an-inexpensive-scalable-behavioral-assay-for-measuring-ethanol

An Inexpensive, Scalable Behavioral Assay for Measuring Ethanol Sedation Sensitivity and Rapid Tolerance in <em>Drosophila</em>

Alcohol use disorder (AUD) is a serious health challenge. Despite a large hereditary component to AUD, few genes have been unambiguously implicated in ...

Virginia Commonwealth University

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&#x9057;&#x4F20;&#x548C;&#x73AF;&#x5883;&#x56E0;&#x7D20;&#x5F71;&#x54CD;&#x8D1F;&#x9762; geotaxis &#x5728;&#x679C;&#x8747;&#x4E0E;&#x5E74;&#x9F84;&#x76F8;&#x5173;&#x51CF;&#x503C;&#x51C6;&#x5907;&#x901A;&#x8FC7;&#x6539;&#x53D8;&#x4F9D;&#x8D56;&#x5E74;&#x9F84;&#x7684;&#x722C;&#x5347;&#x901F;&#x5EA6;&#x3002;

Age-related locomotor impairment in humans is important clinically because it is associated with several co-morbidities and increased risk of death. One of the hallmarks of age-related locomotor impairment in humans is a decrease in walking speed with age. Genetically tractable model organisms such as Drosophila are essential for delineating mechanisms underlying age-related locomotor impairment and age-related decreases in locomotor speed. Negative geotaxis, the ability of flies to move vertically when startled, is a common measure of locomotor behavior that declines with age in Drosophila. Toward further developing Drosophila as a model for age-related locomotor impairment, we investigated whether negative geotaxis reflects climbing or a combination of climbing and other behaviors such as flying and jumping. Additionally, we investigated whether locomotor speed in negative geotaxis assays declines with age in flies as found for walking speed in humans. We find that the vast majority of flies climb during negative geotaxis assays and that removal of hind legs, but not wings, impairs the behavior. We also find that climbing speed decreases with age in four wild type genetic backgrounds, in flies housed at different temperatures, and in control and long-lived flies harboring a mutation in OR83b. The decreases in climbing speed correlate with the age-related impairments in the distance climbed. These studies establish negative geotaxis in Drosophila as a climbing behavior that declines with age due to a decrease in climbing speed. Age-related decreases in locomotor speed are common attributes of locomotor senescence in flies and humans.

Genetic and environmental factors impact age-related impairment of negative geotaxis in Drosophila by altering age-dependent climbing speed.

Li&eacute;e &agrave; l&#39;&acirc;ge de la d&eacute;ficience locomotrice chez les humains est importante sur le plan clinique parce qu&#39;elle est associ&eacute;e &agrave; plusieurs maladies concomitantes et un risque accru de d&eacute;c&egrave;s. Une des caract&eacute;ristiques li&eacute;es &agrave; l&#39;&acirc;ge de la d&eacute;ficience locomotrice chez l&#39;&ecirc;tre humain est une diminution de vitesse avec l&#39;&acirc;ge de la marche. Organismes g&eacute;n&eacute;tiquement tractable mod&egrave;le comme la drosophile sont essentielles pour d&eacute;limiter les m&eacute;canismes sous-jacents d&eacute;ficience locomotrice li&eacute;e &agrave; l&#39;&acirc;ge et la diminution de vitesse locomotrice li&eacute;e &agrave; l&#39;&acirc;ge. G&eacute;otaxie n&eacute;gative, la capacit&eacute; des mouches &agrave; d&eacute;placer verticalement quand surpris, est une mesure commune de comportement locomoteur qui diminue avec l&#39;&acirc;ge chez la drosophile. Vers d&eacute;veloppement drosophile comme mod&egrave;le pour d&eacute;ficience locomotrice li&eacute;e &agrave; l&#39;&acirc;ge, nous avons examin&eacute; si la g&eacute;otaxie n&eacute;gative refl&egrave;te escalade ou une combinaison d&#39;escalade et d&#39;autres comportements tels que le volant et le saut. En outre, nous avons &eacute;tudi&eacute; si vitesse locomotrice dans g&eacute;otaxie n&eacute;gative dosages baisse avec l&#39;&acirc;ge chez les mouches que l&#39;on trouve pour la vitesse de marche chez les humains. Nous trouvons que la grande majorit&eacute; des mouches grimper au cours des essais g&eacute;otaxie n&eacute;gative et que des pattes, mais pas d&#39;ailes, alt&egrave;re le comportement. Nous trouvons aussi que grimper la vitesse diminue avec l&#39;&acirc;ge dans quatre fonds g&eacute;n&eacute;tiques de type sauvage, chez les mouches log&eacute;s &agrave; diff&eacute;rentes temp&eacute;ratures et en contr&ocirc;le et longue dur&eacute;e de vie d&#39;oiseau porteur d&#39;une mutation dans OR83b. La diminution de la vitesse d&#39;escalade sont corr&eacute;l&eacute;s avec la d&eacute;ficiences li&eacute;es &agrave; l&#39;&acirc;ge dans le lointain est mont&eacute;. Ces &eacute;tudes &eacute;tablissent g&eacute;otaxie n&eacute;gative chez la drosophile comme un comportement d&#39;escalade qui diminue avec l&#39;&acirc;ge en raison d&#39;une diminution de la vitesse d&#39;escalade. Diminution de vitesse locomotrice li&eacute;e &agrave; l&#39;&acirc;ge est des attributs communs de s&eacute;nescence locomotrice chez les mouches et les humains.

