acquisition-of-a-high-precision-skilled-forelimb-reaching-task-in-rats

Acquisition of a High-precision Skilled Forelimb Reaching Task in Rats

Movements are the main measurable output of central nervous system function. Developing behavioral paradigms that allow detailed analysis of motor ...

University of Zurich

ETH Zurich

&#x6700;&#x8FD1;&#x7684;&#x8BC1;&#x636E;&#x8868;&#x660E; sub-millisecond &#x8FDF;&#x8FDF;&#x4E0D;&#x80FD;&#x6263;&#x7403;&#x795E;&#x7ECF;&#x5143;&#x53EF;&#x80FD;&#x6709;&#x5173;&#x7684;&#x795E;&#x7ECF;&#x7F16;&#x7801;&#x3002;&#x4F30;&#x8BA1;&#x8FD9;&#x4E9B;&#x5EF6;&#x8FDF;&#x901A;&#x5E38;&#x662F;&#x7531;&#x51B7;&#x85CF;&#x5230; 1 &#x6BEB;&#x79D2;&#x7684;&#x76F4;&#x65B9;&#x56FE;&#x4E92;&#x76F8;&#x5173; (CCH)&#x3002;&#x6211;&#x4EEC;&#x8C03;&#x67E5;&#x7684;&#x7A0B;&#x5EA6;&#x6709;&#x53EF;&#x80FD;&#x8861;&#x91CF; sub-millisecond &#x7CBE;&#x5EA6;&#x5EF6;&#x8BEF;&#x65F6;&#x4E00;&#x4E2A; bin &#x5927;&#x5C0F;&#x8BA1;&#x7B97; CCHs &gt; &#x6216; = 1 &#x6BEB;&#x79D2;&#x3002;&#x4E3A;&#x6B64;&#xFF0C;&#x6211;&#x4EEC; sub-millisecond &#x73ED;&#x5F15;&#x5165;&#x7A57;&#x5217;&#x8F66;&#x4ECE;&#x732B;&#x89C6;&#x89C9;&#x76AE;&#x5C42;&#x7684;&#x8BB0;&#x5F55;&#x3002;2 &#x7B2C; 1 &#x5BF9;&#xFF0C;&#x6700;&#x957F; 2ms &#x7684; bin &#x5927;&#x5C0F;&#x88AB;&#x6D4B;&#x91CF;&#x7684;&#x4EBA;&#x5DE5;&#x8F6C;&#x79FB;&#xFF0C;&#x751A;&#x81F3;&#x5728;&#x68C0;&#x6D4B;&#x53D8;&#x5316;&#x5C0F;&#x4E8E; 0.5ms&#x5E74;&#x65F6;&#x7684;&#x6700;&#x4F18;&#x3002;&#x7814;&#x7A76;&#x7ED3;&#x679C;&#x8868;&#x660E;&#x6700;&#x597D;&#x662F;&#x4E00;&#x4E2A;&#x5E94;&#x4F7F;&#x7528; CCHs &#x4E0E;&#x5927;&#x7EA6; 1ms &#x6B63;&#x9053;&#x751A;&#x81F3;&#x5728;&#x8C03;&#x67E5;&#x4E2D;&#x5927;&#x5927;&#x5C0F;&#x4E8E; 1 &#x6BEB;&#x79D2;&#x7684;&#x5EF6;&#x8FDF;&#x5DEE;&#x5F02;&#x65F6;&#x3002;

&#x6D4B;&#x91CF; sub-millisecond &#x8FDF;&#x8FDF;&#x4E0D;&#x80FD;&#x6263;&#x7403;&#x6BEB;&#x79D2;&#x65F6;&#x95F4;&#x7BB1;&#x4E0E;&#x6D3B;&#x52A8;&#x3002;

Recent evidence indicates that sub-millisecond delays in neuronal spiking activity may be relevant for neural coding. Estimates of these delays are usually made from cross-correlation histograms (CCH) binned to 1ms. We investigated the degree to which it is possible to measure delays with sub-millisecond precision when one computes CCHs with bin sizes > or =1ms. To this end, we introduced sub-millisecond shifts into spike trains recorded from cat visual cortex. The bin sizes of 1/2 to 2ms were the most optimal for measuring the artificial shifts, even when detecting shifts smaller than 0.5ms. The results suggest that preferably, one should use CCHs with approximately 1ms binning even when investigating differences in delays considerably smaller than 1ms.

