automated-rat-single-pellet-reaching-with-3-dimensional

Automated Rat Single-Pellet Reaching with 3-Dimensional Reconstruction of Paw and Digit Trajectories

Rodent skilled reaching is commonly used to study dexterous skills, but requires significant time and effort to implement the task and analyze the ...

University of Michigan

VA Ann Arbor Health System

Fast-spiking interneurons (FSIs) can exert powerful control over striatal output, and deficits in this cell population have been observed in human patients with Tourette syndrome and rodent models of dystonia. However, a direct experimental test of striatal FSI involvement in motor control has never been performed. We applied a novel pharmacological approach to examine the behavioral consequences of selective FSI suppression in mouse striatum. IEM-1460, an inhibitor of GluA2-lacking AMPARs, selectively blocked synaptic excitation of FSIs but not striatal projection neurons. Infusion of IEM-1460 into the sensorimotor striatum reduced the firing rate of FSIs but not other cell populations, and elicited robust dystonia-like impairments. These results provide direct evidence that hypofunction of striatal FSIs can produce movement abnormalities, and suggest that they may represent a novel therapeutic target for the treatment of hyperkinetic movement disorders.

Selective inhibition of striatal fast-spiking interneurons causes dyskinesias.

&#x5E15;&#x91D1;&#x68EE;&#x75C5;&#x60A3;&#x8005;&#x6B63;&#x5E38;&#x8FD0;&#x52A8;&#x5236;&#x6B62;&#x548C;&#x7535;&#x673A;&#x53D7;&#x635F;&#x88AB;&#x7275;&#x8FDE;&#x5230; beta &#x632F;&#x8361;&#x7684;&#x76AE;&#x8D28;&#x57FA;&#x5E95;&#x795E;&#x7ECF;&#x8282; (BG) &#x7535;&#x8DEF;&#x3002;&#x5256;&#x6790;&#x8FD9;&#x4E9B;&#x8282;&#x594F;&#x7684;&#x529F;&#x80FD;&#x5F71;&#x54CD;&#x56E0;&#x7D20;&#x6211;&#x4EEC;&#x5728;&#x56DB;&#x4E2A;&#x4E0D;&#x540C;&#x53D8;&#x79CD;&#x7684;&#x5927;&#x9F20;&#x7684;&#x6807;&#x8BB0;&#x7684;&#x9009;&#x62E9;&#x4EFB;&#x52A1;&#x671F;&#x95F4;&#x76F8;&#x6BD4;&#x795E;&#x7ECF;&#x6D3B;&#x52A8;&#x3002;&#x7B80;&#x77ED; beta (&sim;20 Hz) &#x632F;&#x8361;&#x540C;&#x65F6;&#x53D1;&#x751F;&#x5728;&#x6574;&#x4E2A;&#x76AE;&#x5C42;-BG &#x7F51;&#x7EDC;&#xFF0C;&#x81EA;&#x53D1;&#x6027;&#x548C;&#x4EFB;&#x52A1;&#x7EE9;&#x6548;&#x7684;&#x786E;&#x5207;&#x65F6;&#x523B;&#x3002;Beta &#x9636;&#x6BB5;&#x8FC5;&#x901F;&#x590D;&#x4F4D;&#x7A81;&#x51FA;&#x63D0;&#x793A;&#xFF0C;&#x54CD;&#x5E94;&#x4F46;&#x5347;&#x5E45;&#x7684; beta &#x7248;&#x7535;&#x6E90;&#x6CA1;&#x6709;&#x786C;&#x6027;&#x6302;&#x94A9;&#x63D0;&#x793A;&#x3001; &#x8FD0;&#x52A8;&#x6216;&#x8FD0;&#x52A8;&#x5236;&#x6B62;&#x3002;&#x76F8;&#x53CD;&#xFF0C;beta &#x6743;&#x529B;&#xFF0C;&#x52A0;&#x5F3A;&#x4E86;&#x540E;&#x63D0;&#x793A;&#x7528;&#x6765;&#x786E;&#x5B9A;&#x7535;&#x673A;&#x8F93;&#x51FA;&#x3002;&#x6211;&#x4EEC;&#x5EFA;&#x8BAE; beta &#x632F;&#x8361;&#x53CD;&#x6620;&#x76AE;&#x8D28;-BG &#x7F51;&#x7EDC;&#xFF0C;&#x901A;&#x5E38;&#x53EF;&#x4EE5;&#x51CF;&#x5C11;&#x4ECE;&#x66FF;&#x4EE3;&#x6F5C;&#x5728;&#x884C;&#x52A8;&#x5E72;&#x6270;&#x51B3;&#x7B56;&#x540E;&#x7684;&#x7A33;&#x5B9A;&#x7684;&#x72B6;&#x6001;&#x3002;&#x5728;&#x5E15;&#x91D1;&#x68EE;&#x75C5;&#x4E2D;&#x770B;&#x5230;&#x7684;&#x5F02;&#x5E38;&#x5F3A;&#x5927; beta &#x53EF;&#x80FD;&#x53CD;&#x6620;&#x51FA; overstabilization &#x7684;&#x8FD9;&#x4E9B;&#x7F51;&#x7EDC;&#xFF0C;&#x4EA7;&#x751F;&#x75C5;&#x7406;&#x6301;&#x4E45;&#x6027;&#x7684;&#x7535;&#x673A;&#x7684;&#x5F53;&#x524D;&#x72B6;&#x6001;&#x3002;