Des facteurs g&eacute;n&eacute;tiques et environnementaux impact d&eacute;ficience li&eacute;e &agrave; l&#39;&acirc;ge de la g&eacute;otaxie n&eacute;gative chez la drosophile en modifiant la vitesse de mont&eacute;e selon l&#39;&acirc;ge.

Altersbedingte lokomotorische Wertminderung beim Menschen ist klinisch wichtig, weil es mehrere Komorbidit&auml;ten und erh&ouml;htes Risiko des Todes zugeordnet ist. Eines der Markenzeichen der altersbedingten lokomotorische Wertminderung beim Menschen ist ein R&uuml;ckgang der Schrittgeschwindigkeit mit dem Alter. Genetisch steuerbar Modellorganismen wie Drosophila sind entscheidend f&uuml;r die Abgrenzung Mechanismen altersbedingte lokomotorische Wertminderung und altersbedingten R&uuml;ckgang der lokomotorischen Geschwindigkeit. Negative Geotaxis, ist die F&auml;higkeit von fliegen, vertikal, wenn aufgeschreckt, eine gemeinsame Ma&szlig;nahme lokomotorische Verhalten, das mit dem Alter in Drosophila abnimmt. Zur weiter Entwicklung von Drosophila als Modell f&uuml;r altersbedingte lokomotorische Wertminderung, untersuchten wir, ob negative Geotaxis spiegelt Klettern oder eine Kombination aus Klettern und andere Verhaltensweisen wie fliegen und springen. Dar&uuml;ber hinaus untersucht wir, ob lokomotorische Geschwindigkeit in negative Geotaxis sinkt mit zunehmendem Alter in fliegen als gefunden f&uuml;r Schrittgeschwindigkeit beim Menschen-Proben. Wir finden, dass die &uuml;berwiegende Mehrheit der fliegen w&auml;hrend negative Geotaxis Proben zu klettern und die Entfernung der Hinterbeine, aber keine Fl&uuml;gel, das Verhalten beeintr&auml;chtigt. Wir finden auch, dass Klettern Geschwindigkeit sinkt mit zunehmendem Alter in vier Wildtyp genetische Hintergr&uuml;nde, fliegen, die bei unterschiedlichen Temperaturen untergebracht und in Kontrolle und langlebige fliegen beherbergen eine Mutation in OR83b. Die R&uuml;ckg&auml;nge in Klettern Geschwindigkeit korrelieren mit der altersbedingten Beeintr&auml;chtigungen in der Ferne stieg. Diese Studien stellen negative Geotaxis in Drosophila als ein Klettern Verhalten, das mit dem Alter auf einen R&uuml;ckgang der Klettern Geschwindigkeit sinkt. Altersbedingten R&uuml;ckgang der lokomotorischen Geschwindigkeit sind gemeinsame Attribute des Bewegungsapparates Seneszenz bei fliegen und Menschen.

Genetische und umweltbedingte Faktoren beeinflussen altersbedingte Wertminderung von negative Geotaxis in Drosophila durch altersbedingt Klettern-Geschwindigkeit &auml;ndern.

Compromissione dell&#39;apparato locomotore et&agrave;-correlate negli esseri umani &egrave; importante clinicamente perch&eacute; &egrave; associato con diverse co-morbidit&agrave; e aumento del rischio di morte. Uno dei marchi di compromissione dell&#39;apparato locomotore all&#39;et&agrave; negli esseri umani &egrave; una diminuzione della velocit&agrave; con l&#39;et&agrave; di cammino. Organismi geneticamente trattabili modello come Drosophila sono essenziali per delineare i meccanismi sottostanti la compromissione dell&#39;apparato locomotore legate all&#39;et&agrave; ed et&agrave;-correlate diminuzioni nella velocit&agrave; dell&#39;apparato locomotore. Geotassi negativa, la capacit&agrave; di mosche di muoversi verticalmente quando viene sorpreso, &egrave; una misura comune del comportamento motorio che declina con l&#39;et&agrave; in drosofila. Verso sviluppare ulteriormente la Drosophila come modello per la compromissione dell&#39;apparato locomotore legati all&#39;et&agrave;, abbiamo studiato se geotassi negativa riflette arrampicata o una combinazione di arrampicata e altri comportamenti come volare e saltare. Inoltre, abbiamo studiato se la velocit&agrave; dell&#39;apparato locomotore in geotassi negativa dosaggi declina con l&#39;et&agrave; in mosche come si trova per la velocit&agrave; di cammino in esseri umani. Troviamo che la stragrande maggioranza delle mosche salita durante dosaggi geotassi negativa e che la rimozione delle zampe posteriori, ma non le ali, altera il comportamento. Troviamo anche che arrampicata velocit&agrave; diminuisce con l&#39;et&agrave; in quattro sfondi genetica di tipo selvatico, nelle mosche ospitati a diverse temperature e in controllo e longevi mosche harboring una mutazione in OR83b. Le diminuzioni in arrampicata velocit&agrave; correlano con le disabilit&agrave; legate all&#39;et&agrave; in lontananza &egrave; salito. Questi studi stabiliscono geotassi negativa in Drosophila come un comportamento rampicante che declina con l&#39;et&agrave; a causa di una diminuzione della velocit&agrave; di arrampicata. Et&agrave;-correlate diminuzioni nella velocit&agrave; dell&#39;apparato locomotore sono gli attributi comuni di senescenza dell&#39;apparato locomotore in mosche e gli esseri umani.