Measuring sub-millisecond delays in spiking activity with millisecond time-bins.

Des donn&#xE9;es r&#xE9;centes indiquent que le sous-ordre de la milliseconde des retards dans l&#x26;#39;activit&#xE9; neuronale de dopage peuvent &#xEA;tre pertinents pour le codage neuronal. Les estimations de ces retards sont g&#xE9;n&#xE9;ralement fabriqu&#xE9;s &#xE0; partir de la corr&#xE9;lation crois&#xE9;e des histogrammes (CCH) mis en cellule &#xE0; 1ms. Nous avons &#xE9;tudi&#xE9; la mesure dans laquelle il est possible de mesurer les retards de la sous-milliseconde de pr&#xE9;cision lorsque l&#x26;#39;on calcule l&#x26;#39;ESCC avec des tailles de bacs&#x26;gt; ou = 1 ms. &#xC0; cette fin, nous avons introduit des sous-ordre de la milliseconde changements dans les trains pointes enregistr&#xE9;es &#xE0; partir de cortex visuel du chat. Les tailles bin de 1/2 &#xE0; 2 ms sont les plus optimale pour la mesure des changements artificiels, m&#xEA;me lors de la d&#xE9;tection des changements plus petites que 0,5 ms. Les r&#xE9;sultats sugg&#xE8;rent que, de pr&#xE9;f&#xE9;rence, on devrait utiliser l&#x26;#39;ESCC avec environ 1ms binning m&#xEA;me si pour &#xE9;tudier les diff&#xE9;rences dans les d&#xE9;lais consid&#xE9;rablement plus petites que 1 ms.

Mesure Sous-ordre de la milliseconde retards dans l&#x26;#39;activit&#xE9; de dopage avec milliseconde les bacs

Neuere Beweise gibt, dass Buszykluszeiten Verz&ouml;gerungen bei der neuronalen Blindkontrollen Aktivit&auml;t f&uuml;r die neuronale Kodierung relevant sein k&ouml;nnten. Sch&auml;tzungen diese Verz&ouml;gerungen sind in der Regel aus Kreuzkorrelation Histogramme (CCH) klassifiziert, 1ms hergestellt. Wir untersuchten den Grad, zu dem ist es m&ouml;glich, die Verz&ouml;gerungen mit Buszykluszeiten Pr&auml;zision zu messen, wenn man CCHs mit bin Gr&ouml;&szlig;en berechnet &gt; oder = 1ms. Zu diesem Zweck haben wir Buszykluszeiten Verschiebungen in den Spike Zug registrate Katze Sehrinde eingef&uuml;hrt. Die bin-Gr&ouml;&szlig;en von 1/2 bis 2 MS waren die optimale zur Messung der k&uuml;nstlichen Schichten, auch wenn kleiner als 0.5 Verschiebungen zu erkennen. Die Ergebnisse legen nahe, dass vorzugsweise eine CCHs mit ca. 1ms binning, sogar bei der Untersuchung der Unterschiede in der Versp&auml;tungen deutlich kleiner als 1 MS verwenden sollte.

Messung Buszykluszeiten Verz&ouml;gerungen bei spiking Aktivit&auml;t mit Millisekunde Zeit-Lagerpl&auml;tzen.

Recenti evidenze indicano che ritardi di sub-millisecond nell&#39;attivit&agrave; neuronale spiking possono essere pertinenti per la codifica neurale. Le stime di questi ritardi sono fatti solitamente da cross-correlazione istogrammi (CCH) cestinati a 1ms. Abbiamo studiato il grado a cui &egrave; possibile misurare i ritardi con precisione sub-millisecond quando uno computa CCHs con formati bin &amp;gt; o = 1ms. A tal fine, abbiamo introdotto sub-millisecond turni in treni spike registrati dalla corteccia visiva del gatto. I formati bin di 1/2 a 2 ms erano il pi&ugrave; ottimale per misurare i cambiamenti artificiali, anche quando rilevando spostamenti pi&ugrave; piccoli di 0.5ms. I risultati suggeriscono che preferibilmente, uno dovrebbe usare CCHs con circa 1ms binning anche quando si esaminano le differenze in ritardi considerevolmente inferiore a 1ms.

