Intramuscular Injections Along the Motor End Plates: A Minimally Invasive Approach to Shuttle Tracers Directly into Motor Neurons

Diseases affecting the integrity of spinal cord motor neurons are amongst the most debilitating neurological conditions. Over the last decades, the ...

Expanding the Toolkit for <em>In Vivo</em> Imaging of Axonal Transport

Axonal transport maintains neuronal homeostasis by enabling the bidirectional trafficking of diverse organelles and cargoes. Disruptions in axonal ...

University of New South Wales

University College London

&#x810A;&#x9AD3;&#x635F;&#x4F24;&#x7834;&#x574F;&#x7EA2;&#x6838;&#x810A;&#x9AD3;&#x675F; (RST) &#x5E72;&#x6270;&#x719F;&#x7EC3;&#x524D;&#x80A2;&#x8FD0;&#x52A8;&#xFF0C;&#x4F46;&#x9274;&#x5B9A;&#x7684;&#x8FD9;&#x79CD;&#x884C;&#x4E3A;&#x5728; RST &#x7684;&#x786E;&#x5207;&#x4F5C;&#x7528;&#x963B;&#x788D;&#x4E86;&#x624B;&#x672F;&#x9694;&#x79BB;&#x4ECE;&#x5916;&#x4FA7;&#x73E0; (LF) &#x5185;&#x8FD0;&#x884C;&#x5176;&#x4ED6;&#x9014;&#x5F84; RST &#x7684;&#x56F0;&#x96BE;&#x3002;&#x672C;&#x7814;&#x7A76;&#x7528;&#x719F;&#x7EC3;&#x7684;&#x8FBE;&#x6210;&#x4EFB;&#x52A1;&#x548C;&#x884C;&#x4E3A;/&#x89E3;&#x5256;&#x5939;&#x5C42;&#x52A8;&#x8109;&#x7624;&#x7684;&#x4E00;&#x79CD;&#x65B9;&#x6CD5;&#x6765;&#x6807;&#x8BC6;&#x719F;&#x7EC3;&#x524D;&#x80A2;&#x8FD0;&#x52A8; RST &#x7684;&#x8D21;&#x732E;&#x3002;&#x5927;&#x9F20;&#x57F9;&#x8BAD;&#x719F;&#x7EC3;&#x8FBE;&#x6210;&#x4EFB;&#x52A1;&#xFF0C;&#x906D;&#x53D7; LF &#x75C5;&#x53D8;&#x3002;&#x57FA;&#x4E8E;&#x7EC4;&#x7EC7;&#x5B66;&#x8BC4;&#x4EF7;&#xFF0C;&#x52A8;&#x7269;&#x88AB;&#x5206;&#x914D;&#x7ED9;&#x5927;&#x578B;&#x3001; &#x4E2D;&#x578B;&#x6216;&#x5C0F;&#x578B; LF &#x75C5;&#x53D8;&#x5927;&#x5C0F;&#x56E2;&#x4F53;&#x3002;&#x7EC8;&#x7ED3;&#x70B9;&#x548C; arm/&#x624B;/&#x6570;&#x5B57;&#x8FD0;&#x52A8;&#x540E;&#x6765;&#x88AB;&#x5B9A;&#x4E3A;&#x6BCF;&#x4E2A;&#x7EC4;&#x3002;&#x6210;&#x529F;&#x6709;&#x635F;&#x4E8E;&#x6240;&#x6709;&#x7FA4;&#x4F53;&#xFF0C;&#x4F46;&#x635F;&#x5BB3;&#x75C5;&#x53D8;&#x5927;&#x5C0F;&#x65E0;&#x5173;&#x3002;&#x89C6;&#x9891;&#x5F55;&#x5236;&#x7684;&#x5E27;&#x7684;&#x5B9A;&#x6027;&#x5206;&#x6790;&#x63ED;&#x793A;&#x5927;&#x578B; LF &#x75C5;&#x53D8;&#x53D6;&#x6D88;&#x5173;&#x95ED;&#x6570;&#x5B57;&#x3001; &#x6570;&#x5B57;&#x6253;&#x5F00;&#x3001; &#x7436;&#x97F3;&#x3001; &#x628A;&#x63E1;&#x3001; &#x65CB; 2&#x3001; &#x548C;&#x91CA;&#x653E;&#x7684;&#x5143;&#x7D20;&#x3002;&#x4E2D;&#x578B; LF &#x75C5;&#x53D8;&#x5E72;&#x9884;&#x8868;&#x660E;&#x53D7;&#x5927;&#x578B; LF &#x75C5;&#x53D8;&#xFF0C;&#x5373;&#x7436;&#x97F3;&#x548C;&#x638C;&#x63E1;&#x7684;&#x8FD0;&#x52A8;&#x5143;&#x7D20;&#x7684;&#x5B50;&#x96C6;&#x3002;&#x53EA;&#x6709;&#x7436;&#x97F3;&#x8FD0;&#x52A8;&#x906D;&#x5230;&#x7834;&#x574F;&#x540E;&#x5C0F; LF &#x75C5;&#x53D8;&#x3002;&#x7ED3;&#x679C;&#x663E;&#x793A;&#x65E0; LF &#x6709;&#x52A9;&#x4E8E;&#x8FBE;&#x5230;&#x719F;&#x7EC3;&#xFF0C;&#x4E0D;&#x4EC5;&#x56E0;&#x4E3A; RST &#x53EF;&#x80FD;&#x5DF2;&#x635F;&#x574F;&#x6240;&#x6709;&#x75C5;&#x53D8;&#x7EC4;&#x4E2D;&#xFF0C;RST &#x662F;&#x66F4;&#x591A;&#x5730;&#x53C2;&#x4E0E;&#x5728;&#x624B;&#x4E2D;&#x4F4D;&#x6570;&#x6BD4;&#x65CB;&#x8F6C;&#x4F7F;&#x7528;&#x3002;&#x5C31;&#x6709;&#x53EF;&#x80FD;&#x5728;&#x4E0D;&#x540C;&#x7684; LF &#x75C5;&#x53D8;&#x7EC4;&#x635F;&#x574F;&#x7684;&#x7EA4;&#x7EF4;&#x675F;&#xFF0C;&#x8BA8;&#x8BBA;&#x7ED3;&#x679C;&#x3002;