Fattori genetici e ambientali impatto compromissione legate all&#39;et&agrave; del geotassi negativa in drosofila modificando la velocit&agrave; di arrampicata et&agrave;-dipendente.

&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x4F75;&#x5B58;&#x75BE;&#x60A3;&#x3068;&#x6B7B;&#x306E;&#x30EA;&#x30B9;&#x30AF;&#x5897;&#x52A0;&#x306B;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#x306E;&#x3067;&#x5E74;&#x9F62;&#x95A2;&#x9023;&#x904B;&#x52D5;&#x5668;&#x969C;&#x5BB3;&#x4EBA;&#x9593;&#x3067;&#x81E8;&#x5E8A;&#x7684;&#x306B;&#x91CD;&#x8981;&#x3067;&#x3059;&#x3002;&#x5E74;&#x9F62;&#x95A2;&#x9023;&#x904B;&#x52D5;&#x5668;&#x969C;&#x5BB3;&#x4EBA;&#x9593;&#x3067;&#x306E;&#x7279;&#x5FB4;&#x306E; 1 &#x3064;&#x3067;&#x6B69;&#x884C;&#x901F;&#x5EA6;&#x5E74;&#x9F62;&#x3068;&#x3068;&#x3082;&#x306B;&#x6E1B;&#x5C11;&#x3067;&#x3059;&#x3002;&#x30B7;&#x30E7;&#x30A6;&#x30B8;&#x30E7;&#x30A6;&#x30D0;&#x30A8;&#x306A;&#x3069;&#x306E;&#x907A;&#x4F1D;&#x7684;&#x6271;&#x3044;&#x3084;&#x3059;&#x3044;&#x30E2;&#x30C7;&#x30EB;&#x751F;&#x7269;&#x5E74;&#x9F62;&#x95A2;&#x9023;&#x904B;&#x52D5;&#x6A5F;&#x80FD;&#x969C;&#x5BB3;&#x3068;&#x6B69;&#x884C;&#x901F;&#x5EA6;&#x306E;&#x52A0;&#x9F62;&#x306B;&#x4F34;&#x3046;&#x6E1B;&#x5C11;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x8F2A;&#x90ED;&#x3092;&#x63CF;&#x304F;&#x3053;&#x3068;&#x304C;&#x6B20;&#x304B;&#x305B;&#x307E;&#x305B;&#x3093;&#x3002;&#x9670;&#x6027;&#x8D70;&#x5730;&#x6027;&#x3092;&#x79FB;&#x52D5;&#x3067;&#x304D;&#x308B;&#x3068;&#x3057;&#x3066;&#x3044;&#x308B;&#x30CF;&#x30A8;&#x306E;&#x5782;&#x76F4;&#x306B;&#x9A5A;&#x304B;&#x3055;&#x308C;&#x305F;&#x3068;&#x304D;&#x3001;&#x30B7;&#x30E7;&#x30A6;&#x30B8;&#x30E7;&#x30A6;&#x30D0;&#x30A8;&#x306E;&#x5E74;&#x9F62;&#x3068;&#x3068;&#x3082;&#x306B;&#x4F4E;&#x4E0B;&#x3059;&#x308B;&#x81EA;&#x767A;&#x884C;&#x52D5;&#x306E;&#x4E00;&#x822C;&#x7684;&#x306A;&#x6307;&#x6A19;&#x3067;&#x3059;&#x3002;&#x3055;&#x3089;&#x306B;&#x30B7;&#x30E7;&#x30A6;&#x30B8;&#x30E7;&#x30A6;&#x30D0;&#x30A8;&#x3092;&#x30E2;&#x30C7;&#x30EB;&#x3068;&#x3057;&#x3066;&#x5E74;&#x9F62;&#x95A2;&#x9023;&#x904B;&#x52D5;&#x5668;&#x969C;&#x5BB3;&#x306E;&#x958B;&#x767A;&#x306B;&#x5411;&#x3051;&#x3066;&#x3001;&#x767B;&#x5C71;&#x9670;&#x6027;&#x8D70;&#x5730;&#x6027;&#x3092;&#x3069;&#x3046;&#x53CD;&#x6620;&#x307E;&#x305F;&#x306F;&#x98DB;&#x3093;&#x3067;&#x3001;&#x30B8;&#x30E3;&#x30F3;&#x30D7;&#x306A;&#x3069;&#x306E;&#x767B;&#x5C71;&#x3068;&#x4ED6;&#x306E;&#x52D5;&#x4F5C;&#x306E;