Misura sub-millisecond ritardi nel chiodare attivit&agrave; con MILLISECONDO tempo-bidoni.

&#x6700;&#x8FD1;&#x306E;&#x8A3C;&#x62E0;&#x306F;&#x3001;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306E;&#x30B9;&#x30D1;&#x30A4;&#x30AF;&#x6D3B;&#x52D5;&#x306E;&#x30B5;&#x30D6;&#x30DF;&#x30EA;&#x79D2;&#x306E;&#x9045;&#x5EF6;&#x304C;&#x795E;&#x7D4C;&#x30B3;&#x30FC;&#x30C7;&#x30A3;&#x30F3;&#x30B0;&#x306B;&#x95A2;&#x9023;&#x3059;&#x308B;&#x304B;&#x3082;&#x3057;&#x308C;&#x306A;&#x3044;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x9045;&#x5EF6;&#x306E;&#x63A8;&#x5B9A;&#x5024;&#x306F;&#x901A;&#x5E38;1&#x30DF;&#x30EA;&#x79D2;&#x306B;&#x9078;&#x5225;&#x76F8;&#x4E92;&#x76F8;&#x95A2;&#x30D2;&#x30B9;&#x30C8;&#x30B0;&#x30E9;&#x30E0;&#xFF08;CCH&#xFF09;&#x304B;&#x3089;&#x4F5C;&#x3089;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005;&#x306F;1&#x3064;&#x306E;&#x30D3;&#x30F3;&#x306E;&#x30B5;&#x30A4;&#x30BA;&#x26;gt;&#x307E;&#x305F;&#x306F;= 1ms&#x306E;&#x3067;CCHS&#x3092;&#x8A08;&#x7B97;&#x3059;&#x308B;&#x3068;&#x304D;&#x306F;&#x3001;&#x30B5;&#x30D6;&#x30DF;&#x30EA;&#x79D2;&#x306E;&#x7CBE;&#x5EA6;&#x3067;&#x9045;&#x5EF6;&#x3092;&#x6E2C;&#x5B9A;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x53EF;&#x80FD;&#x3067;&#x3042;&#x308B;&#x5EA6;&#x5408;&#x3044;&#x3092;&#x8ABF;&#x3079;&#x305F;&#x3002;&#x3053;&#x306E;&#x76EE;&#x7684;&#x306E;&#x305F;&#x3081;&#x306B;&#x3001;&#x6211;&#x3005;&#x306F;&#x732B;&#x306E;&#x8996;&#x899A;&#x91CE;&#x304B;&#x3089;&#x8A18;&#x9332;&#x3055;&#x308C;&#x305F;&#x30B9;&#x30D1;&#x30A4;&#x30AF;&#x306B;&#x30B5;&#x30D6;&#x30DF;&#x30EA;&#x79D2;&#x306E;&#x30B7;&#x30D5;&#x30C8;&#x3092;&#x5C0E;&#x5165;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002; 0.5ms&#x306E;&#x3088;&#x308A;&#x5C0F;&#x3055;&#x3044;&#x30B7;&#x30D5;&#x30C8;&#x3092;&#x691C;&#x51FA;&#x3059;&#x308B;&#x5834;&#x5408;&#x3067;&#x3082;&#x3001;1/2&#x301C;2ms&#x306E;&#x30D3;&#x30F3;&#x30B5;&#x30A4;&#x30BA;&#x306F;&#x3001;&#x4EBA;&#x5DE5;&#x7684;&#x306A;&#x30B7;&#x30D5;&#x30C8;&#x3092;&#x6E2C;&#x5B9A;&#x3059;&#x308B;&#x305F;&#x3081;&#x306E;&#x6700;&#x3082;&#x6700;&#x9069;&#x3067;&#x3042;&#x3063;&#x305F;&#x3002;&#x7D50;&#x679C;&#x306F;&#x3001;1ms&#x3088;&#x308A;&#x3082;&#x304B;&#x306A;&#x308A;&#x5C0F;&#x3055;&#x3044;&#x9045;&#x5EF6;&#x306E;&#x9055;&#x3044;&#x3092;&#x8ABF;&#x67FB;&#x3059;&#x308B;&#x969B;&#x306B;&#x3001;&#x597D;&#x307E;&#x3057;&#x304F;&#x306F;1&#x3067;&#x3082;&#x7D04;1ms&#x30D3;&#x30CB;&#x30F3;&#x30B0;&#x3067;CCHS&#x3092;&#x4F7F;&#x7528;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x304A;&#x52E7;&#x3081;&#x3057;&#x307E;&#x3059;&#x3002;