&#x57FA;&#x5E95;&#x795E;&#x7ECF;&#x8282; Beta &#x632F;&#x8361;&#x966A;&#x63D0;&#x793A;&#x5229;&#x7528;&#x3002;

Beta oscillations in cortical-basal ganglia (BG) circuits have been implicated in normal movement suppression and motor impairment in Parkinson's disease. To dissect the functional correlates of these rhythms we compared neural activity during four distinct variants of a cued choice task in rats. Brief beta (âˆ¼20Â Hz) oscillations occurred simultaneously throughout the cortical-BG network, both spontaneously and at precise moments of task performance. Beta phase was rapidly reset in response to salient cues, yet increases in beta power were not rigidly linked to cues, movements, or movement suppression. Rather, beta power was enhanced after cues were used to determine motor output. We suggest that beta oscillations reflect a postdecision stabilized state of cortical-BG networks, which normally reduces interference from alternative potential actions. The abnormally strong beta seen in Parkinson's Disease may reflect overstabilization of these networks, producing pathological persistence of the current motor state.

Basal Ganglia Beta oscillations accompany cue utilization.

Oscillations b&ecirc;ta dans des circuits corticaux-basal ganglia (BG) ont &eacute;t&eacute; impliqu&eacute;es dans les troubles de r&eacute;pression et moteur mouvement normal dans la maladie de Parkinson. Pour diss&eacute;quer les corr&eacute;lations fonctionnelles de ces rythmes, nous avons compar&eacute; l&#39;activit&eacute; neurale durant quatre variantes distinctes d&#39;une t&acirc;che indic&eacute; de choix chez les rats. Oscillations br&egrave;ves b&ecirc;ta (&sim;20 Hz) ont eu lieu simultan&eacute;ment dans tout le r&eacute;seau cortical-BG, tant spontan&eacute;ment et &agrave; des moments pr&eacute;cis de l&#39;ex&eacute;cution des t&acirc;ches. Phase b&ecirc;ta a &eacute;t&eacute; r&eacute;initialis&eacute; rapidement en r&eacute;ponse &agrave; des stimuli saillants, pourtant les augmentations de puissance de b&ecirc;ta n&#39;&eacute;taient pas rigidement li&eacute;es &agrave; queues, mouvements ou r&eacute;pression du mouvement. Au contraire, puissance b&ecirc;ta a &eacute;t&eacute; am&eacute;lior&eacute; apr&egrave;s que rep&egrave;res ont servi &agrave; d&eacute;terminer la puissance moteur. Nous sugg&eacute;rons que les oscillations b&ecirc;ta refl&egrave;tent un &eacute;tat stabilis&eacute; possibilit&eacute; des r&eacute;seaux corticaux-BG, qui normalement r&eacute;duit les interf&eacute;rences provenant d&#39;autres mesures &eacute;ventuelles. La b&ecirc;ta anormalement forte vu dans la maladie de Parkinson peut refl&eacute;ter l&#39;overstabilization de ces r&eacute;seaux, produisant une persistance pathologique de l&#39;&eacute;tat actuel du moteur.

Oscillations b&ecirc;ta de noyaux gris centraux accompagnent utilisation de rep&egrave;re.