&#x53D7;&#x635F;&#x5927;&#x9F20;&#x7EA2;&#x6838;&#x810A;&#x9AD3;&#x675F;&#x75C5;&#x53D8;&#x719F;&#x7EC3;&#x8FBE;&#x6210;&#x7684;&#x7436;&#x97F3;&#x8FD0;&#x52A8;&#xFF1A; &#x884C;&#x4E3A;/&#x89E3;&#x5256;&#x5206;&#x998F;&#x3002;

Spinal cord injury damaging the rubrospinal tract (RST) interferes with skilled forelimb movement, but identification of the precise role of the RST in this behavior is impeded by the difficulty of surgically isolating the RST from other pathways running within the lateral funiculus (LF). The present study used a skilled reaching task and a behavioral/anatomical dissection method to identify the contribution of the RST to skilled forelimb movement. Rats were trained on the skilled reaching task and subjected to lesions of the LF. Based on histological evaluation, the animals were assigned to large, medium, or small LF lesion size groups. End point and arm/hand/digit movements were subsequently identified for each group. Success was impaired in all groups, but the impairment was not related to lesion size. Frame-by-frame qualitative analysis of the video recordings revealed that large LF lesions abolished the elements of digits close, digits open, arpeggio, grasp, supination 2, and release. Medium LF lesions interfered with a subset of the movement elements that were shown to be affected by the large LF lesions, namely arpeggio and grasp. Only the arpeggio movement was compromised after small LF lesions. The results show that not only does the LF contribute to skilled reaching, but because the RST was likely to have been damaged in all lesion groups, the RST is more involved in hand rotation than in digit use. The results are discussed in relation to the fiber tracts that are likely to be damaged in the different LF lesion groups.

Impaired arpeggio movement in skilled reaching by rubrospinal tract lesions in the rat: a behavioral/anatomical fractionation.

L&#xE9;sions de la moelle &#xE9;pini&#xE8;re d&#x26;#39;endommager l&#x26;#39;appareil rubrospinal (TVD) interf&#xE8;re avec le mouvement des membres ant&#xE9;rieurs qualifi&#xE9;e, mais l&#x26;#39;identification du r&#xF4;le pr&#xE9;cis de la TVD dans ce comportement est entrav&#xE9;e par la difficult&#xE9; de l&#x26;#39;isolement du chirurgicalement la TVD aupr&#xE8;s de d&#x26;#39;autres voies en cours d&#x26;#39;ex&#xE9;cution au sein de la partie lat&#xE9;rale du funicule (LF). La pr&#xE9;sente &#xE9;tude a utilis&#xE9; une t&#xE2;che qualifi&#xE9;e port&#xE9;e et une m&#xE9;thode de dissection comportementale / anatomique d&#x26;#39;identifier la contribution de la TVD au mouvement des membres ant&#xE9;rieurs qualifi&#xE9;s. Les rats ont &#xE9;t&#xE9; form&#xE9;s &#xE0; la t&#xE2;che qualifi&#xE9;e port&#xE9;e et soumis &#xE0; des l&#xE9;sions de la LF. Bas&#xE9; sur l&#x26;#39;&#xE9;valuation histologique, les animaux ont &#xE9;t&#xE9; affect&#xE9;s &#xE0; de grandes, moyennes, petites ou LF groupes de taille des l&#xE9;sions. Point final et le bras / main / chiffre mouvements ont ensuite &#xE9;t&#xE9; identifi&#xE9;s pour chaque groupe. Le succ&#xE8;s a &#xE9;t&#xE9; alt&#xE9;r&#xE9;e dans tous les groupes, mais la d&#xE9;pr&#xE9;ciation n&#x26;#39;&#xE9;tait pas li&#xE9;e &#xE0; la taille des l&#xE9;sions. Image par image l&#x26;#39;analyse qualitative des enregistrements vid&#xE9;o a r&#xE9;v&#xE9;l&#xE9; que de grandes l&#xE9;sions LF a aboli les &#xE9;l&#xE9;ments de chiffres pr&#xE8;s, les chiffres ouverte, les arp&#xE8;ges, port&#xE9;e, supination 2, et la lib&#xE9;ration. Moyen des l&#xE9;sions LF interf&#xE9;r&#xE9; avec un sous-ensemble des &#xE9;l&#xE9;ments de d&#xE9;placement qui ont &#xE9;t&#xE9; montr&#xE9;es &#xE0; &#xEA;tre affect&#xE9; par les l&#xE9;sions de grande taille, &#xE0; savoir LF arp&#xE8;ges et le GRASP. Seul le mouvement d&#x26;#39;arp&#xE8;ge a &#xE9;t&#xE9; compromis apr&#xE8;s de petites l&#xE9;sions de la FL. Les r&#xE9;sultats montrent que non seulement la LF contribuer &#xE0; l&#x26;#39;atteinte qualifi&#xE9;e, mais parce que la TVD a &#xE9;t&#xE9; susceptibles d&#x26;#39;avoir &#xE9;t&#xE9; endommag&#xE9; dans tous les groupes l&#xE9;sion, la TVD est plus impliqu&#xE9; dans rotation de la main que dans l&#x26;#39;utilisation chiffres. Les r&#xE9;sultats sont discut&#xE9;s en relation avec les faisceaux de fibres qui sont susceptibles d&#x26;#39;&#xEA;tre endommag&#xE9;s dans les diff&#xE9;rents groupes de l&#xE9;sions de la FL.