&#x30DF;&#x30EA;&#x79D2;&#x306E;&#x6642;&#x9593;&#x30D3;&#x30F3;&#x3067;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D3;&#x30C6;&#x30A3;&#x3092;&#x30B9;&#x30D1;&#x30A4;&#x30AF;&#x3067;&#x30B5;&#x30D6;&#x30DF;&#x30EA;&#x79D2;&#x306E;&#x9045;&#x5EF6;&#x3092;&#x6E2C;&#x5B9A;

&#xCD5C;&#xADFC; &#xC99D;&#xAC70; sub-millisecond &#xC9C0;&#xC5F0; &#xC2E0;&#xACBD; &#xC2A4;&#xD30C;&#xC774;&#xD06C; &#xD65C;&#xB3D9;&#xC5D0; &#xC2E0;&#xACBD; &#xCF54;&#xB529;&#xC5D0; &#xAD00;&#xB828; &#xB420; &#xC218; &#xC788;&#xC74C;&#xC744; &#xB098;&#xD0C0;&#xB0C5;&#xB2C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xC9C0;&#xC5F0;&#xC758; &#xACAC;&#xC801;&#xC740; &#xBCF4;&#xD1B5; &#xAC04; &#xC0C1;&#xAD00; &#xAD00;&#xACC4; &#xD788;&#xC2A4;&#xD1A0;&#xADF8;&#xB7A8; (CCH) 1ms&#xB97C; &#xBC94;&#xC8FC;&#xD654;&#xC5D0;&#xC11C; &#xB9CC;&#xB4E4;&#xC5B4;&#xC9D1;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; &#xADF8;&#xAC83;&#xC774; &#xD558;&#xB098; &#xBE48; &#xD06C;&#xAE30; CCHs &#xACC4;&#xC0B0; &#xB54C; &#xC9C0;&#xC5F0; sub-millisecond &#xC815;&#xBC00; &#xCE21;&#xC815; &#xAC00;&#xB2A5; &#xC815;&#xB3C4; &#xC870;&#xC0AC; &amp;gt; 1ms = &#xB610;&#xB294;. &#xC774; &#xC704;&#xD574; &#xC6B0;&#xB9AC;&#xB294; &#xC2A4;&#xD30C;&#xC774;&#xD06C; &#xAE30;&#xCC28; &#xACE0;&#xC591;&#xC774; &#xC2DC;&#xAC01; &#xD53C; &#xC9C8;&#xC5D0;&#xC11C; &#xAE30;&#xB85D;&#xC73C;&#xB85C; sub-millisecond &#xAD50;&#xB300;&#xB97C; &#xB3C4;&#xC785;. 2Ms&#xC5D0; 1/2&#xC758; &#xBE48; &#xD06C;&#xAE30; 0.5 m s &#xBCF4;&#xB2E4; &#xB354; &#xC791;&#xC740; &#xBCC0;&#xD654;&#xB97C; &#xAC10;&#xC9C0; &#xD558;&#xB294; &#xACBD;&#xC6B0;&#xC5D0; &#xC778;&#xC704;&#xC801;&#xC778; &#xBCC0;&#xD654;&#xB97C; &#xCE21;&#xC815; &#xD558;&#xAE30; &#xC704;&#xD55C; &#xAC00;&#xC7A5; &#xCD5C;&#xC801;&#xC758; &#xD588;&#xB2E4;. &#xACB0;&#xACFC; &#xC120;&#xD638;, &#xD55C; &#xC57D; 1ms binning &#xC9C0;&#xC5F0; 1ms &#xBCF4;&#xB2E4; &#xC0C1;&#xB2F9;&#xD788; &#xC791;&#xC740; &#xCC28;&#xC774; &#xC870;&#xC0AC;&#xD560; &#xB54C;&#xC5D0; &#xD568;&#xAED8; Cchs&#xC744; &#xC0AC;&#xC6A9; &#xD574;&#xC57C; &#xAC83;&#xC774; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xCE21;&#xC815; sub-millisecond &#xC9C0;&#xC5F0;&#xC744; &#xBC00;&#xB9AC;&#xCD08; &#xC2DC;&#xAC04; &#xC4F0;&#xB808;&#xAE30;&#xD1B5; &#xD65C;&#xB3D9; &#xAE09;&#xC0C1;&#xC2B9;.