Beta-Schwingungen in kortikalen basale Ganglien (BG)-Schaltungen haben in normalen Bewegung Unterdr&uuml;ckung und Motor Beeintr&auml;chtigung bei Parkinson-Krankheit verwickelt. Um die funktionale korreliert diese Rhythmen zu sezieren verglichen wir die neuronale Aktivit&auml;t w&auml;hrend vier unterschiedliche Varianten eines Vorgangs Stichnoten Wahl bei Ratten. Kurze Beta (&sim;20 Hz) Schwingungen trat gleichzeitig im gesamten Netzwerk kortikale-BG, sowohl spontan als auch auf pr&auml;zise Momente der Aufgabendurchf&uuml;hrung. Beta-Phase wurde schnell zur&uuml;ckgesetzt, als Antwort auf die wichtigsten Hinweise, aber Anstieg der Beta macht wurden Hinweise, Bewegungen oder Bewegung Unterdr&uuml;ckung nicht starr verbunden. Vielmehr wurde die Beta macht verbessert, nachdem Hinweise verwendet wurden, um zu bestimmen, Motorleistung. Wir schlagen vor, da&szlig; Beta-Oszillationen ein postdecision stabilisierte kortikale-BG-Netzwerke, spiegeln die normalerweise St&ouml;rungen durch alternative m&ouml;glichen Aktionen reduziert. Die ungew&ouml;hnlich starke Beta gesehen bei Parkinson-Krankheit kann Overstabilization dieser Netze produzieren pathologische Persistenz der aktuellen motor widerspiegeln.

Basalganglien Beta Schwingungen begleiten Cue-Auslastung.

Oscillazioni beta nei circuiti dei gangli basali-corticale (BG) sono state implicate nel danno di soppressione e motore normale movimento nel morbo di Parkinson. Per sezionare la correla funzionale di questi ritmi abbiamo confrontato attivit&agrave; neurale durante quattro distinte varianti di un compito di attirare scelta nei ratti. Oscillazioni di breve beta (&sim;20 Hz) si sono verificati contemporaneamente in tutta la rete corticale-BG, sia spontaneamente sia in momenti precisi della prestazione di attivit&agrave;. Fase beta &egrave; stato ripristinato rapidamente in risposta a spunti salienti, ancora aumenti in beta power non erano rigidamente collegati a stecche, movimenti o soppressione di movimento. Piuttosto, beta power &egrave; stata migliorata dopo spunti sono stati utilizzati per determinare l&#39;uscita motore. Suggeriamo che le oscillazioni beta riflettono uno stato stabilizzato postdecision di reti corticali-BG, che normalmente riduce interferenze da azioni potenziali alternative. La beta anormalmente forte vista nella malattia di Parkinson pu&ograve; riflettere overstabilization di queste reti, producendo patologica persistenza dello stato corrente del motore.

Le oscillazioni dei gangli basali Beta accompagnano utilizzo della stecca.