Avec facult&#xE9;s affaiblies Mouvement Arpeggio dans qualifi&#xE9;s Atteindre par des l&#xE9;sions des voies rubrospinal chez le rat: un fractionnement du comportement / anatomique

Verletzung des R&uuml;ckenmarks sch&auml;digen den R&uuml;ckenmark-Darm-Trakt (RST) mit qualifizierten Vorderbein Bewegung st&ouml;rt, aber Identifikation &uuml;ber die genaue Rolle der RST in diesem Verhalten ist behindert durch die Schwierigkeit chirurgisch isolieren RST von anderen wegen in die seitlichen Funiculus (LF) ausgef&uuml;hrt. Die vorliegende Studie verwendet eine qualifizierte reichende Aufgabe und eine Verhaltens-/anatomischen Pr&auml;paration-Methode um den Beitrag der RST zu qualifizierten Vorderbein Bewegung zu identifizieren. Ratten wurden auf die qualifizierte reichende Aufgabe ausgebildet und L&auml;sionen der LF unterworfen. Basierend auf histologische Beurteilung wurden die Tiere gro&szlig;e, mittlere oder kleine LF L&auml;sion Gr&ouml;&szlig;e Gruppen zugewiesen. Endpunkt und Arm/Hand/Ziffer Bewegungen wurden anschlie&szlig;end f&uuml;r jede Gruppe identifiziert. Erfolg in allen Gruppen beeintr&auml;chtigt wurde, aber die Beeintr&auml;chtigung war nicht verwandt mit L&auml;sion Gr&ouml;&szlig;e. Einzelbild-Qualitative Analyse der Videoaufnahmen gezeigt, dass gro&szlig;e LF-L&auml;sionen die Elemente der Ziffern schlie&szlig;en, offene Stellen, Arpeggio, Griff Supination 2 und Freigabe abgeschafft. Mittlere LF L&auml;sionen mischte sich mit einer Teilmenge der Bewegung-Elemente, die gezeigt wurden, durch die gro&szlig;en LF-L&auml;sionen, n&auml;mlich Arpeggio betroffen sein und zu begreifen. Nur die Arpeggio-Bewegung wurde nach kleinen LF L&auml;sionen kompromittiert. Die Ergebnisse zeigen, dass nicht nur das LF zu qualifizierten erreichen tr&auml;gt, sondern weil das RST voraussichtlich in allen Gruppen der L&auml;sion besch&auml;digt worden war, das RST ist aufw&auml;ndiger Drehung als Ziffer in der hand verwenden. Die Ergebnisse werden in Bezug auf den Faser-Tracts diskutiert, die in den verschiedenen Gruppen der LF-L&auml;sion besch&auml;digt zu sein d&uuml;rften.

Beeintr&auml;chtigte Arpeggio-Bewegung in qualifizierten erreichen durch R&uuml;ckenmark Trakt L&auml;sionen bei der Ratte: eine Verhaltens-/anatomische Fraktionierung.

Lesioni del midollo spinale, danneggiando il tratto di rubrospinal (RST) interferisce con il movimento degli arti anteriori qualificati, ma l&#39;identificazione del ruolo preciso della RST in questo comportamento &egrave; ostacolata dalla difficolt&agrave; di isolare chirurgicamente la RST da altre vie, in esecuzione all&#39;interno il funiculus laterale (LF). Il presente studio utilizzato un&#39;attivit&agrave; raggiungendo qualificata e un metodo di dissezione anatomica/comportamentale per identificare il contributo di RST al movimento degli arti anteriori qualificati. Ratti sono stati addestrati sull&#39;attivit&agrave; raggiungendo qualificati e sottoposti a lesioni di LF. Basato sulla valutazione istologica, gli animali sono stati assegnati ai gruppi di dimensione di lesione LF da grandi, medie o piccole. Punto finale e movimenti del braccio/mano/cifre successivamente sono stati individuati per ogni gruppo. Successo &egrave; stato alterato in tutti i gruppi, ma il danno non era correlato alla dimensione di lesione. Frame-by-frame analisi qualitativa delle registrazioni video ha rivelato che grandi lesioni LF abolito gli elementi delle cifre nelle vicinanze, cifre aperti, arpeggio, afferrare, supinazione 2 e rilascio. Lesioni LF medie ha interferito con un sottoinsieme degli elementi di movimento che hanno dimostrato di essere colpiti da grandi lesioni LF, vale a dire l&#39;arpeggio e afferrare. Solo il movimento di arpeggio &egrave; stata compromessa dopo piccole lesioni LF. I risultati mostrano che non solo il LF contribuisce al raggiungimento di qualificati, ma perch&eacute; il primo &egrave; stato probabilmente sono state danneggiate in tutti i gruppi di lesione, la RST &egrave; pi&ugrave; coinvolto nella mano utilizzare rotazione rispetto in cifre. I risultati sono discussi in relazione i tratti di fibra che rischiano di essere danneggiati in diversi gruppi di lesione LF.

Con problemi di movimento arpeggio in abili raggiungendo da lesioni del tratto rubrospinal nel ratto: un frazionamento del comportamento/anatomico.