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x3092;&#x691C;&#x8A0E;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;&#x6211;&#x3005; &#x306F;&#x6B69;&#x884C;&#x901F;&#x5EA6;&#x306E;&#x9670;&#x6027;&#x8D70;&#x5730;&#x6027;&#x30CF;&#x30A8;&#x898B;&#x3064;&#x304B;&#x308A;&#x307E;&#x3057;&#x305F;&#x3068;&#x3057;&#x3066;&#x4EBA;&#x9593;&#x306E;&#x6B69;&#x884C;&#x901F;&#x5EA6;&#x306E;&#x305F;&#x3081;&#x5E74;&#x9F62;&#x3068;&#x3068;&#x3082;&#x306B;&#x6E1B;&#x5C11;&#x8A66;&#x91D1;&#x3059;&#x308B;&#x304B;&#x3069;&#x3046;&#x304B;&#x3092;&#x8ABF;&#x3079;&#x305F;&#x3002;&#x5927;&#x591A;&#x6570;&#x306E;&#x30CF;&#x30A8;&#x306E;&#x9670;&#x6027;&#x8D70;&#x5730;&#x6027;&#x30A2;&#x30C3;&#x30BB;&#x30A4;&#x4E2D;&#x3092;&#x767B;&#x308B;&#x3057;&#x3001;&#x5F8C;&#x308D;&#x8DB3;&#x3001;&#x3057;&#x304B;&#x3057;&#x306A;&#x3044;&#x7FFC;&#x306E;&#x9664;&#x53BB;&#x52D5;&#x4F5C;&#x3092;&#x640D;&#x306A;&#x3046;&#x3053;&#x3068;&#x3092;&#x898B;&#x3064;&#x3051;&#x307E;&#x3059;&#x3002;&#x307E;&#x305F;&#x3001;&#x901F;&#x5EA6;&#x3092;&#x30AF;&#x30E9;&#x30A4;&#x30DF;&#x30F3;&#x30B0;&#x5E74;&#x9F62; 4 &#x91CE;&#x751F;&#x578B;&#x306E;&#x907A;&#x4F1D;&#x7684;&#x80CC;&#x666F;&#x3001;&#x30CF;&#x30A8;&#x306E;&#x7570;&#x306A;&#x308B;&#x6E29;&#x5EA6;&#x3067;&#x3001;&#x53CE;&#x5BB9;&#x304A;&#x3088;&#x3073;&#x30B3;&#x30F3;&#x30C8;&#x30ED;&#x30FC;&#x30EB;&#x3068; OR83b &#x306E;&#x7A81;&#x7136;&#x5909;&#x7570;&#x3092;&#x8535;&#x533F;&#x9577;&#x547D;&#x306E;&#x30CF;&#x30A8;&#x3092;&#x4F4E;&#x4E0B;&#x3055;&#x305B;&#x308B;&#x3053;&#x3068;&#x3092;&#x898B;&#x3064;&#x3051;&#x307E;&#x3059;&#x3002;&#x767B;&#x5742;&#x901F;&#x5EA6;&#x306E;&#x4F4E;&#x4E0B;&#x304C;&#x767B;&#x3063;&#x305F;&#x8DDD;&#x96E2;&#x306B;&#x304A;&#x3051;&#x308B;&#x5E74;&#x9F62;&#x95A2;&#x9023;&#x969C;&#x5BB3;&#x3068;&#x76F8;&#x95A2;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x7814;&#x7A76;&#x767B;&#x5742;&#x901F;&#x5EA6;&#x306E;&#x6E1B;&#x5C11;&#x306B;&#x3088;&#x308A;&#x5E74;&#x9F62;&#x3068;&#x3068;&#x3082;&#x306B;&#x4F4E;&#x4E0B;&#x767B;&#x5C71;&#x884C;&#x52D5;&#x3068;&#x3057;&#x3066;&#x30B7;&#x30E7;&#x30A6;&#x30B8;&#x30E7;&#x30A6;&#x30D0;&#x30A8;&#x306E;&#x9670;&#x6027;&#x8D70;&#x5730;&#x6027;&#x3092;&#x78BA;&#x7ACB;&#x3057;&#x307E;&#x3059;&#x3002;&#x6B69;&#x884C;&#x901F;&#x5EA6;&#x306E;&#x52A0;&#x9F62;&#x306B;&#x4F34;&#x3046;&#x6E1B;&#x5C11;&#x30ED;&#x30B3;&#x30E2;&#x30FC;&#x30BF;&#x8001;&#x5316;&#x30CF;&#x30A8;&#x3068;&#x4EBA;&#x9593;&#x306E;&#x5171;&#x901A;&#x306E;&#x5C5E;&#x6027;&#x3067;&#x3059;&#x3002;