&#x76AE;&#x8CEA;-&#x57FA;&#x5E95;&#x6838; (BG &#x306F;) &#x56DE;&#x8DEF;&#x306B;&#x304A;&#x3051;&#x308B; &beta; &#x632F;&#x52D5;&#x306F;&#x6B63;&#x5E38;&#x306A;&#x52D5;&#x304D;&#x306E;&#x6291;&#x5236;&#x3068;&#x30E2;&#x30FC;&#x30BF;&#x30FC;&#x6E1B;&#x640D;&#x30D1;&#x30FC;&#x30AD;&#x30F3;&#x30BD;&#x30F3;&#x75C5;&#x306B;&#x95A2;&#x4E0E;&#x3057;&#x3066;&#x3044;&#x308B;.&#x3053;&#x308C;&#x3089;&#x306E;&#x30EA;&#x30BA;&#x30E0;&#x306E;&#x6A5F;&#x80FD;&#x7684;&#x306A;&#x76F8;&#x4E92;&#x95A2;&#x4FC2;&#x3092;&#x89E3;&#x5256;&#x3059;&#x308B;&#x306B;&#x306F;&#x3001;&#x6211;&#x3005; 4 &#x3064;&#x306E;&#x7570;&#x306A;&#x308B;&#x30D0;&#x30EA;&#x30A8;&#x30FC;&#x30B7;&#x30E7;&#x30F3; &#x30E9;&#x30C3;&#x30C8;&#x306B;&#x304A;&#x3051;&#x308B;&#x30AD;&#x30E5;&#x30FC;&#x9078;&#x629E;&#x30BF;&#x30B9;&#x30AF;&#x306E;&#x4E2D;&#x306E;&#x795E;&#x7D4C;&#x6D3B;&#x52D5;&#x3092;&#x6BD4;&#x8F03;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x7C21;&#x5358;&#x306A;&#x30D9;&#x30FC;&#x30BF; (&sim;20 Hz) &#x306E;&#x632F;&#x52D5;&#x306F;&#x3001;&#x540C;&#x6642;&#x306B;&#x81EA;&#x767A;&#x7684;&#x306B;&#x304A;&#x3088;&#x3073;&#x30BF;&#x30B9;&#x30AF; &#x30D1;&#x30D5;&#x30A9;&#x30FC;&#x30DE;&#x30F3;&#x30B9;&#x306E;&#x6B63;&#x78BA;&#x306A;&#x77AC;&#x9593;&#x306B;&#x76AE;&#x8CEA; BG &#x30CD;&#x30C3;&#x30C8;&#x30EF;&#x30FC;&#x30AF;&#x5168;&#x4F53;&#x304C;&#x767A;&#x751F;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x30D9;&#x30FC;&#x30BF; &#x30FB; &#x30D5;&#x30A7;&#x30FC;&#x30BA;&#x304C;&#x6025;&#x901F;&#x306B;&#x9855;&#x8457;&#x306A;&#x624B;&#x304C;&#x304B;&#x308A;&#x306E;&#x5FDC;&#x7B54;&#x3067;&#x30EA;&#x30BB;&#x30C3;&#x30C8;&#x3055;&#x308C;&#x305F;&#x307E;&#x3060;&#x30D9;&#x30FC;&#x30BF;&#x96FB;&#x529B;&#x306E;&#x5897;&#x52A0;&#x306F;&#x3001;&#x5805;&#x304F;&#x624B;&#x639B;&#x304B;&#x308A;&#x3001;&#x52D5;&#x304D;&#x3001;&#x307E;&#x305F;&#x306F;&#x904B;&#x52D5;&#x6291;&#x5236;&#x306B;&#x30EA;&#x30F3;&#x30AF;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x305B;&#x3093;&#x3002;&#x30E2;&#x30FC;&#x30BF;&#x30FC;&#x51FA;&#x529B;&#x3092;&#x6C7A;&#x5B9A;&#x3059;&#x308B;&#x624B;&#x304C;&#x304B;&#x308A;&#x304C;&#x4F7F;&#x7528;&#x3055;&#x308C;&#x305F;&#x5F8C;&#x3067;&#x306F;&#x306A;&#x304F;&#x3001;&#x30D9;&#x30FC;&#x30BF;&#x7248;&#x529B;&#x304C;&#x5F37;&#x5316;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x6211;&#x3005; &#x306F;&#x30D9;&#x30FC;&#x30BF;&#x7248;&#x632F;&#x52D5;&#x901A;&#x5E38;&#x4EE3;&#x66FF;&#x306E;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x884C;&#x52D5;&#x304B;&#x3089;&#x306E;&#x5E72;&#x6E09;&#x3092;&#x4F4E;&#x6E1B;&#x76AE;&#x8CEA; BG &#x30CD;&#x30C3;&#x30C8;&#x30EF;&#x30FC;&#x30AF;&#x306E; postdecision &#x5B89;&#x5B9A;&#x5316;&#x72B6;&#x614B;&#x3092;&#x53CD;&#x6620;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x304A;&#x52E7;&#x3081;&#x3057;&#x307E;&#x3059;&#x3002;&#x30D1;&#x30FC;&#x30AD;&#x30F3;&#x30BD;&#x30F3;&#x75C5;&#x306B;&#x898B;&#x3089;&#x308C;&#x308B;&#x7570;&#x5E38;&#x306B;&#x5F37;&#x3044;&#x30D9;&#x30FC;&#x30BF; &#x30E2;&#x30FC;&#x30BF;&#x30FC;&#x306E;&#x73FE;&#x5728;&#x306E;&#x72B6;&#x614B;&#x306E;&#x75C5;&#x7406;&#x5B66;&#x7684;&#x6C38;&#x7D9A;&#x6027;&#x306E;&#x751F;&#x7523;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x30CD;&#x30C3;&#x30C8;&#x30EF;&#x30FC;&#x30AF;&#x306E; overstabilization &#x3092;&#x53CD;&#x6620;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;

&#x5927;&#x8133;&#x57FA;&#x5E95;&#x6838;&#x306E; &beta; &#x632F;&#x52D5; cue &#x5229;&#x7528;&#x3092;&#x540C;&#x884C;&#x3057;&#x307E;&#x3059;&#x3002;