&#x8D64;&#x6838;&#x810A;&#x9AC4;&#x8DEF;&#xFF08;RST&#xFF09;&#x3092;&#x640D;&#x50B7;&#x810A;&#x9AC4;&#x640D;&#x50B7;&#x306F;&#x3001;&#x719F;&#x7DF4;&#x3057;&#x305F;&#x524D;&#x80A2;&#x306E;&#x52D5;&#x304D;&#x3092;&#x59A8;&#x5BB3;&#x3059;&#x308B;&#x304C;&#x3001;&#x3053;&#x306E;&#x52D5;&#x4F5C;&#x3067;RST&#x306E;&#x6B63;&#x78BA;&#x306A;&#x5F79;&#x5272;&#x306E;&#x8B58;&#x5225;&#x306F;&#x3001;&#x624B;&#x8853;&#x5074;&#x7D22;&#xFF08;LF&#xFF09;&#x5185;&#x3067;&#x5B9F;&#x884C;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x4ED6;&#x306E;&#x7D4C;&#x8DEF;&#x304B;&#x3089;&#x306E;RST&#x3092;&#x5206;&#x96E2;&#x3059;&#x308B;&#x3053;&#x3068;&#x306E;&#x96E3;&#x3057;&#x3055;&#x306B;&#x3088;&#x308A;&#x59A8;&#x3052;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#x3002;&#x672C;&#x7814;&#x7A76;&#x3067;&#x306F;&#x3001;&#x719F;&#x7DF4;&#x3057;&#x305F;&#x5E83;&#x7BC4;&#x306A;&#x30BF;&#x30B9;&#x30AF;&#x3068;&#x719F;&#x7DF4;&#x3057;&#x305F;&#x524D;&#x80A2;&#x306E;&#x52D5;&#x304D;&#x306B;RST&#x306E;&#x5BC4;&#x4E0E;&#x3092;&#x8B58;&#x5225;&#x3059;&#x308B;&#x305F;&#x3081;&#x306E;&#x89E3;&#x5256;&#x5B66;/&#x884C;&#x52D5;&#x306E;&#x89E3;&#x5256;&#x6CD5;&#x3092;&#x7528;&#x3044;&#x305F;&#x3002;&#x30E9;&#x30C3;&#x30C8;&#x306F;&#x3001;&#x719F;&#x7DF4;&#x3057;&#x305F;&#x5E83;&#x7BC4;&#x306A;&#x30BF;&#x30B9;&#x30AF;&#x306B;&#x8A13;&#x7DF4;&#x3055;&#x308C;&#x3001;LF&#x306E;&#x75C5;&#x5909;&#x306B;&#x4F9B;&#x3057;&#x305F;&#x3002;&#x7D44;&#x7E54;&#x5B66;&#x7684;&#x8A55;&#x4FA1;&#x306B;&#x57FA;&#x3065;&#x3044;&#x3066;&#x3001;&#x52D5;&#x7269;&#x306F;&#x3001;&#x5927;&#x898F;&#x6A21;&#x3001;&#x4E2D;&#x898F;&#x6A21;&#x3001;&#x5C0F;&#x898F;&#x6A21;&#x306A;LF&#x75C5;&#x5909;&#x30B5;&#x30A4;&#x30BA;&#x306E;&#x30B0;&#x30EB;&#x30FC;&#x30D7;&#x306B;&#x5272;&#x308A;&#x5F53;&#x3066;&#x3089;&#x308C;&#x3066;&#x3044;&#x305F;&#x3002;&#x30A8;&#x30F3;&#x30C9;&#x30DD;&#x30A4;&#x30F3;&#x30C8;&#x3068;&#x8155;/&#x624B;/&#x6570;&#x5B57;&#x306E;&#x52D5;&#x304D;&#x306F;&#x3001;&#x305D;&#x306E;&#x5F8C;&#x3001;&#x30B0;&#x30EB;&#x30FC;&#x30D7;&#x3054;&#x3068;&#x306B;&#x540C;&#x5B9A;&#x3055;&#x308C;&#x305F;&#x3002;&#x6210;&#x529F;&#x306F;&#x3059;&#x3079;&#x3066;&#x306E;&#x7FA4;&#x3067;&#x4F4E;&#x4E0B;&#x3057;&#x3066;&#x3044;&#x308B;&#x304C;&#x3001;&#x969C;&#x5BB3;&#x306F;&#x75C5;&#x5909;&#x306E;&#x5927;&#x304D;&#x3055;&#x306B;&#x306F;&#x95A2;&#x4FC2;&#x3042;&#x308A;&#x307E;&#x305B;&#x3093;&#x3067;&#x3057;&#x305F;&#x3002;&#x30D3;&#x30C7;&#x30AA;&#x9332;&#x753B;&#x306E;&#x30D5;&#x30EC;&#x30FC;&#x30E0;&#x3054;&#x3068;&#x306B;&#x5B9A;&#x6027;&#x5206;&#x6790;&#x306F;&#x3001;&#x5927;&#x898F;&#x6A21;&#x306A;LF&#x75C5;&#x5909;&#x306B;&#x8FD1;&#x3044;&#x6570;&#x5B57;&#x306E;&#x8981;&#x7D20;&#x3092;&#x3001;&#x958B;&#x3044;&#x3066;&#x3044;&#x308B;&#x6570;&#x5B57;&#x3001;&#x30A2;&#x30EB;&#x30DA;&#x30B8;&#x30AA;&#x3001;&#x628A;&#x63E1;&#x3001;&#x56DE;&#x5916;2&#x3001;&#x304A;&#x3088;&#x3073;&#x30EA;&#x30EA;&#x30FC;&#x30B9;&#x3092;&#x5EC3;&#x6B62;&#x3057;&#x305F;&#x3053;&#x3068;&#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x305F;&#x3002;&#x3059;&#x306A;&#x308F;&#x3061;&#x5927;&#x898F;&#x6A21;&#x306A;LF&#x75C5;&#x5909;&#x3001;&#x30A2;&#x30EB;&#x30DA;&#x30B8;&#x30AA;&#x3068;&#x628A;&#x63E1;&#x306B;&#x3088;&#x3063;&#x3066;&#x5F71;&#x97FF;&#x3055;&#x308C;&#x308B;&#x3053;&#x3068;&#x304C;&#x793A;&#x3055;&#x308C;&#x305F;&#x904B;&#x52D5;&#x8981;&#x7D20;&#x306E;&#x30B5;&#x30D6;&#x30BB;&#x30C3;&#x30C8;&#x3092;&#x59A8;&#x5BB3;&#x3059;&#x308B;&#x57F9;&#x5730;LF&#x75C5;&#x5909;&#x3002;&#x552F;&#x4E00;&#x306E;&#x30A2;&#x30EB;&#x30DA;&#x30B8;&#x30AA;&#x306E;&#x52D5;&#x304D;&#x306F;&#x5C0F;&#x3055;&#x3044;LF&#x75C5;&#x5909;&#x3057;&#x305F;&#x5F8C;&#x306B;&#x4FB5;&#x5BB3;&#x3055;&#x308C;&#x305F;&#x3002;&#x7D50;&#x679C;&#x306F;&#x3001;LF&#x306F;&#x719F;&#x7DF4;&#x3057;&#x305F;&#x5230;&#x9054;&#x306B;&#x8CA2;&#x732E;&#x3057;&#x306A;&#x3044;&#x306E;&#x307F;&#x306A;&#x3089;&#x305A;&#x3001;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x305F;&#x304C;&#x3001;RST&#x306F;&#x3001;&#x3059;&#x3079;&#x3066;&#x306E;&#x75C5;&#x5909;&#x30B0;&#x30EB;&#x30FC;&#x30D7;&#x306B;&#x7834;&#x640D;&#x3057;&#x3066;&#x3044;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x3063;&#x305F;&#x306E;&#x3067;&#x3001;RST&#x306F;&#x3088;&#x308A;&#x591A;&#x304F;&#x306E;&#x6841;&#x3092;&#x4F7F;&#x7528;&#x3059;&#x308B;&#x3088;&#x308A;&#x3082;&#x624B;&#x306E;&#x56DE;&#x8EE2;&#x306B;&#x95A2;&#x4E0E;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;&#x7D50;&#x679C;&#x306F;&#x3001;&#x7570;&#x306A;&#x308B;LF&#x75C5;&#x5909;&#x30B0;&#x30EB;&#x30FC;&#x30D7;&#x306B;&#x7834;&#x640D;&#x3059;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308B;&#x7E4A;&#x7DAD;&#x7BA1;&#x3068;&#x306E;&#x95A2;&#x4FC2;&#x3067;&#x8AAC;&#x660E;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

