An Open-Source Virtual Reality System for the Measurement of Spatial Learning in Head-Restrained Mice

Head-restrained behavioral experiments in mice allow neuroscientists to observe neural circuit activity with high-resolution electrophysiological and ...

New York State Psychiatric Institute

Columbia University

Columbia College

Throughout the adult life of most mammals, new neurons are continuously generated in the dentate gyrus of the hippocampal formation. Recent work has documented specific cognitive deficits after elimination of adult hippocampal neurogenesis in rodents, suggesting that these neurons may contribute to information processing in hippocampal circuits. Young adult-born neurons exhibit enhanced excitability and have altered capacity for synaptic plasticity in hippocampal slice preparations in vitro. Still, little is known about the effect of adult-born granule cells on hippocampal activity in vivo. To assess the impact of these new neurons on neural circuits in the dentate, we recorded perforant-path evoked responses and spontaneous network activity from the dentate gyrus of urethane-anesthetized mice whose hippocampus had been focally X-irradiated to eliminate the population of young adult-born granule cells. After X-irradiation, perforant-path responses were reduced in magnitude. In contrast, there was a marked increase in the amplitude of spontaneous γ-frequency bursts in the dentate gyrus and hilus, as well as increased synchronization of dentate neuron firing to these bursts. A similar increase in gamma burst amplitude was also found in animals in which adult neurogenesis was eliminated using the GFAP:TK pharmacogenetic ablation technique. These data suggest that young neurons may inhibit or destabilize recurrent network activity in the dentate and hilus. This unexpected result yields a new perspective on how a modest number of young adult-generated granule cells may modulate activity in the larger population of mature granule cells, rather than acting solely as independent encoding units.

Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus.

&#x7CBE;&#x5FC3;&#x8BBE;&#x8BA1;&#x7684;&#x52A8;&#x7269;&#x6A21;&#x578B;&#x7684;&#x9057;&#x4F20;&#x5371;&#x9669;&#x56E0;&#x7D20;&#x6709;&#x53EF;&#x80FD;&#x5E2E;&#x52A9;&#x6211;&#x4EEC;&#x7406;&#x89E3;&#x7684;&#x7CBE;&#x795E;&#x5206;&#x88C2;&#x75C7;&#x53D1;&#x75C5;&#x673A;&#x5236;&#x7684;&#x7814;&#x7A76;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x7814;&#x7A76;&#x4E0E;&#x8BBE;&#x8BA1;&#x6A21;&#x578B;&#x7CBE;&#x795E;&#x5206;&#x88C2;&#x75C7;&#x6613;&#x611F;&#x7A81;&#x53D8;&#x7684;&#x5F71;&#x54CD;&#xFF0C;&#x63D0;&#x4F9B;&#x8BE6;&#x5C3D;&#x7684;&#x540E;&#x679C;&#xFF0C;&#x8FD9;&#x4E2A;&#x7A81;&#x53D8;&#x5BF9;&#x53D1;&#x5C55;&#x548C;&#x6D77;&#x9A6C;&#x7684;&#x7535;&#x8DEF;&#x529F;&#x80FD;&#x7684;&#x5185;&#x6E90;&#x6027; Disc1 ortholog &#x622A;&#x65AD;&#x75C5;&#x53D8;&#x7684;&#x5C0F;&#x9F20;&#x54C1;&#x7CFB;&#x3002;&#x6211;&#x4EEC;&#x53D1;&#x73B0;&#x5728;&#x65B0;&#x751F;&#x513F;&#x548C;&#x6210;&#x4EBA;&#x5927;&#x8111;&#x7684;&#x6D77;&#x9A6C;&#x9F7F;&#x72B6;&#x56DE;&#x4E2D;&#x7684;&#x666E;&#x904D;&#x5B58;&#x5728;&#x548C;&#x7D2F;&#x79EF;&#x96CF;&#x9E21;&#x6539;&#x52A8;&#x662F;&#x8F74;&#x7A81;&#x9776;&#x5411;&#x5305;&#x62EC;&#x9519;&#x8BEF;&#xFF0C;&#x5E76;&#x9644;&#x6709;&#x82D4;&#x85D3;&#x7EA4;&#x7EF4;/CA3 &#x7535;&#x8DEF;&#x5728;&#x77ED;&#x671F;&#x53EF;&#x5851;&#x6027;&#x53D8;&#x5316;&#x3002;&#x6211;&#x4EEC;&#x8FD8;&#x63D0;&#x4F9B;&#x8BC1;&#x636E;&#x8425;&#x5730;&#x7684;&#x7EA7;&#x522B;&#x90FD;&#x5347;&#x9AD8;&#x7684; Disc1 &#x7A81;&#x53D8;&#xFF0C;&#x7531;&#x4E8E;&#x5BFC;&#x81F4;&#x6539;&#x53D8;&#x5F25;&#x6F2B;&#x6027;&#x8F74;&#x7D22;&#x9776;&#x5411;&#x548C;&#x6811;&#x7A81;&#x7684;&#x751F;&#x957F;&#x3002;&#x5728;&#x6700;&#x5927;&#x7A0B;&#x5EA6;&#xFF0C;&#x786E;&#x5B9A;&#x7ED3;&#x6784;&#x6539;&#x52A8;&#x63A8;&#x65AD;&#x4EE5;&#x524D;&#x57FA;&#x4E8E; RNAi Disc1 &#x2477; &#x4E0E;&#x4FC3;&#x8FDB;&#x589E;&#x957F;&#x548C;&#x8FC7;&#x65E9;&#x6210;&#x719F;&#x5F71;&#x54CD;&#x4E0D;&#x76F8;&#x7B26;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7814;&#x7A76;&#x7ED3;&#x679C;&#x63D0;&#x4F9B;&#x652F;&#x6301;&#x8FD9;&#x4E00;&#x6982;&#x5FF5;&#x8FD9;&#x6E29;&#x548C;&#x7684;&#x795E;&#x7ECF;&#x5143;&#x8FDE;&#x63A5;&#x52A8;&#x4E71;&#x548C;&#x966A;&#x540C;&#x4E2D;&#x77ED;&#x671F;&#x7684;&#x7A81;&#x89E6;&#x52A8;&#x529B;&#x5B66;&#x7684;&#x8D64;&#x5B57;&#x662F;&#x7CBE;&#x795E;&#x5206;&#x88C2;&#x75C7;&#x6613;&#x611F;&#x57FA;&#x56E0;&#x7A81;&#x53D8;&#x7684;&#x4E00;&#x822C;&#x7279;&#x6027;&#x3002;