&#xD53C; &#xC9C8; &#xAE30;&#xC800; ganglia (BG) &#xD68C;&#xB85C;&#xC5D0;&#xC11C; &#xBCA0;&#xD0C0; &#xC9C4;&#xB3D9; &#xD30C; &#xD0A8; &#xC2A8; &#xBCD1;&#xC5D0;&#xC11C; &#xC815;&#xC0C1;&#xC801;&#xC778; &#xC6C0;&#xC9C1;&#xC784; &#xC5B5;&#xC81C; &#xBC0F; &#xBAA8;&#xD130; &#xC7A5;&#xC560;&#xC5D0; &#xC5F0;&#xB8E8; &#xB418;&#xC5B4;. &#xC774;&#xB7EC;&#xD55C; &#xB9AC;&#xB4EC;&#xC758; &#xAE30;&#xB2A5; &#xC5F0;&#xAD00; &#xD574; &#xBD80; &#xC6B0;&#xB9AC; &#xC950;&#xC5D0;&#xC11C; &#xBB38;&#xC7A5;&#xC744;&#xB41C; &#xC120;&#xD0DD; &#xC791;&#xC5C5;&#xC758; &#xB124; &#xAC00;&#xC9C0; &#xBCC0;&#xD615; &#xC911; &#xC2E0;&#xACBD; &#xD65C;&#xB3D9;&#xC744; &#xBE44;&#xAD50;. &#xAC04;&#xB7B5; &#xD55C; &#xBCA0;&#xD0C0; (&sim;20 Hz) &#xC9C4;&#xB3D9; &#xBC1C;&#xC0DD; &#xB3D9;&#xC2DC;&#xC5D0; &#xB300;&#xB1CC; &#xD53C; &#xC9C8;&#xC758; BG &#xB124;&#xD2B8;&#xC6CC;&#xD06C;&#xB97C; &#xD1B5;&#xD574; &#xC790;&#xBC1C;&#xC801;&#xC73C;&#xB85C; &#xC5C5;&#xBB34; &#xC131;&#xACFC;&#xC758; &#xC815;&#xD655;&#xD55C; &#xC21C;&#xAC04;&#xC5D0;. &#xBCA0;&#xD0C0; &#xB2E8;&#xACC4;&#xB294; &#xAE09;&#xC18D; &#xD558; &#xAC8C; &#xD604;&#xC800;&#xD55C; &#xB2E8;&#xC11C;&#xC5D0; &#xB300; &#xD55C; &#xC751;&#xB2F5;&#xC5D0;&#xC11C; &#xB2E4;&#xC2DC; &#xC124;&#xC815; &#xC544;&#xC9C1; &#xBCA0;&#xD0C0; &#xD30C;&#xC6CC; &#xC99D;&#xAC00; &#xC2E0;&#xD638;, &#xC6C0;&#xC9C1;&#xC784;, &#xB610;&#xB294; &#xC6B4;&#xB3D9; &#xC5B5;&#xC81C;&#xC5D0; &#xC5C4;&#xACA9; &#xD558; &#xAC8C; &#xC5F0;&#xACB0; &#xB418;&#xC9C0; &#xC54A;&#xC740;. &#xC624;&#xD788;&#xB824;, &#xC2E0;&#xD638; &#xBAA8;&#xD130; &#xCD9C;&#xB825;&#xC744; &#xACB0;&#xC815; &#xD558;&#xB294; &#xB370; &#xC0AC;&#xC6A9;&#xD55C; &#xD6C4; &#xBCA0;&#xD0C0; &#xD30C;&#xC6CC; &#xD5A5;&#xC0C1; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xBCA0;&#xD0C0; &#xC9C4;&#xB3D9; &#xC77C;&#xBC18;&#xC801;&#xC73C;&#xB85C; &#xB2E4;&#xB978; &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xC791;&#xC5C5; &#xAC04;&#xC12D; &#xAC10;&#xC18C;&#xB294; &#xB300;&#xB1CC; &#xD53C; &#xC9C8;&#xC758; BG &#xB124;&#xD2B8;&#xC6CC;&#xD06C;&#xC758; postdecision &#xC548;&#xC815;&#xB41C; &#xC0C1;&#xD0DC;&#xB97C; &#xBC18;&#xC601; &#xD558;&#xB294; &#xAC83;&#xC774; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;. &#xD30C; &#xD0A8; &#xC2A8; &#xBCD1;&#xC5D0;&#xC11C; &#xBE44;&#xC815;&#xC0C1;&#xC801;&#xC73C;&#xB85C; &#xAC15;&#xD55C; &#xBCA0;&#xD0C0; &#xD604;&#xC7AC; &#xBAA8;&#xD130; &#xC0C1;&#xD0DC;&#xC758; &#xBCD1; &#xC801;&#xC778; &#xC9C0; &#xC18D;&#xC131;&#xC744; &#xC0DD;&#xC131; &#xD558;&#xB294; &#xC774;&#xB7EC;&#xD55C; &#xB124;&#xD2B8;&#xC6CC;&#xD06C;&#xC758; overstabilization&#xC744; &#xBC18;&#xC601; &#xB420; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xAE30;&#xC800; Ganglia &#xBCA0;&#xD0C0; &#xC9C4;&#xB3D9; &#xD568;&#xAED8; &#xD050; &#xD65C;&#xC6A9;.