&#x30E9;&#x30C3;&#x30C8;&#x8D64;&#x6838;&#x810A;&#x9AC4;&#x8DEF;&#x306E;&#x75C5;&#x5909;&#x3092;&#x4F34;&#x3046;&#x5230;&#x9054;&#x6280;&#x80FD;&#x306E;&#x969C;&#x5BB3;&#x30A2;&#x30EB;&#x30DA;&#x30B8;&#x30AA;&#x30E0;&#x30FC;&#x30D6;&#x30E1;&#x30F3;&#x30C8;&#xFF1A;&#x89E3;&#x5256;&#x5B66;/&#x884C;&#x52D5;&#x753B;

Rubrospinal&#xB85C; (RST) &#xC190;&#xC0C1; &#xCC99;&#xC218; &#xBD80;&#xC0C1; &#xC219;&#xB828; forelimb &#xC6C0;&#xC9C1;&#xC784;&#xC744; &#xBC29;&#xD574; &#xD558;&#xC9C0;&#xB9CC;&#xC774; &#xB3D9;&#xC791;&#xC774; RST&#xC758; &#xC815;&#xD655;&#xD55C; &#xC5ED;&#xD560;&#xC758; &#xCE21;&#xBA74; &#xC0AD; &#xC870; (LF) &#xB0B4;&#xC5D0;&#xC11C; &#xC2E4;&#xD589; &#xC911;&#xC778; &#xB2E4;&#xB978; &#xACBD;&#xB85C;&#xC5D0;&#xC11C; RST&#xB97C; &#xBD84;&#xB9AC; &#xC218;&#xC220;&#xC758; &#xB09C;&#xC774;&#xB3C4; &#xC7A5;&#xC560;&#xAC00;. &#xD604;&#xC7AC;&#xC758; &#xC5F0;&#xAD6C; &#xC219;&#xB828; &#xB41C; &#xB3C4;&#xB2EC; &#xC791;&#xC5C5;&#xACFC; &#xD589;&#xB3D9;/&#xD574; &#xBD80; &#xD574; &#xBD80; &#xBC29;&#xBC95; &#xC0AC;&#xC6A9; &#xB418;&#xB294; RST &#xC219;&#xB828; forelimb &#xC6B4;&#xB3D9;&#xC5D0;&#xC758; &#xAE30;&#xC5EC;&#xB97C; &#xC2DD;&#xBCC4;. &#xC950; LF&#xC758; &#xBCD1; &#xBCC0;&#xC73C;&#xB85C; &#xBCF5;&#xC885; &#xD558; &#xACE0; &#xB3C4;&#xB2EC; &#xC219;&#xB828; &#xB41C; &#xC791;&#xC5C5;&#xC5D0; &#xB300; &#xD55C; &#xD6C8;&#xB828; &#xD588;&#xB2E4;. &#xC870;&#xC9C1;&#xD559; &#xD3C9;&#xAC00; &#xBC14;&#xD0D5;&#xC73C;&#xB85C;, &#xB3D9;&#xBB3C;, &#xC911;&#xAC04;, &#xD070; &#xB610;&#xB294; &#xC791;&#xC740; LF &#xBCD1; &#xBCC0; &#xD06C;&#xAE30; &#xADF8;&#xB8F9;&#xC5D0; &#xD560;&#xB2F9; &#xD588;&#xB2E4;. &#xB05D;&#xC810; &#xBC0F; &#xD314;/&#xC190;/&#xC190;&#xAC00;&#xB77D; &#xC6B4;&#xB3D9; &#xC774;&#xD6C4;&#xC5D0; &#xAC01; &#xADF8;&#xB8F9;&#xC5D0; &#xB300; &#xD55C; &#xBC1C;&#xACAC; &#xD588;&#xB2E4;. &#xC131;&#xACF5; &#xBAA8;&#xB4E0; &#xADF8;&#xB8F9;&#xC5D0;&#xC11C; &#xC7A5;&#xC560;&#xB294; &#xBCD1; &#xBCC0; &#xD06C;&#xAE30;&#xB294; &#xC7A5;&#xC560; &#xAD00;&#xB828; &#xB418;&#xC9C0; &#xC54A;&#xC558;&#xC2B5;&#xB2C8;&#xB2E4;. &#xD504;&#xB808;&#xC784;&#xBCC4;&#xC73C;&#xB85C; &#xBE44;&#xB514;&#xC624; &#xB808;&#xCF54;&#xB529;&#xC758; &#xC9C8;&#xC801; &#xBD84;&#xC11D; &#xBC1D;&#xD600; &#xD070; LF &#xBCD1; &#xBCC0;&#xC5D0; &#xAC00;&#xAE4C;&#xC6B4; &#xC790;&#xB9AC;, &#xC22B;&#xC790; &#xC624;&#xD508;, arpeggio, &#xC774;&#xD574;, supination 2, &#xBC0F; &#xB9B4;&#xB9AC;&#xC2A4; &#xC694;&#xC18C; &#xD3D0;&#xC9C0;. &#xC911;&#xAC04; LF &#xBCD1; &#xBCC0; &#xB300;&#xD615; LF &#xBCD1; &#xBCC0;, &#xC989; arpeggio &#xC601;&#xD5A5;&#xC744; &#xD30C;&#xC545;&#xC744; &#xD45C;&#xC2DC; &#xD588;&#xB2E4; &#xC6C0;&#xC9C1;&#xC784; &#xC694;&#xC18C;&#xC758; &#xD558;&#xC704; &#xC9D1;&#xD569;&#xC744; &#xBC29;&#xD574;. Arpeggio &#xC774;&#xB3D9;&#xB9CC; &#xC791;&#xC740; LF &#xBCD1; &#xBCC0; &#xD6C4; &#xD6FC;&#xC190; &#xB410;&#xB2E4;. &#xACB0;&#xACFC; &#xBFD0;&#xB9CC; &#xC544;&#xB2C8;&#xB77C; &#xC219;&#xB828; &#xB41C; &#xB3C4;&#xB2EC;&#xC5D0; &#xAE30;&#xC5EC; &#xD558;&#xB294; LF&#xAC00; &#xD558;&#xC9C0;&#xB9CC; RST &#xBAA8;&#xB4E0; &#xBCD1; &#xBCC0; &#xADF8;&#xB8F9;&#xC5D0;&#xC11C; &#xC190;&#xC0C1; &#xB41C; &#xAC00;&#xB2A5;&#xC131;&#xC774; &#xC788;&#xAE30; &#xB54C;&#xBB38;&#xC5D0;, RST&#xB294; &#xB354; &#xC190;&#xC5D0; &#xC790;&#xB9AC;&#xC5D0; &#xBCF4;&#xB2E4; &#xD68C;&#xC804; &#xC0AC;&#xC6A9; &#xAD00;&#xB828;. &#xACB0;&#xACFC; &#xB2E4;&#xB978; LF &#xBCD1; &#xBCC0; &#xADF8;&#xB8F9;&#xC5D0;&#xC11C; &#xC190;&#xC0C1; &#xB420; &#xAC00;&#xB2A5;&#xC131;&#xC774; &#xC788;&#xB294; &#xC12C;&#xC720; &#xCC45;&#xC790;&#xC5D0; &#xAD00;&#xD558;&#xC5EC; &#xC124;&#xBA85; &#xD569;&#xB2C8;&#xB2E4;.