&#x6539;&#x53D8;&#x5F25;&#x6F2B;&#x6027;&#x8F74;&#x7D22;&#x9776;&#x5411;&#x548C;&#x77ED;&#x671F; Disc1 &#x57FA;&#x56E0;&#x7A81;&#x53D8;&#x5C0F;&#x9F20;&#x6D77;&#x9A6C;&#x53EF;&#x5851;&#x6027;&#x3002;

Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice.

Des mod&#xE8;les animaux soigneusement con&#xE7;u de facteurs de risque g&#xE9;n&#xE9;tiques sont susceptibles de faciliter notre compr&#xE9;hension de la pathogen&#xE8;se de la schizophr&#xE9;nie. Ici, nous &#xE9;tudions une souche de souris avec une l&#xE9;sion dans le tronquant orthologue endog&#xE8;ne Disc1 con&#xE7;u pour mod&#xE9;liser les effets d&#x26;#39;une mutation pr&#xE9;disposant &#xE0; la schizophr&#xE9;nie et d&#x26;#39;offrir un compte rendu d&#xE9;taill&#xE9; des cons&#xE9;quences que cette mutation a sur le d&#xE9;veloppement et la fonction d&#x26;#39;un circuit hippocampique. Nous d&#xE9;couvrons r&#xE9;pandues et cumulatif des modifications cytoarchitecturales dans le gyrus dent&#xE9; cours de la neurogen&#xE8;se n&#xE9;onatale et adulte, qui comprennent les erreurs de ciblage axonal et sont accompagn&#xE9;es par des changements &#xE0; court terme de plasticit&#xE9; &#xE0; la mousse fiber/CA3 circuit. Nous avons &#xE9;galement fournir la preuve que les taux d&#x26;#39;AMPc sont &#xE9;lev&#xE9;s en raison de la mutation Disc1, conduisant &#xE0; un ciblage axonal alt&#xE9;r&#xE9;e et la croissance dendritique. Les modifications structurelles identifi&#xE9;es sont, pour la plupart, pas compatible avec les effets de maturation favorisant la croissance et pr&#xE9;matur&#xE9;e d&#xE9;duites pr&#xE9;c&#xE9;dente ARNi bas&#xE9;e sur Disc1 knockdown. Nos r&#xE9;sultats fournissent un support &#xE0; la notion que les perturbations modestes de la connectivit&#xE9; neuronale et les d&#xE9;ficits d&#x26;#39;accompagnement &#xE0; court terme la dynamique synaptiques est une caract&#xE9;ristique g&#xE9;n&#xE9;rale de la schizophr&#xE9;nie-pr&#xE9;disposant mutations.