Oscilaciones de beta en los circuitos de los ganglios basales-cortical (BG) han sido implicadas en el deterioro de la supresi&oacute;n y el motor de movimiento normal en la enfermedad de Parkinson. Para diseccionar los correlatos funcionales de estos ritmos comparamos la actividad neuronal durante cuatro variantes diferentes de una tarea de elecci&oacute;n contado en ratas. Oscilaciones de breve beta (&sim;20 Hz) ocurrieron simult&aacute;neamente en toda la red cortical-BG, tanto espont&aacute;neamente y en momentos precisos de rendimiento. Fase beta se restableci&oacute; r&aacute;pidamente en respuesta a se&ntilde;ales salientes, pero aumenta en el poder de la beta no estaban vinculada r&iacute;gidamente a se&ntilde;ales, movimientos o supresi&oacute;n del movimiento. Por el contrario, poder beta mejor&oacute; despu&eacute;s de se&ntilde;ales fueron utilizados para determinar la salida del motor. Sugerimos que las oscilaciones de la beta reflejan un estado estabilizado postdecision de redes corticales-BG, que normalmente reduce la interferencia de acciones posibles alternativas. La beta anormalmente fuerte en la enfermedad de Parkinson puede reflejar la overstabilization de estas redes, produciendo la persistencia patol&oacute;gica de la situaci&oacute;n actual del motor.

Las oscilaciones de los ganglios basales Beta acompa&ntilde;ar&aacute;n utilizaci&oacute;n de cue.

Salient cues can prompt the rapid interruption of planned actions. It has been proposed that fast, reactive behavioral inhibition involves specific basal ganglia pathways, and we tested this by comparing activity in multiple rat basal ganglia structures during performance of a stop-signal task. Subthalamic nucleus (STN) neurons exhibited low-latency responses to 'Stop' cues, irrespective of whether actions were canceled or not. By contrast, neurons downstream in the substantia nigra pars reticulata (SNr) only responded to Stop cues in trials with successful cancellation. Recordings and simulations together indicate that this sensorimotor gating arises from the relative timing of two distinct inputs to neurons in the SNr dorsolateral 'core' subregion: cue-related excitation from STN and movement-related inhibition from striatum. Our results support race models of action cancellation, with stopping requiring Stop-cue information to be transmitted from STN to SNr before increased striatal input creates a point of no return. 

Canceling actions involves a race between basal ganglia pathways.

Incomplete understanding of the systems-level pathophysiology of Parkinson Disease (PD) remains a significant barrier to improving its treatment. Substantial progress has been made, however, due to the availability of neurotoxins that selectively target monoaminergic (in particular, dopaminergic) neurons. This review discusses the in vivo electrophysiology of basal ganglia (BG), thalamic, and cortical regions after dopamine-depleting lesions. These include firing rate changes, neuronal burst-firing, neuronal oscillations, and neuronal synchrony that result from a combination of local microanatomic changes and network-level interactions. While much is known of the clinical and electrophysiological phenomenology of dopamine loss, a critical gap in our conception of PD pathophysiology is the link between them. We discuss potential mechanisms by which these systems-level electrophysiological changes may emerge, as well as how they may relate to clinical parkinsonism. Proposals for an updated understanding of BG function are reviewed, with an emphasis on how emerging frameworks will guide future research into the pathophysiology and treatment of PD. 

Review: electrophysiology of basal ganglia and cortex in models of Parkinson disease.