&#xC950;&#xC5D0;&#xC11C; rubrospinal &#xC694;&#xB85C; &#xBCD1; &#xBCC0;&#xC73C;&#xB85C; &#xC219;&#xB828; &#xB41C; &#xB3C4;&#xB2EC; arpeggio &#xC6B4;&#xB3D9; &#xC7A5;&#xC560;: &#xD589;&#xB3D9;/&#xD574; &#xBD80; &#xBD84;&#xB958;.

Lesi&#xF3;n de la m&#xE9;dula espinal da&#xF1;os en el tracto rubroespinal (RST) interfiere con el movimiento del miembro superior especializada, pero la identificaci&#xF3;n de la funci&#xF3;n precisa de la RST de este comportamiento se ve obstaculizada por la dificultad de aislar quir&#xFA;rgicamente de la RST de otras v&#xED;as que se ejecutan en el lateral fun&#xED;culo (LF). El presente estudio se utiliz&#xF3; una tarea de expertos y de largo alcance un m&#xE9;todo de disecci&#xF3;n del comportamiento / anat&#xF3;mica para identificar la contribuci&#xF3;n de la RST de movimiento de la extremidad anterior calificada. Las ratas fueron entrenados en la tarea de largo alcance capacitado y sometido a las lesiones de la LF. Sobre la base de la evaluaci&#xF3;n histol&#xF3;gica, los animales fueron asignados a los grandes, medianos, o peque&#xF1;os grupos de LF lesi&#xF3;n de tama&#xF1;o. Punto final y el brazo / mano / d&#xED;gitos movimientos fueron identificados para cada grupo. El &#xE9;xito se vio afectada en todos los grupos, pero el deterioro no se relaciona con el tama&#xF1;o de la lesi&#xF3;n. Cuadro por cuadro el an&#xE1;lisis cualitativo de las grabaciones de v&#xED;deo revel&#xF3; que las grandes lesiones LF aboli&#xF3; los elementos de cierre d&#xED;gitos, los d&#xED;gitos abierto, arpegio, comprensi&#xF3;n, supinaci&#xF3;n 2, y la liberaci&#xF3;n. Media lesiones LF interferido con un subconjunto de los elementos del movimiento que se demuestre que est&#xE1;n afectados por las lesiones de gran tama&#xF1;o LF, es decir, arpegios y agarrar. S&#xF3;lo el movimiento de arpegio se vio comprometida despu&#xE9;s de peque&#xF1;as lesiones LF. Los resultados muestran que no s&#xF3;lo el LF contribuir al logro de expertos, sino porque el RST es probable que haya sido da&#xF1;ado en todos los grupos de la lesi&#xF3;n, la RST est&#xE1; m&#xE1;s involucrado en la rotaci&#xF3;n de la mano que en el uso de d&#xED;gitos. Los resultados se discuten en relaci&#xF3;n con los tractos de fibras que son propensos a sufrir da&#xF1;os en los grupos de la lesi&#xF3;n LF diferentes.

