual fear memory, and cognitive decline. Using this method, we nominate the Trio gene as a modulator of working memory ability. Finally, we propose a conceptual framework for identifying strains exhibiting cognitive reserve and/or resilience to assess whether these traits can be observed in middle-aged B6-BXDs. Though we found that earlier cognitive reserve evident early in life protects against cognitive impairment later in life, cognitive performance and age-related decline fell along a continuum, with no clear genotypes emerging as exemplars of exceptional reserve or resilience – leading to recommendations for future use of aging mouse populations to understand the nature of cognitive reserve and resilience.
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影响因子：
4.2
作者：
Boros BD;Greathouse KM;Gearing M;Herskowitz JH
通讯作者：
Herskowitz JH
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
与海马体积相关的新型遗传基因座。
影响因子：
16.6
作者：
Hibar DP;Adams HHH;Jahanshad N;Chauhan G;Stein JL;Hofer E;Renteria ME;Bis JC;Arias-Vasquez A;Ikram MK;Desrivières S;Vernooij MW;Abramovic L;Alhusaini S;Amin N;Andersson M;Arfanakis K;Aribisala BS;Armstrong NJ;Athanasiu L;Axelsson T;Beecham AH;Beiser A;Bernard M;Blanton SH;Bohlken MM;Boks MP;Bralten J;Brickman AM;Carmichael O;Chakravarty MM;Chen Q;Ching CRK;Chouraki V;Cuellar-Partida G;Crivello F;Den Braber A;Doan NT;Ehrlich S;Giddaluru S;Goldman AL;Gottesman RF;Grimm O;Griswold ME;Guadalupe T;Gutman BA;Hass J;Haukvik UK;Hoehn D;Holmes AJ;Hoogman M;Janowitz D;Jia T;Jørgensen KN;Karbalai N;Kasperaviciute D;Kim S;Klein M;Kraemer B;Lee PH;Liewald DCM;Lopez LM;Luciano M;Macare C;Marquand AF;Matarin M;Mather KA;Mattheisen M;McKay DR;Milaneschi Y;Muñoz Maniega S;Nho K;Nugent AC;Nyquist P;Loohuis LMO;Oosterlaan J;Papmeyer M;Pirpamer L;Pütz B;Ramasamy A;Richards JS;Risacher SL;Roiz-Santiañez R;Rommelse N;Ropele S;Rose EJ;Royle NA;Rundek T;Sämann PG;Saremi A;Satizabal CL;Schmaal L;Schork AJ;Shen L;Shin J;Shumskaya E;Smith AV;Sprooten E;Strike LT;Teumer A;Tordesillas-Gutierrez D;Toro R;Trabzuni D;Trompet S;Vaidya D;Van der Grond J;Van der Lee SJ;Van der Meer D;Van Donkelaar MMJ;Van Eijk KR;Van Erp TGM;Van Rooij D;Walton E;Westlye LT;Whelan CD;Windham BG;Winkler AM;Wittfeld K;Woldehawariat G;Wolf C;Wolfers T;Yanek LR;Yang J;Zijdenbos A;Zwiers MP;Agartz I;Almasy L;Ames D;Amouyel P;Andreassen OA;Arepalli S;Assareh AA;Barral S;Bastin ME;Becker DM;Becker JT;Bennett DA;Blangero J;van Bokhoven H;Boomsma DI;Brodaty H;Brouwer RM;Brunner HG;Buckner RL;Buitelaar JK;Bulayeva KB;Cahn W;Calhoun VD;Cannon DM;Cavalleri GL;Cheng CY;Cichon S;Cookson MR;Corvin A;Crespo-Facorro B;Curran JE;Czisch M;Dale AM;Davies GE;De Craen AJM;De Geus EJC;De Jager PL;De Zubicaray GI;Deary IJ;Debette S;DeCarli C;Delanty N;Depondt C;DeStefano A;Dillman A;Djurovic S;Donohoe G;Drevets WC;Duggirala R;Dyer TD;Enzinger C;Erk S;Espeseth T;Fedko IO;Fernández G;Ferrucci L;Fisher SE;Fleischman DA;Ford I;Fornage M;Foroud TM;Fox PT;Francks C;Fukunaga M;Gibbs JR;Glahn DC;Gollub RL;Göring HHH;Green RC;Gruber O;Gudnason V;Guelfi S;Håberg AK;Hansell NK;Hardy J;Hartman CA;Hashimoto R;Hegenscheid K;Heinz A;Le Hellard S;Hernandez DG;Heslenfeld DJ;Ho