Altered ciblage axonal et &#xE0; court terme Plasticit&#xE9; dans l&#x26;#39;hippocampe des souris mutantes Disc1

Sorgf&auml;ltig entworfene Tiermodellen f&uuml;r genetische Risikofaktoren werden voraussichtlich unser Verst&auml;ndnis der Pathogenese der Schizophrenie. Hier untersuchen wir eine Maus-Sorte mit einer &#x2584;berlanges L&auml;sion in der endogenen Disc1-Ortholog bieten eine detaillierte Darstellung der Folgen, die diese Mutation auf die Entwicklung und Funktion einer hippocampal Schaltung und model die Auswirkungen der Schizophrenie-pr&auml;disponierenden Mutation. Wir entdecken weit verbreitet und kumulative Cytoarchitectural Ver&auml;nderungen der Gyrus dentatus bei Neugeborenen und adulten Neurogenese, zu denen St&ouml;rungen ins Visier nehmen, axonale in kurzfristige Plastizit&auml;t auf dem moosigen Faser/CA3-Circuit von Ver&auml;nderungen begleitet werden. Wir bieten auch Hinweise darauf, dass cAMP Ebenen durch die Mutation Disc1 erhoben werden, f&uuml;hrt zu ver&auml;nderten axonale targeting und dendritischen Wachstums. Die ermittelten strukturellen &Auml;nderungen sind in den meisten F&auml;llen, nicht im Einklang mit der wachstumsf&ouml;rdernde und vorzeitige Reifung Effekte hergeleitet aus vorherigen RNAi-basierte Disc1 Niederschlag. Unsere Ergebnisse bieten Unterst&uuml;tzung der Vorstellung dieser bescheidenen St&ouml;rungen der neuronalen Verbindungen und begleitende Defizite in der kurzfristigen synaptische Dynamik ist eine allgemeine Funktion von Schizophrenie-pr&auml;disponierenden Mutationen.

Ver&auml;nderte axonale targeting und kurzfristige Plastizit&auml;t im Hippocampus Disc1-mutant-M&auml;use.

Accuratamente progettati modelli animali di fattori di rischio genetici sono probabilmente aiutare la nostra comprensione della patogenesi della schizofrenia. Qui, lo studio di un ceppo di topo con una lesione troncante l&#39;endogeno Disc1 ortholog progettato per modellare gli effetti di una mutazione che predispongono di schizofrenia e di offrire un resoconto dettagliato delle conseguenze che questa mutazione ha sullo sviluppo e la funzione di un circuito ippocampale. Noi scoprire alterazioni citoarchitettonica diffusa e cumulativo del giro dentato durante la neurogenesi adulta e neonatale, che includono Errori nel targeting assonale e sono accompagnati da cambiamenti nella plasticit&agrave; a breve termine presso il circuito di fibra/CA3 muschioso. Forniamo inoltre evidenza che i livelli di campi sono elevati come risultato della mutazione Disc1, portando a alterata targeting assonale e dendritica crescita. Le alterazioni strutturali individuate sono, per la maggior parte, non coerente con gli effetti di promozione della crescita e prematura maturazione dedotto da precedente basati su RNAi Disc1 atterramento. I nostri risultati forniscono sostegno alla nozione che modeste dispersioni di connettivit&agrave; neuronale e deficit nella dinamica sinaptica a breve termine di accompagnamento &egrave; una caratteristica generale delle mutazioni che predispongono di schizofrenia.

Alterato targeting assonale e plasticit&agrave; a breve termine nell&#39;ippocampo di topi mutanti Disc1.