Deterioro del movimiento en el arpegio especializada Llegar por rubrospinal lesiones del tracto de la rata: un fraccionamiento del Comportamiento / anat&#xF3;mica

Viral-mediated gene therapy for spinal cord injury (SCI) from a translational neuroanatomical perspective.

Tetanus (TeNT) and botulinum (BoNT) neurotoxins, the causative agents of tetanus and botulism, respectively, are the most potent toxic molecules known to mankind. This extreme potency is attributed to: i) their specificity for essential components of the neurotransmitter release machinery present at vertebrate synapses, and ii) their high-affinity targeting to motor neurons by binding to polysialogangliosides and protein receptors. Comprising the clostridial neurotoxin family, TeNT and BoNTs engage distinct surface receptors and intracellular sorting pathways in neurons. BoNTs bind to the intraluminal domain of specific synaptic vesicle proteins that are exposed to the extracellular milieu upon exocytosis, and are taken up by synaptic vesicle recycling. A sizeable proportion of BoNT molecules remain at the neuromuscular junction, where their protease moiety is released into the cytoplasm, blocking synaptic transmission and causing flaccid paralysis. In contrast, TeNT undergoes binding to specific components of the basal membrane at the neuromuscular junction, is endocytosed into motor neurons and sorted to axonal signalling endosomes. Following this, TeNT is transported to the soma of motor neurons located in the spinal cord or brainstem, and then transcytosed to inhibitory interneurons, where it blocks synaptic transmission. TeNT-induced impairment of inhibitory input leads to hyperactivity of motor neurons, causing spastic paralysis, which is the hallmark of tetanus. This review examines the molecular mechanisms leading to the entry, sorting and intracellular trafficking of TeNT and BoNTs.

The travel diaries of tetanus and botulinum neurotoxins.

Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA. This milestone was achieved through extensive pre-clinical research and patient trials, which together have spawned fundamental insights into motor neuron gene therapy. We have thus tried to distil key information garnered from SMA research, in the hope that it may stimulate a more directed approach to ALS gene therapy. Not only must the type of therapeutic (e.g., antisense oligonucleotide vs. viral vector) be sensibly selected, but considerable thought must be applied to the , , , and  in order to enhance treatment benefit: to where (cell types and tissues) must the drug be delivered and how can this be best achieved? Which perturbed pathways must be corrected and can they be concurrently targeted? What dosing regime and concentration should be used? When should medication be administered? These questions are intuitive, but central to identifying and optimizing a successful gene therapy. Providing definitive solutions to these quandaries will be difficult, but clear thinking about therapeutic testing is necessary if we are to have the best chance of developing viable ALS gene therapies and improving upon early generation SMA treatments.

Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis.

Editorial: Gene Therapy for the Central and Peripheral Nervous System.

Inhibition of histone deacetylase 6 (HDAC6) was shown to support axon growth on the nonpermissive substrates myelin-associated glycoprotein (MAG) and chondroitin sulfate proteoglycans (CSPGs). Though HDAC6 deacetylates α-tubulin, we find that another HDAC6 substrate contributes to this axon growth failure. HDAC6 is known to impact transport of mitochondria, and we show that mitochondria accumulate in distal axons after HDAC6 inhibition. Miro and Milton proteins link mitochondria to motor proteins for axon transport. Exposing neurons to MAG and CSPGs decreases acetylation of Miro1 on Lysine 105 (K105) and decreases axonal mitochondrial transport. HDAC6 inhibition increases acetylated Miro1 in axons, and acetyl-mimetic Miro1 K105Q prevents CSPG-dependent decreases in mitochondrial transport and axon growth. MAG- and CSPG-dependent deacetylation of Miro1 requires RhoA/ROCK activation and downstream intracellular Ca increase, and Miro1 K105Q prevents the decrease in axonal mitochondria seen with activated RhoA and elevated Ca These data point to HDAC6-dependent deacetylation of Miro1 as a mediator of axon growth inhibition through decreased mitochondrial transport.

Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition.

Axonal transport is the process whereby motor proteins actively navigate microtubules to deliver diverse cargoes, such as organelles, from one end of the axon to the other, and is widely regarded as essential for nerve development, function and survival. Mutations in genes encoding key components of the transport machinery, including motor proteins, motor adaptors and microtubules, have been discovered to cause neurological disease. Moreover, disruptions in axonal cargo trafficking have been extensively reported across a wide range of nervous system disorders. However, whether these impairments have a major causative role in, are contributing to or are simply a consequence of neuronal degeneration remains unclear. Therefore, the fundamental relevance of defective trafficking along axons to nerve dysfunction and pathology is often debated. In this article, we review the latest evidence emerging from human and in vivo studies on whether perturbations in axonal transport are indeed integral to the pathogenesis of neurological disease.

Axonal transport and neurological disease.

Neurons are highly polarized cells that critically depend on long-range, bidirectional transport between the cell body and synapse for their function. This continual and highly coordinated trafficking process, which takes place via the axon, has fascinated researchers since the early 20th century. Ramon y Cajal first proposed the existence of axonal trafficking of biological material after observing that dissociation of the axon from the cell body led to neuronal degeneration. Since these first indirect observations, the field has come a long way in its understanding of this fundamental process. However, these advances in our knowledge have been aided by breakthroughs in other scientific disciplines, as well as the parallel development of novel tools, techniques and model systems. In this review, we summarize the evolution of tools used to study axonal transport and discuss how their deployment has refined our understanding of this process. We also highlight innovative tools currently being developed and how their addition to the available axonal transport toolkit might help to address key outstanding questions.

The evolution of the axonal transport toolkit.