BC;Hoekstra PJ;Hoffmann W;Hofman A;Holsboer F;Homuth G;Hosten N;Hottenga JJ;Huentelman M;Hulshoff Pol HE;Ikeda M;Jack CR Jr;Jenkinson M;Johnson R;Jönsson EG;Jukema JW;Kahn RS;Kanai R;Kloszewska I;Knopman DS;Kochunov P;Kwok JB;Lawrie SM;Lemaître H;Liu X;Longo DL;Lopez OL;Lovestone S;Martinez O;Martinot JL;Mattay VS;McDonald C;McIntosh AM;McMahon FJ;McMahon KL;Mecocci P;Melle I;Meyer-Lindenberg A;Mohnke S;Montgomery GW;Morris DW;Mosley TH;Mühleisen TW;Müller-Myhsok B;Nalls MA;Nauck M;Nichols TE;Niessen WJ;Nöthen MM;Nyberg L;Ohi K;Olvera RL;Ophoff RA;Pandolfo M;Paus T;Pausova Z;Penninx BWJH;Pike GB;Potkin SG;Psaty BM;Reppermund S;Rietschel M;Roffman JL;Romanczuk-Seiferth N;Rotter JI;Ryten M;Sacco RL;Sachdev PS;Saykin AJ;Schmidt R;Schmidt H;Schofield PR;Sigursson S;Simmons A;Singleton A;Sisodiya SM;Smith C;Smoller JW;Soininen H;Steen VM;Stott DJ;Sussmann JE;Thalamuthu A;Toga AW;Traynor BJ;Troncoso J;Tsolaki M;Tzourio C;Uitterlinden AG;Hernández MCV;Van der Brug M;van der Lugt A;van der Wee NJA;Van Haren NEM;van 't Ent D;Van Tol MJ;Vardarajan BN;Vellas B;Veltman DJ;Völzke H;Walter H;Wardlaw JM;Wassink TH;Weale ME;Weinberger DR;Weiner MW;Wen W;Westman E;White T;Wong TY;Wright CB;Zielke RH;Zonderman AB;Martin NG;Van Duijn CM;Wright MJ;Longstreth WT;Schumann G;Grabe HJ;Franke B;Launer LJ;Medland SE;Seshadri S;Thompson PM;Ikram MA
通讯作者：
Ikram MA
全基因组对言语记忆的言论性记忆的研究：基因组流行病学财团的心脏和衰老研究的同龄人。
影响因子：
10.6
作者：
Debette S;Ibrahim Verbaas CA;Bressler J;Schuur M;Smith A;Bis JC;Davies G;Wolf C;Gudnason V;Chibnik LB;Yang Q;deStefano AL;de Quervain DJ;Srikanth V;Lahti J;Grabe HJ;Smith JA;Priebe L;Yu L;Karbalai N;Hayward C;Wilson JF;Campbell H;Petrovic K;Fornage M;Chauhan G;Yeo R;Boxall R;Becker J;Stegle O;Mather KA;Chouraki V;Sun Q;Rose LM;Resnick S;Oldmeadow C;Kirin M;Wright AF;Jonsdottir MK;Au R;Becker A;Amin N;Nalls MA;Turner ST;Kardia SL;Oostra B;Windham G;Coker LH;Zhao W;Knopman DS;Heiss G;Griswold ME;Gottesman RF;Vitart V;Hastie ND;Zgaga L;Rudan I;Polasek O;Holliday EG;Schofield P;Choi SH;Tanaka T;An Y;Perry RT;Kennedy RE;Sale MM;Wang J;Wadley VG;Liewald DC;Ridker PM;Gow AJ;Pattie A;Starr JM;Porteous D;Liu X;Thomson R;Armstrong NJ;Eiriksdottir G;Assareh AA;Kochan NA;Widen E;Palotie A;Hsieh YC;Eriksson JG;Vogler C;van Swieten JC;Shulman JM;Beiser A;Rotter J;Schmidt CO;Hoffmann W;Nöthen MM;Ferrucci L;Attia J;Uitterlinden AG;Amouyel P;Dartigues JF;Amieva H;Räikkönen K;Garcia M;Wolf PA;Hofman A;Longstreth WT Jr;Psaty BM;Boerwinkle E;DeJager PL;Sachdev PS;Schmidt R;Breteler MM;Teumer A;Lopez OL;Cichon S;Chasman DI;Grodstein F;Müller-Myhsok B;Tzourio C;Papassotiropoulos A;Bennett DA;Ikram MA;Deary IJ;van Duijn CM;Launer L;Fitzpatrick AL;Seshadri S;Mosley TH Jr;Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium
通讯作者：
Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium
影响因子：
11
作者：
Davies G;Harris SE;Reynolds CA;Payton A;Knight HM;Liewald DC;Lopez LM;Luciano M;Gow AJ;Corley J;Henderson R;Murray C;Pattie A;Fox HC;Redmond P;Lutz MW;Chiba-Falek O;Linnertz C;Saith S;Haggarty P;McNeill G;Ke X;Ollier W;Horan M;Roses AD;Ponting CP;Porteous DJ;Tenesa A;Pickles A;Starr JM;Whalley LJ;Pedersen NL;Pendleton N;Visscher PM;Deary IJ
通讯作者：
Deary IJ