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&#xC5EC;&#xB7EC; co-morbidities &#xC8FD;&#xC74C;&#xC758; &#xC704;&#xD5D8; &#xC99D;&#xAC00;&#xC640; &#xAD00;&#xB828; &#xC788;&#xC73C;&#xBBC0;&#xB85C; &#xC778;&#xAC04;&#xC5D0;&#xC11C; &#xB098;&#xC774; &#xAD00;&#xB828; &#xC6B4;&#xC804; &#xC7A5;&#xC560;&#xB97C; &#xC784;&#xC0C1;&#xC801;&#xC73C;&#xB85C; &#xC911;&#xC694; &#xD558;&#xB2E4;. &#xC778;&#xAC04;&#xC758; &#xB098;&#xC774; &#xAD00;&#xB828; &#xC6B4;&#xC804; &#xC7A5;&#xC560;&#xC758; &#xD2B9;&#xC9D5; &#xC911; &#xD558;&#xB098;&#xAC00; &#xC6CC;&#xD0B9; &#xC18D;&#xB3C4; &#xB098; &#xC774;&#xC640; &#xD568;&#xAED8; &#xAC10;&#xC18C;&#xC785;&#xB2C8;&#xB2E4;. &#xCD08;&#xD30C;&#xB9AC;&#xC640; &#xAC19;&#xC740; &#xC720;&#xC804;&#xC790; &#xC138;&#xACF5; &#xBAA8;&#xB378; &#xC720;&#xAE30; &#xCCB4; &#xC5F0;&#xB839; &#xAD00;&#xB828; &#xC6B4;&#xC804; &#xC7A5;&#xC560; &#xBC0F; &#xC5F0;&#xB839; &#xAD00;&#xB828; &#xC6B4;&#xC804; &#xC18D;&#xB3C4; &#xAC10;&#xC18C; &#xAE30;&#xBCF8; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xBB18;&#xC0AC; &#xD558;&#xB294; &#xAC83;&#xC5D0; &#xB300; &#xD55C; &#xD544;&#xC218;&#xC801;&#xC785;&#xB2C8;&#xB2E4;. &#xBD80;&#xC815;&#xC801;&#xC778; geotaxis &#xD30C;&#xB9AC;&#xC758; &#xC774;&#xB3D9; &#xC138;&#xB85C;&#xB85C; &#xB54C; &#xAE5C;&#xC9DD;, &#xAE30;&#xB2A5;&#xC740; &#xCD08;&#xD30C;&#xB9AC;&#xC5D0;&#xC11C; &#xB098; &#xC774;&#xC640; &#xD568;&#xAED8; &#xAC10;&#xC18C; &#xC6B4;&#xC804; &#xB3D9;&#xC791;&#xC758; &#xC77C;&#xBC18;&#xC801;&#xC778; &#xCE21;&#xC815;. &#xB098;&#xC774; &#xAD00;&#xB828; &#xC6B4;&#xC804; &#xC7A5;&#xC560;&#xC5D0; &#xB300; &#xD55C; &#xBAA8;&#xB378; &#xCD08;&#xD30C;&#xB9AC;&#xB97C; &#xCD94;&#xAC00; &#xAC1C;&#xBC1C;&#xC5D0; &#xB300; &#xC6B0;&#xB9AC;&#xAC00; &#xBD80;&#xC815;&#xC801;&#xC778; geotaxis &#xB4F1;&#xBC18;&#xC744; &#xBC18;&#xC601; &#xD558;&#xB294; &#xC5EC;&#xBD80; &#xB610;&#xB294; &#xBE44;&#xD589;, &#xC810;&#xD504; &#xB4F1; &#xB4F1;&#xBC18; &#xBC0F; &#xB2E4;&#xB978; &#xB3D9;&#xC791;&#xC758; &#xC870;&#xD569;&#xC744; &#xC870;&#xC0AC; &#xD588;&#xB2E4;. &#xB610;&#xD55C;, &#xC6B0;&#xB9AC;&#xB294; &#xBD80;&#xC815;&#xC801;&#xC778; geotaxis&#xC5D0;&#xC11C; &#xC6B4;&#xC804; &#xC18D;&#xB3C4; &#xD558;&#xB77D; &#xC778; &#xAC04;&#xC5D0; &#xC788;&#xB294; &#xC6CC;&#xD0B9; &#xC18D;&#xB3C4; &#xB300; &#xD55C; &#xBCFC; &#xC218; &#xC788;&#xB294; &#xD30C;&#xB9AC;&#xC5D0; &#xB098;&#xC774; &#xBD84;&#xC11D; &#xC2E4;&#xD5D8; &#xC5EC;&#xBD80; &#xC870;&#xC0AC;. &#xC6B0;&#xB9AC;&#xB294; &#xD30C;&#xB9AC;&#xC758; &#xB300;&#xB2E4;&#xC218; &#xBD80;&#xC815;&#xC801;&#xC778; geotaxis &#xBD84;&#xC11D; &#xC2E4;&#xD5D8; &#xC911; &#xB4F1;&#xBC18; &#xD558; &#xACE0; &#xB4B7; &#xB2E4;&#xB9AC;, &#xB0A0;&#xAC1C;&#xC758; &#xC81C;&#xAC70; &#xB3D9;&#xC791;&#xC744; &#xC190;&#xC0C1; &#xCC3E;&#xC73C;&#xC2ED;&#xC2DC;&#xC624;. &#xADF8; 4 &#xAC1C;&#xC758; &#xC57C;&#xC0DD; &#xD0C0;&#xC785; &#xC720;&#xC804;&#xC801; &#xBC30;&#xACBD;, &#xD30C;&#xB9AC; &#xB2E4;&#xB978; &#xC628;&#xB3C4;&#xC5D0;&#xC11C; &#xC9C0; &#xB0B4;&#xAC8C; &#xBC0F; &#xC81C;&#xC5B4; &#xD558; &#xACE0; &#xC218;&#xBA85;&#xC774; &#xAE34; &#xD30C;&#xB9AC; or83b&#xC5D0; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xC740;&#xB2C9;&#xC5D0; &#xB098; &#xC774;&#xC640; &#xD568;&#xAED8; &#xAC10;&#xC18C; &#xC18D;&#xB3C4; &#xB4F1;&#xBC18; &#xD558;&#xB294; &#xAC83;&#xC774; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC18D;&#xB3C4; &#xB4F1;&#xBC18;&#xC758; &#xAC10;&#xC18C; &#xC0C1;&#xC2B9; &#xAC70;&#xB9AC;&#xC5D0;&#xC11C; &#xB098;&#xC774; &#xAD00;&#xB828; &#xC7A5;&#xC560;&#xAC00; &#xC5F0;&#xAD00;. &#xC774;&#xB7EC;&#xD55C; &#xC5F0;&#xAD6C;&#xB294; &#xC18D;&#xB3C4; &#xB4F1;&#xBC18;&#xC758; &#xAC10;&#xC18C; &#xB54C;&#xBB38;&#xC5D0; &#xB098; &#xC774;&#xC640; &#xD568;&#xAED8; &#xAC10;&#xC18C; &#xB4F1;&#xBC18; &#xB3D9;&#xC791;&#xC73C;&#xB85C; &#xCD08;&#xD30C;&#xB9AC;&#xC5D0; &#xBD80;&#xC815;&#xC801;&#xC778; geotaxis&#xB97C; &#xC124;&#xC815; &#xD569;&#xB2C8;&#xB2E4;. &#xC6B4;&#xC804; &#xC18D;&#xB3C4;&#xC5D0;&#xC11C; &#xB098;&#xC774; &#xAD00;&#xB828; &#xAC10;&#xC18C; &#xD30C;&#xB9AC;&#xC640; &#xC778;&#xAC04; &#xC6B4;&#xC804; &#xB178;&#xD654;&#xC758; &#xC77C;&#xBC18;&#xC801;&#xC778; &#xD2B9;&#xC131;&#xC785;&#xB2C8;&#xB2E4;.