This chapter focuses on neurodevelopmental diseases that are tightly linked to abnormal function of the striatum and connected structures. We begin with an overview of three representative diseases in which striatal dysfunction plays a key role--Tourette syndrome and obsessive-compulsive disorder, Rett's syndrome, and primary dystonia. These diseases highlight distinct etiologies that disrupt striatal integrity and function during development, and showcase the varied clinical manifestations of striatal dysfunction. We then review striatal organization and function, including evidence for striatal roles in online motor control/action selection, reinforcement learning, habit formation, and action sequencing. A key barrier to progress has been the relative lack of animal models of these diseases, though recently there has been considerable progress. We review these efforts, including their relative merits providing insight into disease pathogenesis, disease symptomatology, and basal ganglia function.

Mouse models of neurodevelopmental disease of the basal ganglia and associated circuits.

Striatal dopamine is an important modulator of current behavior, as seen in the rapid and dramatic effects of dopamine replacement therapy in Parkinson Disease (PD). Yet there is also extensive evidence that dopamine acts as a learning signal, modulating synaptic plasticity within striatum to affect future behavior. Disentangling these "performance" and "learning" functions is important for designing effective, long-term PD treatments. We conducted a series of unilateral drug manipulations and dopamine terminal lesions in the dorsolateral striatum of rats highly-trained to perform brief instructed head/neck movements (two-alternative forced choice task). Reaction times and accuracy were measured longitudinally to determine if task behavior changed immediately, progressed over time, and/or persisted after drug withdrawal. Enhanced dopamine signaling with amphetamine caused an immediate, nonprogressive, and bilateral decrease in reaction times (RT). The altered RT distributions were consistent with reduced distance to threshold in the linear approach to threshold with ergodic rate (LATER) model of decision-making. Conversely, the dopamine antagonist flupenthixol caused experience-dependent, persistent changes in RT and accuracy indicative of a "learning" effect. These RT distributions were consistent with a slowed rate of approach to decision threshold. Our results show that dopaminergic signaling makes dissociable contributions to current and future behavior even within a single striatal subregion, and provide important clues for both models of normal decision-making and the design of novel drug therapies in PD.

Dissociable effects of dopamine on learning and performance within sensorimotor striatum.

The suppression of inappropriate actions is critical for flexible behavior. Cortical-basal ganglia networks provide key gating mechanisms for action suppression, yet the specific roles of neuronal subpopulations are poorly understood. Here, we examine Arkypallidal (‘‘Arky’’) and Prototypical (‘‘Proto’’) globus pallidus neurons during a Stop task, which requires abrupt cancellation of an imminent action. We first establish that Arky neurons can be identified by their firing properties across the natural sleep/wake cycle. We then show that Stop responses are earlier and stronger in the Arky compared to the Proto subpopulation. In contrast to other basal ganglia neurons, pallidal Stop responses are selective to Stop, rather than Go, cues. Furthermore, the timing of these Stop responses matches the suppression of developing striatal Go-related activity. Our results support a two-step model of action suppression: actions-inpreparation are first paused via a subthalamic-nigral pathway, then cancelled via Arky GABAergic projections to striatum.

Arkypallidal Cells Send a Stop Signal to Striatum.

A comprehensive, multidisciplinary screening process for deep brain stimulation (DBS) candidates is recommended, but is often time-consuming.

A suggested minimum standard deep brain stimulation evaluation for essential tremor.

Single pellet reaching is an established task for studying fine motor control in which rats reach for, grasp, and eat food pellets in a stereotyped sequence. Most incarnations of this task require constant attention, limiting the number of animals that can be tested and the number of trials per session. Automated versions allow more interventions in more animals, but must be robust and reproducible.

An automated rat single pellet reaching system with high-speed video capture.

The missing, the short, and the long: Levodopa responses and dopamine actions.

Reply to "the missing, the short, and the long: Exploring the borderland between psychiatry and neurology".