Sensitive and objective biomarkers of neuronal injury, degeneration, and regeneration can help facilitate translation of experimental findings into clinical testing. Whereas measures of upper motor neuron connectivity have been readily established, functional assessments of lower motor neuron (LMN) innervation of forelimb muscles are lacking. Compound muscle action potential (CMAP) and motor unit (MU) number estimation (MUNE) are well-established methods that allow longitudinal MU integrity monitoring in patients. In analogy we refined CMAP and MUNE methods for assessing spinal MU input in the rat forelimb and hindlimb. Repeated CMAP and MUNE recordings are robust (coefficients of variability: 4.5-11.3%), and MUNE measurements from forelimb wrist flexor muscles (415 ± 8 [SEM]) align with back-traced anatomical LMN counts (336 ± 16 [SEM]). For disease validation, cross-sectional blinded electrophysiological and muscle contractility measurements were obtained in a cohort of G93A SOD1 mutant overexpressing rats and compared with controls. Longitudinal assessment of mutant animals demonstrated progressive motor unit decline in the hindlimb to a greater extent than the forelimb. Hindlimb CMAP and MUNE demonstrated strong correlations with plantarflexion muscle contractility. Cross-species assessment of upper/fore- limb and lower/hind- limb motor units using objective electrophysiological CMAP and MUNE values as biomarkers will guide and improve bi-directional translation.

Assessing Rat Forelimb and Hindlimb Motor Unit Connectivity as Objective and Robust Biomarkers of Spinal Motor Neuron Function.

Axonal transport is critical for neuronal homeostasis and relies on motor complexes bound to cargoes via specific adaptors. However, the mechanisms responsible for the spatiotemporal regulation of axonal transport are not completely understood. A recent study by Liao et al. contributes to filling this gap by reporting that RNA granules 'hitchhike' on LAMP1-positive organelles using annexin A11 as a tether.

Travelling Together: A Unifying Pathomechanism for ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease resulting from a complex interplay between genetics and environment. Impairments in axonal transport have been identified in several ALS models, but in vivo evidence remains limited, thus their pathogenetic importance remains to be fully resolved. We therefore analyzed the in vivo dynamics of retrogradely transported, neurotrophin-containing signaling endosomes in nerve axons of two ALS mouse models with mutations in the RNA processing genes TARDBP and FUS. TDP-43 mice, which show neuromuscular pathology without motor neuron loss, display axonal transport perturbations manifesting between 1.5 and 3 months and preceding symptom onset. Contrastingly, despite 20% motor neuron loss, transport remained largely unaffected in Fus mice. Deficiencies in retrograde axonal transport of signaling endosomes are therefore not shared by all ALS-linked genes, indicating that there are mechanistic distinctions in the pathogenesis of ALS caused by mutations in different RNA processing genes.

Mice Carrying ALS Mutant TDP-43, but Not Mutant FUS, Display In Vivo Defects in Axonal Transport of Signaling Endosomes.

Axonal transport, which is the process mediating the active shuttling of a variety cargoes from one end of an axon to the other, is essential for the development, function, and survival of neurons. Impairments in this dynamic process are linked to diverse nervous system diseases and advanced ageing. It is thus essential that we quantitatively study the kinetics of axonal transport to gain an improved understanding of neuropathology as well as the molecular and cellular mechanisms regulating cargo trafficking. One of the best ways to achieve this goal is by imaging individual, fluorescent cargoes in live systems and analyzing the kinetic properties of their progression along the axon. We have therefore developed an intravital technique to visualize different organelles, such as signaling endosomes and mitochondria, being actively transported in the axons of both motor and sensory neurons in live, anesthetized rodents. In this chapter, we provide step-by-step instructions on how to deliver specific organelle-targeting, fluorescent probes using several routes of administration to image individual cargoes being bidirectionally transported along axons within the exposed sciatic nerve. This method can provide detailed, physiologically relevant information on axonal transport, and is thus poised to elucidate mechanisms regulating this process in both health and disease.

In Vivo Imaging of Anterograde and Retrograde Axonal Transport in Rodent Peripheral Nerves.

Virus-mediated gene therapy has the potential to deliver exogenous genetic material into specific cell types to promote survival and counteract disease. This is particularly enticing for neuronal conditions, as the nervous system is renowned for its intransigence to therapeutic targeting. Administration of gene therapy viruses into skeletal muscle, where distal terminals of motor and sensory neurons reside, has been shown to result in extensive transduction of cells within the spinal cord, brainstem, and sensory ganglia. This route is minimally invasive and therefore clinically relevant for gene therapy targeting to peripheral nerve soma. For successful transgene expression, viruses administered into muscle must undergo a series of processes, including host cell interaction and internalization, intracellular sorting, long-range retrograde axonal transport, endosomal liberation, and nuclear import. In this review article, we outline key characteristics of major gene therapy viruses-adenovirus, adeno-associated virus (AAV), and lentivirus-and summarize the mechanisms regulating important steps in the virus journey from binding at peripheral nerve terminals to nuclear delivery. Additionally, we describe how neuropathology can negatively influence these pathways, and conclude by discussing opportunities to optimize the intramuscular administration route to maximize gene delivery and thus therapeutic potential.

Andrew P. Tosolini

Translational Neuroscience Facility,
School of Medical Sciences,
Translational Neuroscience Facility, School of Medical Sciences

University of New South Wales

Intramuscular Injections Along the Motor End Plates: A Minimally Invasive Approach to Shuttle Tracers Directly into Motor Neurons

Expanding the Toolkit for In Vivo Imaging of Axonal Transport

Andrew P. Tosolini

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Translational Neuroscience Facility,School of Medical Sciences,Translational Neuroscience Facility, School of Medical Sciences

University of New South Wales

Intramuscular Injections Along the Motor End Plates: A Minimally Invasive Approach to Shuttle Tracers Directly into Motor Neurons

Expanding the Toolkit for In Vivo Imaging of Axonal Transport

Translational Neuroscience Facility,
School of Medical Sciences,
Translational Neuroscience Facility, School of Medical Sciences