&#xC720;&#xC804;&#xACFC; &#xD658;&#xACBD; &#xC694;&#xC778; &#xC5F0;&#xB839;&#xC5D0; &#xB530;&#xB77C; &#xB4F1;&#xBC18; &#xC18D;&#xB3C4; &#xBCC0;&#xACBD; &#xD558; &#xC5EC; &#xCD08;&#xD30C;&#xB9AC;&#xC5D0; &#xBD80;&#xC815;&#xC801;&#xC778; geotaxis&#xC758; &#xB098;&#xC774; &#xAD00;&#xB828; &#xC7A5;&#xC560;&#xC5D0; &#xC601;&#xD5A5;&#xC744;.

Deterioro locomotor relacionada con la edad en los seres humanos es importante cl&iacute;nicamente porque se asocia con varias comorbilidades y mayor riesgo de muerte. Una de las caracter&iacute;sticas distintivas del deterioro locomotor relacionada con la edad en los seres humanos es una disminuci&oacute;n en la velocidad con la edad que camina. Organismos modelo gen&eacute;ticamente manejable como Drosophila son esenciales para delinear los mecanismos que subyacen a deterioro locomotor relacionada con la edad y relacionada con la edad disminuye en la velocidad del aparato locomotor. Geotaxis negativa, la capacidad de moscas para mover verticalmente cuando sorprendi&oacute;, es una medida com&uacute;n de comportamiento locomotor que disminuye con la edad en Drosophila. Hacia el m&aacute;s desarrollo de Drosophila como modelo para el deterioro locomotor relacionada con la edad, investigamos si geotaxis negativa refleja la escalada o una combinaci&oacute;n de escalada y otros comportamientos tales como volar y saltar. Adem&aacute;s, investigamos si velocidad locomotor en geotaxis negativa ensayos disminuye con la edad en moscas que se encuentran para la velocidad al caminar en los seres humanos. Encontramos que la mayor&iacute;a de las moscas sube durante ensayos geotaxis negativa y que la eliminaci&oacute;n de las patas traseras, pero no alas, da&ntilde;a el comportamiento. Tambi&eacute;n encontramos que subir la velocidad disminuye con la edad en cuatro fondos gen&eacute;ticos de tipo salvaje, en moscas ubicados a diferentes temperaturas y en control y moscas duraderos que una mutaci&oacute;n en OR83b. La disminuci&oacute;n en la velocidad de ascenso se correlaciona con la discapacidad relacionada con la edad en la distancia subido. Estos estudios establecen geotaxis negativa en Drosophila como un comportamiento de escalada que disminuye con la edad debido a una disminuci&oacute;n en la velocidad de ascenso. Relacionada con la edad disminuye en velocidad locomotor es atributos comunes de senescencia locomotor en moscas y los seres humanos.

Factores gen&eacute;ticos y ambientales impactan deterioro senil de geotaxis negativa en Drosophila alterando velocidad escalada dependiente de la edad.

Oxidative damage has been proposed as an important factor in the progression of pathological and non-pathological age-related functional declines. Here, we examine functional deterioration in short-lived flies mutant for the mitochondrial antioxidant Manganese Superoxide Dismutase (Sod2). We find that the decline of several functional measures of aging occurs, in an accelerated fashion, in Sod2 mutants. Olfactory behavior, locomotor ability and cardiac performance were all seen to decline rapidly in Sod2 mutants. On average, functional declines in Sod2 mutants occur in a pattern similar to that seen in late-life Drosophila with a normal complement of Sod2. In longitudinal experiments, however, we find that functional failures occur in every possible sequence in Sod2 mutants. Significantly, failure of these functional measures is not irreversible, as spontaneous functional recovery was sometimes observed. These findings support a model where ROS-related damage strikes at multiple organ systems in parallel, rather than a "chain of dominos" model, in which primary organ failure contributes to the deterioration of further organ systems.

Multiple measures of functionality exhibit progressive decline in a parallel, stochastic fashion in Drosophila Sod2 null mutants.