&#x907A;&#x4F1D;&#x7684;&#x5371;&#x967A;&#x56E0;&#x5B50;&#x306E;&#x614E;&#x91CD;&#x306B;&#x8A2D;&#x8A08;&#x3055;&#x308C;&#x305F;&#x52D5;&#x7269;&#x30E2;&#x30C7;&#x30EB;&#x304C;&#x7D71;&#x5408;&#x5931;&#x8ABF;&#x75C7;&#x306E;&#x75C5;&#x56E0;&#x306E;&#x6211;&#x3005;&#x306E;&#x7406;&#x89E3;&#x3092;&#x52A9;&#x3051;&#x308B;&#x305F;&#x3081;&#x306B;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x7D71;&#x5408;&#x5931;&#x8ABF;&#x75C7;&#x7D20;&#x56E0;&#x7A81;&#x7136;&#x5909;&#x7570;&#x306E;&#x5F71;&#x97FF;&#x3092;&#x30E2;&#x30C7;&#x30EB;&#x5316;&#x3057;&#x3001;&#x3053;&#x306E;&#x5909;&#x7570;&#x306F;&#x3001;&#x6D77;&#x99AC;&#x56DE;&#x8DEF;&#x306E;&#x958B;&#x767A;&#x3068;&#x6A5F;&#x80FD;&#x306B;&#x4E0E;&#x3048;&#x308B;&#x5F71;&#x97FF;&#x306E;&#x8A73;&#x7D30;&#x306A;&#x8AAC;&#x660E;&#x3092;&#x63D0;&#x4F9B;&#x3059;&#x308B;&#x3088;&#x3046;&#x306B;&#x8A2D;&#x8A08;&#x3055;&#x308C;&#x305F;&#x5185;&#x56E0;&#x6027;&#x306E;Disc1&#x306E;&#x306E;&#x30AA;&#x30EB;&#x30BD;&#x30ED;&#x30B0;&#x3067;&#x5207;&#x308A;&#x6368;&#x3066;&#x308B;&#x75C5;&#x5909;&#x3092;&#x6301;&#x3064;&#x30DE;&#x30A6;&#x30B9;&#x7CFB;&#x7D71;&#x306E;&#x7814;&#x7A76;&#x3092;&#x884C;&#x3063;&#x3066;&#x3044;&#x308B;&#x3002;&#x6211;&#x3005;&#x306F;&#x8EF8;&#x7D22;&#x306E;&#x6A19;&#x7684;&#x306B;&#x30A8;&#x30E9;&#x30FC;&#x304C;&#x542B;&#x307E;&#x308C;&#x3066;&#x304A;&#x308A;&#x3001;&#x82D4;fiber/CA3&#x56DE;&#x8DEF;&#x306E;&#x77ED;&#x671F;&#x53EF;&#x5851;&#x6027;&#x306E;&#x5909;&#x5316;&#x3092;&#x4F34;&#x3046;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3001;&#x65B0;&#x751F;&#x5150;&#x3068;&#x6210;&#x4EBA;&#x306E;&#x795E;&#x7D4C;&#x65B0;&#x751F;&#x6642;&#x306B;&#x6B6F;&#x72B6;&#x56DE;&#x3067;&#x5E83;&#x304F;&#x3001;&#x7D2F;&#x7A4D;&#x7684;&#x306A;&#x7D30;&#x80DE;&#x69CB;&#x7BC9;&#x306E;&#x5909;&#x5316;&#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x307E;&#x3059;&#x3002;&#x307E;&#x305F;&#x3001;cAMP&#x30EC;&#x30D9;&#x30EB;&#x304C;&#x5909;&#x66F4;&#x3055;&#x308C;&#x305F;&#x8EF8;&#x7D22;&#x306E;&#x6A19;&#x7684;&#x3068;&#x6A39;&#x72B6;&#x7A81;&#x8D77;&#x306E;&#x6210;&#x9577;&#x306B;&#x3064;&#x306A;&#x304C;&#x308B;&#x3001;Disc1&#x306E;&#x7A81;&#x7136;&#x5909;&#x7570;&#x306E;&#x7D50;&#x679C;&#x3068;&#x3057;&#x3066;&#x4E0A;&#x6607;&#x3057;&#x3066;&#x3044;&#x308B;&#x3068;&#x3044;&#x3046;&#x8A3C;&#x62E0;&#x3092;&#x63D0;&#x4F9B;&#x3059;&#x308B;&#x3002;&#x7279;&#x5B9A;&#x3055;&#x308C;&#x305F;&#x69CB;&#x9020;&#x5909;&#x5316;&#x306F;&#x3001;&#x307B;&#x3068;&#x3093;&#x3069;&#x306E;&#x90E8;&#x5206;&#x306F;&#x3001;&#x4EE5;&#x524D;&#x306E;RNAi&#x30D9;&#x30FC;&#x30B9;Disc1&#x306E;&#x30CE;&#x30C3;&#x30AF;&#x30C0;&#x30A6;&#x30F3;&#x304B;&#x3089;&#x63A8;&#x6E2C;&#x3055;&#x308C;&#x308B;&#x6210;&#x9577;&#x4FC3;&#x9032;&#x3068;&#x65E9;&#x671F;&#x6210;&#x719F;&#x3078;&#x306E;&#x5F71;&#x97FF;&#x3068;&#x4E00;&#x81F4;&#x3057;&#x3066;&#x3044;&#x307E;&#x305B;&#x3093;&#x3002;&#x6211;&#x3005;&#x306E;&#x7D50;&#x679C;&#x306F;&#x77ED;&#x671F;&#x7684;&#x306A;&#x30B7;&#x30CA;&#x30D7;&#x30B9;&#x30C0;&#x30A4;&#x30CA;&#x30DF;&#x30AF;&#x30B9;&#x306E;&#x795E;&#x7D4C;&#x63A5;&#x7D9A;&#x3068;&#x305D;&#x308C;&#x306B;&#x4F34;&#x3046;&#x8CA1;&#x653F;&#x8D64;&#x5B57;&#x306E;&#x3055;&#x3055;&#x3084;&#x304B;&#x306A;&#x969C;&#x5BB3;&#x304C;&#x7D71;&#x5408;&#x5931;&#x8ABF;&#x75C7;&#x7D20;&#x56E0;&#x5909;&#x7570;&#x306E;&#x4E00;&#x822C;&#x7684;&#x306A;&#x7279;&#x5FB4;&#x3067;&#x3042;&#x308B;&#x3068;&#x3044;&#x3046;&#x6982;&#x5FF5;&#x306B;&#x30B5;&#x30DD;&#x30FC;&#x30C8;&#x3092;&#x63D0;&#x4F9B;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