La evidencia reciente indica que el sub-milisegundos retrasos en la actividad neuronal de un r&#xE1;pido aumento puede ser relevante para la codificaci&#xF3;n neural. Las estimaciones de estos retrasos se hacen generalmente de la correlaci&#xF3;n cruzada de histogramas (CCH) agrupada de 1 ms. Hemos investigado el grado en que es posible medir los retrasos con sub-milisegundo precisi&#xF3;n cuando uno calcula CCHs con tama&#xF1;os bin&#x26;gt; o = 1 ms. Para ello, hemos introducido cambios sub-milisegundos en los trenes pico registrados a partir de la corteza visual del gato. Los tama&#xF1;os de basura de 1/2 a 2 ms fueron los m&#xE1;s &#xF3;ptima para medir los cambios artificiales, incluso cuando la detecci&#xF3;n de cambios menores que 0,5 ms. Los resultados sugieren que la preferencia, se debe usar CCHs con aproximadamente 1 ms hurgar en la basura, incluso cuando la investigaci&#xF3;n de las diferencias en los retrasos considerablemente inferiores a 1 ms.

Medici&#xF3;n de Sub-milisegundos retrasos en la actividad spiking con milisegundos de tiempo de los contenedores

We have generated a transgenic rat model using RNAi and used it to study the role of the membrane protein Nogo-A in synaptic plasticity and cognition. The membrane protein Nogo-A is expressed in CNS oligodendrocytes and subpopulations of neurons, and it is known to suppress neurite growth and regeneration. The constitutively expressed polymerase II-driven transgene was composed of a microRNA-targeting Nogo-A placed into an intron preceding the coding sequence for EGFP, thus quantitatively labeling cells according to intracellular microRNA expression. The transgenic microRNA in vivo efficiently reduced the concentration of Nogo-A mRNA and protein preferentially in neurons. The resulting significant increase in long-term potentiation in both hippocampus and motor cortex indicates a repressor function of Nogo-A in synaptic plasticity. The transgenic rats exhibited prominent schizophrenia-like behavioral phenotypes, such as perseveration, disrupted prepulse inhibition, and strong withdrawal from social interactions. This fast and efficient microRNA-mediated knockdown provides a way to silence gene expression in vivo in transgenic rats and shows a role of Nogo-A in regulating higher cognitive brain functions.

Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function.