Age-related locomotor impairment (ARLI) is one of the most detrimental changes that occurs during aging. Elderly individuals with ARLI are at increased risks for falls, depression and a number of other co-morbidities. Despite its clinical significance, little is known about the genes that influence ARLI. We consequently performed a forward genetic screen to identify Drosophila strains with delayed ARLI using negative geotaxis as an index of locomotor function. One of the delayed ARLI strains recovered from the screen had a P-element insertion that decreased expression of the insulin signaling gene phosphoinositide-dependent kinase 1 (PDK1) Precise excision of the P-element insertion reverted PDK1 expression and ARLI to the same as control flies, indicating that disruption of PDK1 leads to delayed ARLI. Follow-up studies showed that additional loss of function mutations in PDK1 as well as loss of function alleles of two other insulin signaling genes, Dp110 and Akt (the genes for the catalytic subunit of phosphoinositide 3-kinase and AKT), also forestalled ARLI. Interestingly, only some of the strains with delayed ARLI had elevated resistance to paraquat, indicating that enhanced resistance to this oxidative stressor is not required for preservation of locomotor function across age. Our studies implicate insulin signaling as a key regulator of ARLI in Drosophila.

A forward genetic screen in Drosophila implicates insulin signaling in age-related locomotor impairment.

Superoxide dismutase 1 (SOD1) is an important antioxidant previously shown to impact life span in Drosophila. We examined the consequences of manipulating Sod1 expression throughout the body or in the nervous system or musculature on life span and age-related locomotor impairment (ARLI) in Drosophila. Ubiquitous overexpression of SOD1 extended life span but did not substantially forestall ARLI, whereas ubiquitous knock-down of Sod1 shortened life span and accelerated ARLI. Interestingly, neither overexpression of Sod1 nor expression of Sod1 RNAi in the nervous system or muscle altered life span or ARLI. Our studies suggest that the control of reactive oxygen species by SOD1 in tissues other than the nervous system and musculature support life span and ARLI in Drosophila.

Manipulation of Sod1 expression ubiquitously, but not in the nervous system or muscle, impacts age-related parameters in Drosophila.

Oxidative damage to cell macromolecules by reactive oxygen species is associated with numerous diseases and aging. In Drosophila, RNAi-mediated silencing of the mitochondrial antioxidant manganese superoxide dismutase (SOD2) throughout the body dramatically reduces life span, accelerates senescence of locomotor function, and enhances sensitivity to applied oxidative stress. Here, we show that Sod2 knockdown in the musculature alone is sufficient to cause the shortened life span and accelerated locomotor declines observed with knockdown of Sod2 throughout the body, indicating that Sod2 deficiency in muscle is central to these phenotypes. Knockdown of Sod2 in the muscle also increased caspase activity (a marker for apoptosis) and caused a mitochondrial pathology characterized by swollen mitochondria, decreased mitochondrial content, and reduced ATP levels. These findings indicate that Sod2 plays a crucial role in the musculature in Drosophila and that the consequences of SOD2 loss in this tissue extend to the viability of the organism as a whole.

Sod2 knockdown in the musculature has whole-organism consequences in Drosophila.

Ethanol induces similar behavioral responses in mammals and the fruit fly, Drosophila melanogaster. By coupling assays for ethanol-related behavior to the genetic tools available in flies, a number of genes have been identified that influence physiological responses to ethanol. To enhance the utility of the Drosophila model for investigating genes involved in ethanol-related behavior, we explored the value of an assay that measures the sedative effects of ethanol on negative geotaxis, an evoked locomotor response.

An assay for evoked locomotor behavior in Drosophila reveals a role for integrins in ethanol sensitivity and rapid ethanol tolerance.

Aging is a multifaceted phenomenon that occurs in most species including humans and the fruit fly, Drosophila melanogaster. One of the most fundamental features of aging is the progressive decline in functional capacity that occurs with age (i.e. functional senescence). Age-related declines in function undermine many aspects of normal youthful physiology including behavior. Age-related behavioral declines are quite telling because they presumably reflect primary functional defects in the nervous system or musculature. Consequently, a more detailed understanding of behavioral declines that occur with age, including mechanisms that impinge on them, could ultimately lead to improved treatment or diagnosis of age-related defects in physiological processes that depend on normal function of the nervous system or musculature. Such advances in diagnosis or treatment would translate into tremendous gains in quality of life for elderly populations. In this article, we review progress using Drosophila to better understand age-related behavioral declines with a focus on age-related locomotor impairment.

Drosophila as a model for age-related impairment in locomotor and other behaviors.

Ethanol (EtOH) is metabolized by a 2-step process in which alcohol dehydrogenase (ADH) oxidizes EtOH to acetaldehyde, which is further oxidized to acetate by aldehyde dehydrogenase (ALDH). Although variation in EtOH metabolism in humans strongly influences the propensity to chronically abuse alcohol, few data exist on the behavioral effects of altered EtOH metabolism. Here, we used the nematode Caenorhabditis elegans to directly examine how changes in EtOH metabolism alter behavioral responses to alcohol during an acute exposure. Additionally, we investigated EtOH solution osmolarity as a potential explanation for contrasting published data on C. elegans EtOH sensitivity.

Ethanol metabolism and osmolarity modify behavioral responses to ethanol in C. elegans.