Disc1&#x306E;&#x5909;&#x7570;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x6D77;&#x99AC;&#x306B;&#x304A;&#x3051;&#x308B;&#x8EF8;&#x7D22;&#x30BF;&#x30FC;&#x30B2;&#x30C6;&#x30A3;&#x30F3;&#x30B0;&#x3068;&#x77ED;&#x671F;&#x53EF;&#x5851;&#x6027;&#x3092;&#x5909;&#x5316;&#x3055;&#x305B;

&#xC815;&#xC2E0; &#xBD84;&#xC5F4; &#xC99D;&#xC758; &#xBCD1; &#xC778; &#xC6B0;&#xB9AC;&#xC758; &#xC774;&#xD574;&#xB97C; &#xB3D5;&#xAE30; &#xC704;&#xD574; &#xC2E0;&#xC911; &#xD558; &#xAC8C; &#xC124;&#xACC4; &#xB41C; &#xB3D9;&#xBB3C; &#xBAA8;&#xB378; &#xC720;&#xC804;&#xC801; &#xC704;&#xD5D8; &#xC694;&#xC778;&#xC758; &#xD655;&#xB960;&#xC774; &#xB192;&#xB2E4;&#xC785;&#xB2C8;&#xB2E4;. &#xC5EC;&#xAE30;&#xC5D0;, &#xC6B0;&#xB9AC;&#xB294; &#xC815;&#xC2E0; &#xBD84;&#xC5F4; &#xC99D; predisposing &#xB3CC;&#xC5F0;&#xBCC0;&#xC774;&#xC758; &#xD6A8;&#xACFC; &#xBAA8;&#xB378;&#xB9C1; &#xD558; &#xACE0;&#xC774; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xAC1C;&#xBC1C; &#xACB0;&#xACFC;&#xC758; &#xC138;&#xBD80; &#xACC4;&#xC815;&#xACFC; hippocampal &#xD68C;&#xB85C;&#xC758; &#xAE30;&#xB2A5;&#xC744; &#xC81C;&#xACF5; &#xD558;&#xB3C4;&#xB85D; &#xC124;&#xACC4; &#xB41C; &#xC0DD; Disc1 ortholog&#xC5D0;&#xC11C; &#xC798;&#xB77C;&#xB0B8; &#xBCD1; &#xBCC0;&#xC73C;&#xB85C; &#xB9C8;&#xC6B0;&#xC2A4; &#xC2A4;&#xD2B8;&#xB808;&#xC778; &#xC5F0;&#xAD6C;. &#xC6B0;&#xB9AC; &#xBC1D;&#xD788;&#xAE30; axonal &#xD0C0;&#xAC9F;&#xD305;&#xC5D0;&#xC11C; &#xC624;&#xB958;&#xB97C; &#xD3EC;&#xD568; &#xD558; &#xACE0; &#xC774;&#xB07C; &#xC12C;&#xC720;/CA3 &#xD68C;&#xB85C;&#xC5D0;&#xC11C; &#xB2E8;&#xAE30;&#xAC00; &#xC18C;&#xC131;&#xC758; &#xBCC0;&#xD654;&#xB97C; &#xB3D9;&#xBC18; &#xD558;&#xB294; &#xB3D9;&#xC548; &#xC2E0;&#xC0DD;&#xC544; &#xBC0F; &#xC131;&#xC778; &#xC131;&#xCCB4;&#xAC00; &#xB1CC;&#xC5D0; &#xAD11;&#xBC94;&#xC704; &#xD558; &#xACE0; &#xB204;&#xC801; cytoarchitectural &#xBCC0;&#xACBD; &#xD569;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC; &#xB610;&#xD55C; &#xBCC0;&#xACBD; axonal &#xD0C0;&#xAC9F;&#xD305; &#xBC0F; &#xC218;&#xC9C0;&#xC0C1; &#xC131;&#xC7A5; &#xCEA0;&#xD504; &#xB808;&#xBCA8; Disc1 &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xACB0;&#xACFC;&#xB85C; &#xC2B9;&#xACA9; &#xB418; &#xC99D;&#xAC70;&#xB97C; &#xC81C;&#xACF5; &#xD569;&#xB2C8;&#xB2E4;. &#xC2DD;&#xBCC4; &#xB41C; &#xAD6C;&#xC870;&#xC801; &#xBCC0;&#xACBD;, &#xAC00;&#xC7A5; &#xC911;&#xC694; &#xD55C; &#xBD80;&#xBD84;, &#xC774;&#xC804; RNAi &#xAE30;&#xBC18; Disc1 &#xCD5C;&#xC800;&#xC758;&#xC5D0;&#xC11C; &#xC131;&#xC7A5; &#xCD09;&#xC9C4; &#xBC0F; &#xC870;&#xAE30; &#xC131;&#xC219; &#xD6A8;&#xACFC;&#xACFC; &#xC77C;&#xCE58; &#xD558;&#xC9C0; &#xC720;&#xCD94;. &#xC6B0;&#xB9AC;&#xC758; &#xACB0;&#xACFC; &#xC2E0;&#xACBD; &#xC5F0;&#xACB0;&#xC758; &#xADF8; &#xACB8;&#xC190; &#xD55C; &#xC7A5;&#xC560; &#xAC1C;&#xB150;&#xC5D0; &#xC9C0;&#xC6D0;&#xC744; &#xC81C;&#xACF5; &#xD558; &#xACE0; &#xB2E8;&#xAE30; &#xC2DC; &#xB0C5; &#xC2A4; &#xC5ED;&#xD559;&#xC758; &#xC801;&#xC790; &#xB3D9;&#xBC18;&#xC740; &#xC815;&#xC2E0; &#xBD84;&#xC5F4; &#xC99D; predisposing &#xB3CC;&#xC5F0;&#xBCC0;&#xC774;&#xC758; &#xC77C;&#xBC18;&#xC801;&#xC778; &#xAE30;&#xB2A5;.

Axonal &#xD0C0;&#xAC9F;&#xD305; &#xBC0F; &#xB2E8;&#xAE30; &#xC18C;&#xC131; Disc1 &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xC950;&#xC758; &#xD574; &#xB9C8;&#xC5D0;&#xC11C; &#xBCC0;&#xACBD;.