Nogo-A is a membrane protein of the central nervous system (CNS) restricting neurite growth and synaptic plasticity via two extracellular domains: Nogo-66 and Nogo-A-Δ20. Receptors transducing Nogo-A-Δ20 signaling remained elusive so far. Here we identify the G protein-coupled receptor (GPCR) sphingosine 1-phosphate receptor 2 (S1PR2) as a Nogo-A-Δ20-specific receptor. Nogo-A-Δ20 binds S1PR2 on sites distinct from the pocket of the sphingolipid sphingosine 1-phosphate (S1P) and signals via the G protein G13, the Rho GEF LARG, and RhoA. Deleting or blocking S1PR2 counteracts Nogo-A-Δ20- and myelin-mediated inhibition of neurite outgrowth and cell spreading. Blockade of S1PR2 strongly enhances long-term potentiation (LTP) in the hippocampus of wild-type but not Nogo-A(-/-) mice, indicating a repressor function of the Nogo-A/S1PR2 axis in synaptic plasticity. A similar increase in LTP was also observed in the motor cortex after S1PR2 blockade. We propose a novel signaling model in which a GPCR functions as a receptor for two structurally unrelated ligands, a membrane protein and a sphingolipid. Elucidating Nogo-A/S1PR2 signaling platforms will provide new insights into regulation of synaptic plasticity.

The sphingolipid receptor S1PR2 is a receptor for Nogo-a repressing synaptic plasticity.

Superfusion of the squid giant synapse with artificial seawater (ASW) based on isotonic saline containing oxygen nanobubbles (RNS60 ASW) generates an enhancement of synaptic transmission. This was determined by examining the postsynaptic response to single and repetitive presynaptic spike activation, spontaneous transmitter release, and presynaptic voltage clamp studies. In the presence of RNS60 ASW single presynaptic stimulation elicited larger postsynaptic potentials (PSP) and more robust recovery from high frequency stimulation than in control ASW. Analysis of postsynaptic noise revealed an increase in spontaneous transmitter release with modified noise kinetics in RNS60 ASW. Presynaptic voltage clamp demonstrated an increased EPSP, without an increase in presynaptic ICa(++) amplitude during RNS60 ASW superfusion. Synaptic release enhancement reached stable maxima within 5-10 min of RNS60 ASW superfusion and was maintained for the entire recording time, up to 1 h. Electronmicroscopic morphometry indicated a decrease in synaptic vesicle density and the number at active zones with an increase in the number of clathrin-coated vesicles (CCV) and large endosome-like vesicles near junctional sites. Block of mitochondrial ATP synthesis by presynaptic injection of oligomycin reduced spontaneous release and prevented the synaptic noise increase seen in RNS60 ASW. After ATP block the number of vesicles at the active zone and CCV was reduced, with an increase in large vesicles. The possibility that RNS60 ASW acts by increasing mitochondrial ATP synthesis was tested by direct determination of ATP levels in both presynaptic and postsynaptic structures. This was implemented using luciferin/luciferase photon emission, which demonstrated a marked increase in ATP synthesis following RNS60 administration. It is concluded that RNS60 positively modulates synaptic transmission by up-regulating ATP synthesis, thus leading to synaptic transmission enhancement.

Enhanced synaptic transmission at the squid giant synapse by artificial seawater based on physically modified saline.

The membrane protein Nogo-A is known as an inhibitor of axonal outgrowth and regeneration in the CNS. However, its physiological functions in the normal adult CNS remain incompletely understood. Here, we investigated the role of Nogo-A in cortical synaptic plasticity and motor learning in the uninjured adult rodent motor cortex. Nogo-A and its receptor NgR1 are present at cortical synapses. Acute treatment of slices with function-blocking antibodies (Abs) against Nogo-A or against NgR1 increased long-term potentiation (LTP) induced by stimulation of layer 2/3 horizontal fibers. Furthermore, anti-Nogo-A Ab treatment increased LTP saturation levels, whereas long-term depression remained unchanged, thus leading to an enlarged synaptic modification range. In vivo, intrathecal application of Nogo-A-blocking Abs resulted in a higher dendritic spine density at cortical pyramidal neurons due to an increase in spine formation as revealed by in vivo two-photon microscopy. To investigate whether these changes in synaptic plasticity correlate with motor learning, we trained rats to learn a skilled forelimb-reaching task while receiving anti-Nogo-A Abs. Learning of this cortically controlled precision movement was improved upon anti-Nogo-A Ab treatment. Our results identify Nogo-A as an influential molecular modulator of synaptic plasticity and as a regulator for learning of skilled movements in the motor cortex.

Ajmal Zemmar

Brain Research Institute

University of Zurich

Acquisition of a High-precision Skilled Forelimb Reaching Task in Rats