Wolfram syndrome (WFS) is a progressive neurodegenerative disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. WFS1 and WFS2 are caused by recessive mutations in the genes Wolfram Syndrome 1 (WFS1) and CDGSH iron sulfur domain 2 (CISD2), respectively. To explore the function of CISD2, we performed genetic studies in flies with altered expression of its Drosophila orthologue, cisd2. Surprisingly, flies with strong ubiquitous RNAi-mediated knockdown of cisd2 had no obvious signs of altered life span, stress resistance, locomotor behavior or several other phenotypes. We subsequently found in a targeted genetic screen, however, that altered function of cisd2 modified the effects of overexpressing the fly orthologues of two lysosomal storage disease genes, palmitoyl-protein thioesterase 1 (PPT1 in humans, Ppt1 in flies) and ceroid-lipofuscinosis, neuronal 3 (CLN3 in humans, cln3 in flies), on eye morphology in flies. We also found that cln3 modified the effects of overexpressing Ppt1 in the eye and that overexpression of cln3 interacted with a loss of function mutation in cisd2 to disrupt locomotor ability in flies. Follow-up multi-species bioinformatic analyses suggested that a gene network centered on CISD2, PPT1 and CLN3 might impact disease through altered carbohydrate metabolism, protein folding and endopeptidase activity. Human genetic studies indicated that copy number variants (duplications and deletions) including CLN3, and possibly another gene in the CISD2/PPT1/CLN3 network, are over-represented in individuals with developmental delay. Our studies indicate that cisd2, Ppt1 and cln3 function in concert in flies, suggesting that CISD2, PPT1 and CLN3 might also function coordinately in humans. Further, our studies raise the possibility that WFS2 and some lysosomal storage disorders might be influenced by common mechanisms and that the underlying genes might have previously unappreciated effects on developmental delay.

Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease.

The fruit fly Drosophila melanogaster has been used extensively to investigate genetic mechanisms of ethanol (EtOH)-related behaviors. Many past studies in flies, including studies from our laboratory, have manipulated gene expression using transposons carrying the genetic-phenotypic marker mini-white(mini-w), a derivative of the endogenous gene white(w). Whether the mini-w transgenic marker or the endogenous w gene influences behavioral responses to acute EtOH exposure in flies has not been systematically investigated.

Contrasting influences of Drosophila white/mini-white on ethanol sensitivity in two different behavioral assays.

Exposure to Paraquat and RNA interference knockdown of mitochondrial superoxide dismutase (Sod2) are known to result in significant lifespan reduction, locomotor dysfunction, and mitochondrial degeneration in Drosophila melanogaster. Both perturbations increase the flux of the progenitor ROS, superoxide, but the molecular underpinnings of the resulting phenotypes are poorly understood. Improved understanding of such processes could lead to advances in the treatment of numerous age-related disorders. Superoxide toxicity can act through protein carbonylation. Analysis of carbonylated proteins is attractive since carbonyl groups are not present in the 20 canonical amino acids and are amenable to labeling and enrichment strategies. Here, carbonylated proteins were labeled with biotin hydrazide and enriched on streptavidin beads. On-bead digestion was used to release carbonylated protein peptides, with relative abundance ratios versus controls obtained using the iTRAQ MS-based proteomics approach. Western blotting and biotin quantitation assay approaches were also investigated. By both Western blotting and proteomics, Paraquat exposure, but not Sod2 knockdown, resulted in increased carbonylated protein relative abundance. For Paraquat exposure versus control, the median carbonylated protein relative abundance ratio (1.53) determined using MS-based proteomics was in good agreement with that obtained using a commercial biotin quantitation kit (1.36).

Article	Year
Genetic and environmental factors impact age-related impairment of negative geotaxis in Drosophila by altering age-dependent climbing speed. Experimental gerontology\| PubMed ID: 18515028	2008
Multiple measures of functionality exhibit progressive decline in a parallel, stochastic fashion in Drosophila Sod2 null mutants. Biogerontology\| PubMed ID: 19148770	2009
A forward genetic screen in Drosophila implicates insulin signaling in age-related locomotor impairment. Experimental gerontology\| PubMed ID: 19481596	2009
Manipulation of Sod1 expression ubiquitously, but not in the nervous system or muscle, impacts age-related parameters in Drosophila. FEBS letters\| PubMed ID: 19540235	2009
Sod2 knockdown in the musculature has whole-organism consequences in Drosophila. Free radical biology & medicine\| PubMed ID: 19545620	2009
An assay for evoked locomotor behavior in Drosophila reveals a role for integrins in ethanol sensitivity and rapid ethanol tolerance. Alcoholism, clinical and experimental research\| PubMed ID: 19645731	2009
Drosophila as a model for age-related impairment in locomotor and other behaviors. Experimental gerontology\| PubMed ID: 20800672	2011
Ethanol metabolism and osmolarity modify behavioral responses to ethanol in C. elegans. Alcoholism, clinical and experimental research\| PubMed ID: 22486589	2012
Genetic studies in Drosophila and humans support a model for the concerted function of CISD2, PPT1 and CLN3 in disease. Biology open\| PubMed ID: 24705017	2014
Contrasting influences of Drosophila white/mini-white on ethanol sensitivity in two different behavioral assays. Alcoholism, clinical and experimental research\| PubMed ID: 24890118	2014
Paraquat exposure and Sod2 knockdown have dissimilar impacts on the Drosophila melanogaster carbonylated protein proteome. Proteomics\| PubMed ID: 25091824	2014

Mike Grotewiel

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