Cuidadosamente dise&#xF1;ado modelos animales de los factores de riesgo gen&#xE9;ticos es probable que ayudar a nuestra comprensi&#xF3;n de la patog&#xE9;nesis de la esquizofrenia. En este caso, se estudia una cepa de ratones con una lesi&#xF3;n de truncar en el ort&#xF3;logo Disc1 end&#xF3;geno dise&#xF1;ado para modelar los efectos de una mutaci&#xF3;n que predispone a la esquizofrenia y ofrecer una relaci&#xF3;n detallada de las consecuencias que esta mutaci&#xF3;n tiene sobre el desarrollo y la funci&#xF3;n de un circuito del hipocampo. Descubrimos cytoarchitectural alteraciones generalizadas y acumulado en el giro dentado durante la neurog&#xE9;nesis neonatal y de adultos, que los errores en la orientaci&#xF3;n de los axones y se acompa&#xF1;an de cambios en el corto plazo plasticidad en la cubierta de musgo fiber/CA3 circuito. Tambi&#xE9;n proporcionan evidencia de que los niveles de AMPc est&#xE1;n elevados como resultado de la mutaci&#xF3;n Disc1, dando lugar a la orientaci&#xF3;n alterada axonal y crecimiento dendr&#xED;tico. Las alteraciones identificadas estructurales son, en su mayor parte, no consistentes con los efectos de maduraci&#xF3;n que promueven el crecimiento y prematura inferidas a partir anterior ARNi basado Disc1 desmontables. Nuestros resultados proporcionan apoyo a la idea de que las alteraciones moderadas de la conectividad neuronal y los d&#xE9;ficit que se acompa&#xF1;an en el corto plazo la din&#xE1;mica sin&#xE1;ptica es una caracter&#xED;stica general de la predisposici&#xF3;n a la esquizofrenia mutaciones.

Alteraci&#xF3;n de Orientaci&#xF3;n axonal y la plasticidad de corto plazo en el hipocampo de los ratones mutantes Disc1

Anatomical observations, theoretical work and lesion experiments have led to the idea that an important function of the dentate gyrus of the mammalian hippocampus is pattern separation, a neural computation that ensures new memories are encoded without interference from previously stored memories that share similar features. The dentate gyrus also exhibits a unique form of neural plasticity that results from the continuous integration of newly born excitatory granule cells, termed adult hippocampal neurogenesis. However, the manner in which adult neurogenesis contributes to dentate gyrus network activity and computations is incompletely understood. Here, we first describe the prevailing models for the role of adult neurogenesis in dentate gyrus network function and then re-evaluate these models in the light of recent findings regarding the in vivo activity of the dentate gyrus and synaptic interactions of adult born granule cells with local circuit components, as well as, inputs, and outputs of the dentate gyrus. We propose that adult neurogenesis provides flexibility for the dentate gyrus to rapidly generate a context specific, distributed representation of important sensory stimuli such as spatial cues, which ultimately gives rise to behavioral discrimination.

Contributions of adult neurogenesis to dentate gyrus network activity and computations.

The increasing interest in manipulating neural circuits in developing brains has created a demand for reliable and accurate methods for delivering viruses to newborn mice. Here we describe a novel 3D-printed mouse neonatal stereotaxic adaptor for intracerebral viral injection that provides enhanced precision and reliability. Using this device, we injected  mice with a -dependent hM4D-mCherry viral construct at postnatal day 1 (P1) and demonstrated selective expression in the striatal indirect pathway neurons on days P7, P11 and P25. Similarly, dopaminergic midbrain neurons were selectively targeted with a -dependent green fluorescent protein virus in -IRES- neonates and expression examined at P25. Our open-source neonatal stereotaxic mouse adaptor facilitates neonatal neuronal targeting, which should improve the ability to label and modify neural circuits in developing mouse brains.

A device for stereotaxic viral delivery into the brains of neonatal mice.

Hair greying is a hallmark of aging generally believed to be irreversible and linked to psychological stress.

Quantitative mapping of human hair greying and reversal in relation to life stress.

The brain's ability to process complex information relies on the constant supply of energy through aerobic respiration by mitochondria. Neurons contain three anatomically distinct compartments-the soma, dendrites, and projecting axons-which have different energetic and biochemical requirements, as well as different mitochondrial morphologies in cultured systems. In this study, we apply quantitative three-dimensional electron microscopy to map mitochondrial network morphology and complexity in the mouse brain. We examine somatic, dendritic, and axonal mitochondria in the dentate gyrus and cornu ammonis 1 (CA1) of the mouse hippocampus, two subregions with distinct principal cell types and functions. We also establish compartment-specific differences in mitochondrial morphology across these cell types between young and old mice, highlighting differences in age-related morphological recalibrations. Overall, these data define the nature of the neuronal mitochondrial network in the mouse hippocampus, providing a foundation to examine the role of mitochondrial morpho-function in the aging brain.

3D neuronal mitochondrial morphology in axons, dendrites, and somata of the aging mouse hippocampus.