Brief epochs of beta oscillations have been implicated in sensorimotor control in the basal ganglia of task-performing healthy animals. However, which neural processes underlie their generation and how they are affected by sensorimotor processing remains unclear. To determine the mechanisms underlying transient beta oscillations in the LFP, we combined computational modeling of the subthalamo-pallidal network for the generation of beta oscillations with realistic stimulation patterns derived from single-unit data recorded from different basal ganglia subregions in rats performing a cued choice task. In the recordings, we found distinct firing patterns in the striatum, globus pallidus, and subthalamic nucleus related to sensory and motor events during the behavioral task. Using these firing patterns to generate realistic inputs to our network model led to transient beta oscillations with the same time course as the rat LFP data. In addition, our model can account for further nonintuitive aspects of beta modulation, including beta phase resets after sensory cues and correlations with reaction time. Overall, our model can explain how the combination of temporally regulated sensory responses of the subthalamic nucleus, ramping activity of the subthalamic nucleus, and movement-related activity of the globus pallidus leads to transient beta oscillations during behavior. Transient beta oscillations emerge in the normal functioning cortico-basal ganglia loop during behavior. Here, we used a unique approach connecting a computational model closely with experimental data. In this way, we achieved a simulation environment for our model that mimics natural input patterns in awake, behaving animals. We demonstrate that a computational model for beta oscillations in Parkinson's disease (PD) can also account for complex patterns of transient beta oscillations in healthy animals. Therefore, we propose that transient beta oscillations in healthy animals share the same mechanism with pathological beta oscillations in PD. This important result connects functional and pathological roles of beta oscillations in the basal ganglia.

Sensorimotor Processing in the Basal Ganglia Leads to Transient Beta Oscillations during Behavior.

Motor thalamus (Mthal) comprises the ventral anterior, ventral lateral, and ventral medial thalamic nuclei in rodents. This subcortical hub receives input from the basal ganglia (BG), cerebellum, and reticular thalamus in addition to connecting reciprocally with motor cortical regions. Despite the central location of Mthal, the mechanisms by which it influences movement remain unclear. To determine its role in generating ballistic, goal-directed movement, we recorded single-unit Mthal activity as male rats performed a two-alternative forced-choice task. A large population of Mthal neurons increased their firing briefly near movement initiation and could be segregated into functional groups based on their behavioral correlates. The activity of "initiation" units was more tightly locked to instructional cues than movement onset, did not predict which direction the rat would move, and was anticorrelated with reaction time (RT). Conversely, the activity of "execution" units was more tightly locked to movement onset than instructional cues, predicted which direction the rat would move, and was anticorrelated with both RT and movement time. These results suggest that Mthal influences choice RT performance in two stages: short latency, nonspecific action initiation followed by action selection/invigoration. We discuss the implications of these results for models of motor control incorporating BG and cerebellar circuits. Motor thalamus (Mthal) is a central node linking subcortical and cortical motor circuits, though its precise role in motor control is unclear. Here, we define distinct populations of Mthal neurons that either encode movement initiation, or both action selection and movement vigor. These results have important implications for understanding how basal ganglia, cerebellar, and motor cortical signals are integrated. Such an understanding is critical to defining the pathophysiology of a range of BG- and cerebellum-linked movement disorders, as well as refining pharmacologic and neuromodulatory approaches to their treatment.

Article	Year
Selective inhibition of striatal fast-spiking interneurons causes dyskinesias. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 22049415	2011
Basal Ganglia Beta oscillations accompany cue utilization. Neuron\| PubMed ID: 22325204	2012
Canceling actions involves a race between basal ganglia pathways. Nature neuroscience\| PubMed ID: 23852117	2013
Review: electrophysiology of basal ganglia and cortex in models of Parkinson disease. Journal of Parkinson's disease\| PubMed ID: 23948994	2013
Mouse models of neurodevelopmental disease of the basal ganglia and associated circuits. Current topics in developmental biology\| PubMed ID: 24947237	2014
Dissociable effects of dopamine on learning and performance within sensorimotor striatum. Basal ganglia\| PubMed ID: 24949283	2014
Arkypallidal Cells Send a Stop Signal to Striatum. Neuron\| PubMed ID: 26777273	2016
A suggested minimum standard deep brain stimulation evaluation for essential tremor. Journal of the neurological sciences\| PubMed ID: 26944141	2016
An automated rat single pellet reaching system with high-speed video capture. Journal of neuroscience methods\| PubMed ID: 27450925	2016
The missing, the short, and the long: Levodopa responses and dopamine actions. Annals of neurology\| PubMed ID: 28543679	2017
Reply to "the missing, the short, and the long: Exploring the borderland between psychiatry and neurology". Annals of neurology\| PubMed ID: 28856716	2017
Sensorimotor Processing in the Basal Ganglia Leads to Transient Beta Oscillations during Behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 29038241	2017
Distinct Populations of Motor Thalamic Neurons Encode Action Initiation, Action Selection, and Movement Vigor. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 29934350	2018

Daniel Leventhal

Biography

JoVE Journal Publications

Other Publications