During exploration, animals form an internal map of an environment by combining information about landmarks and the animal's movement, a process that depends on the hippocampus. The dentate gyrus (DG) is the first stage of the hippocampal circuit where self-motion ("where") and sensory cue information ("what") are integrated, but it remains unknown how DG neurons encode this information during cognitive map formation. Using two-photon calcium imaging in mice running on a treadmill along with online cue manipulation, we identify robust sensory cue responses in DG granule cells. Cue cell responses are stable, stimulus-specific, and accompanied by inhibition of nearby neurons. This demonstrates the existence of "cue cells" in addition to better characterized "place cells" in the DG. We hypothesize that the DG supports parallel channels of spatial and non-spatial information that contribute distinctly to downstream computations and affect roles of the DG in spatial navigation and episodic memory.

Parallel processing of sensory cue and spatial information in the dentate gyrus.

The serotonin system modulates a wide variety of emotional behaviors and states, including reward processing, anxiety, and social interaction. To reveal the underlying patterns of neural activity, we visualized serotonergic neurons in the dorsal raphe nucleus (DRN) of mice using miniaturized microscopy during diverse emotional behaviors. We discovered ensembles of cells with highly correlated activity and found that DRN neurons are preferentially recruited by emotionally salient stimuli as opposed to neutral stimuli. Individual DRN neurons responded to diverse combinations of salient stimuli, with some preference for valence and sensory modality. Anatomically defined subpopulations projecting to either a reward-related structure (the ventral tegmental area) or an anxiety-related structure (the bed nucleus of the stria terminalis) contained all response types but were enriched in reward- and anxiety-responsive cells, respectively. Our results suggest that the DRN serotonin system responds to emotional salience using ensembles with mixed selectivity and biases in downstream connectivity.

Single-cell activity and network properties of dorsal raphe nucleus serotonin neurons during emotionally salient behaviors.

It has been suggested that the dorsomedial striatum (DMS) is engaged in the early stages of motor learning for goal-directed actions, whereas at later stages, control is transferred to the dorsolateral striatum (DLS), a process that enables learned motor actions to become a skill or habit. It is not known whether these striatal regions are simultaneously active while the expertise is acquired. To address this question, we developed a mouse "Treadmill Training Task" that tracks changes in mouse locomotor coordination during running practice and simultaneously provides a means to measure local neuronal activity using photometry. To measure change in motor coordination over treadmill practice sessions, we used DeepLabCut (DLC) and custom-built code to analyze body position and paw movements. By evaluating improvements in motor coordination during training with simultaneous neuronal calcium activity in the striatum, we found that DMS direct pathway neurons exhibited decreased activity as the mouse gained proficiency at running. In contrast, direct pathway activity in the DLS was similar throughout training. Pharmacological blockade of D1 dopamine receptors in these subregions during task performance demonstrated that dopamine neurotransmission in the direct pathway activity is necessary for efficient motor coordination learning. These results provide new tools to measure changes in fine motor skills with simultaneous recordings of brain activity and reveal fundamental features of the neuronal substrates of motor learning.

Decreased Dorsomedial Striatum Direct Pathway Neuronal Activity Is Required for Learned Motor Coordination.

In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess "bridging" collaterals within the globus pallidus (GPe), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches to dissect the roles of bridging collaterals in motor function. We find that dSPNs projecting to the SNr send synchronous motor-related information to the GPe via axon collaterals. Inhibition of native activity in dSPN GPe terminals impairs motor activity and function via regulation of pallidostriatal Npas1 neurons. We propose a model by which dSPN GPe collaterals ("striatopallidal Go pathway") act in concert with the canonical terminals in the SNr to support motor control by inhibiting Npas1 signals going back to the striatum.

A non-canonical striatopallidal "Go" pathway that supports motor control.

In vivo brainstem imaging with miniature microscopy has been challenging due to surgical difficulty, high motion, and correlated activity between neurons. Here, we present a protocol for brainstem imaging in freely moving mice using the dorsal raphe nucleus as an example. We describe surgical procedures to inject a virus encoding GCaMP6m and securely implant a GRIN lens in the brainstem. We then detail motion correction and cell segmentation from the data to parse single-cell activity from correlated networks. For complete details on the use and execution of this protocol, please refer to Paquelet et al. (2022)..

Clay Lacefield

Division of Systems Neuroscience

New York State Psychiatric Institute

An Open-Source Virtual Reality System for the Measurement of Spatial Learning in Head-Restrained Mice

Clay Lacefield

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Division of Systems Neuroscience

New York State Psychiatric Institute

An Open-Source Virtual Reality System for the Measurement of Spatial Learning in Head-Restrained Mice

Division of Systems Neuroscience