handling-techniques-to-reduce-stress-in-mice

Handling Techniques to Reduce Stress in Mice

Laboratory animals are subjected to multiple manipulations by scientists or animal care providers. The stress this causes can have profound effects ...

Université de Bordeaux

In an attempt to characterize the contribution of the 5-HT1B receptor to behavior, 5-HT1B knock-out (KO) mice were subjected to a battery of behavioral paradigms aimed at differentiating various components of cognitive and emotional behaviors. In an object exploration task, wild-type (WT) and 5-HT1B KO mice did not differ in locomotor activity. 5-HT1B KO mice, however, displayed lower thigmotaxis (an index of anxiety) associated with a higher level of object exploratory activity, but no genotype differences were observed in the elevated plus maze. 5-HT1B KO mice also displayed a lack of exploratory habituation. In the spatial version of the Morris water maze, 5-HT1B KO mice showed higher performances in acquisition and transfer test, which was not observed in the visual version of the task. No genotype differences were found in contextual fear conditioning, because both WT and 5-HT1B KO mice were able to remember the context where they had received the aversive stimulus. The deletion of the 5-HT1B receptor, associated with appropriate behavioral paradigms, thus allowed us to dissociate anxiety from response to novelty, and perseverative behavior (lack of habituation) from adaptive behavioral inhibition underlying cognitive flexibility (transfer stage in the water maze). The deletion of the 5-HT1B receptor did not result in significant developmental plasticities for other major 5-HT receptor types but may have influenced other neurotransmission systems. The 5-HT1B receptor may be a key target for serotonin in the modulation of cognitive behavior, particularly in situations involving a high cognitive demand.

5-HT1B receptor knock-out mice exhibit increased exploratory activity and enhanced spatial memory performance in the Morris water maze.

Somatostatin (SS14) &#xB2E4;&#xC591; &#xD55C; &#xC778;&#xC9C0; &#xC7A5;&#xC560;&#xC5D0; &#xC5F0;&#xB8E8; &#xB418;&#xC5B4;&#xC788;&#xB2E4; &#xACE0; &#xB3D9;&#xBB3C; &#xC5F0;&#xAD6C;&#xC5D0;&#xC11C; &#xC218;&#xB834; &#xC99D;&#xAC70; SS14 &#xC2E0;&#xACBD; &#xCC28;&#xB3D9; hippocampal &#xBC0F; striatal-&#xC885;&#xC18D;&#xC801;&#xC778; &#xBA54;&#xBAA8;&#xB9AC; &#xD615;&#xC131;&#xC744; &#xC870;&#xC808; &#xD569;&#xB2C8;&#xB2E4;. 4 &#xAC1C;&#xC758; SS14 &#xC218;&#xC6A9; &#xCCB4; &#xD558;&#xC704; (SSTR1-4)&#xB294; &#xD574; &#xB9C8;&#xC5D0;&#xC11C; &#xD45C;&#xD604; &#xB418;&#xB294; &#xD558;&#xC9C0;&#xB9CC; &#xBA54;&#xBAA8;&#xB9AC; &#xD504;&#xB85C;&#xC138;&#xC2A4;&#xC5D0;&#xC11C; &#xAC01;&#xAC01;&#xC758; &#xC5ED;&#xD560; &#xACB0;&#xC815; &#xB0A8;&#xC544; &#xC788;&#xB2E4;.

Hippocampal SSTR4 somatostatin &#xC218;&#xC6A9; &#xCCB4; &#xBA54;&#xBAA8;&#xB9AC; &#xC804;&#xB7B5;&#xC758; &#xC120;&#xD0DD;&#xC744; &#xC81C;&#xC5B4; &#xD569;&#xB2C8;&#xB2E4;.

Somatostatina (TC 14) se ha implicado en varios trastornos cognitivos, y evidencia convergente de estudios en animales sugiere que las neuronas SS14 diferencialmente regulan formaci&oacute;n hippocampal estriado-dependientes y de la memoria. Cuatro subtipos de receptores SS14 (SSTR1-4) se expresan en el hipocampo, pero sus respectivos papeles en los procesos de memoria quedan por determinarse.

Receptores de la somatostatina de hipocampales SSTR4 controlan la selecci&oacute;n de estrategias de memoria.

Somatostatina (SS14) &egrave; stata implicata in vari disturbi cognitivi e convergenti da studi su animali suggeriscono che i neuroni SS14 differenzialmente regolano formazione memoria ippocampale e striatali-dipendente. Quattro sottotipi di recettore SS14 (SSTR1-4) sono espressi nell&#39;ippocampo, ma restano dei rispettivi ruoli nei processi di memoria per essere determinata.

I recettori della somatostatina di SSTR4 hippocampal controllano la selezione delle strategie di memoria.

&#x30BD;&#x30DE;&#x30C8;&#x30B9;&#x30BF;&#x30C1;&#x30F3; (SS14) &#x306B;&#x5404;&#x7A2E;&#x306E;&#x8A8D;&#x77E5;&#x969C;&#x5BB3;&#x306B;&#x95A2;&#x4E0E;&#x3057;&#x3066;&#x3044;&#x308B;&#x3057;&#x3001;&#x52D5;&#x7269;&#x7814;&#x7A76;&#x304B;&#x3089;&#x306E;&#x53CE;&#x675F;&#x306E;&#x8A3C;&#x62E0; SS14 &#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x7279;&#x7570;&#x7684;&#x6D77;&#x99AC;&#x3068;&#x7DDA;&#x6761;&#x4F53;&#x4F9D;&#x5B58;&#x8A18;&#x61B6;&#x5F62;&#x6210;&#x3092;&#x8ABF;&#x7BC0;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;4 &#x3064;&#x306E; SS14 &#x53D7;&#x5BB9;&#x4F53;&#x30B5;&#x30D6;&#x30BF;&#x30A4;&#x30D7; (SSTR1 4) &#x306F;&#x3001;&#x6D77;&#x99AC;&#x3067;&#x8868;&#x73FE;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x304C;&#x6C7A;&#x5B9A;&#x3059;&#x308B;&#x8A18;&#x61B6;&#x904E;&#x7A0B;&#x306B;&#x304A;&#x3051;&#x308B;&#x305D;&#x308C;&#x305E;&#x308C;&#x306E;&#x5F79;&#x5272;&#x3092;&#x6B8B;&#x3063;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

&#x6D77;&#x99AC; SSTR4 &#x30BD;&#x30DE;&#x30C8;&#x30B9;&#x30BF;&#x30C1;&#x30F3;&#x53D7;&#x5BB9;&#x4F53;&#x8A18;&#x61B6;&#x65B9;&#x7565;&#x306E;&#x9078;&#x629E;&#x3092;&#x5236;&#x5FA1;&#x3057;&#x307E;&#x3059;&#x3002;

&#x751F;&#x957F;&#x6291;&#x7D20; (SS14) &#x4E00;&#x76F4;&#x5728;&#x53C2;&#x4E0E;&#x5404;&#x79CD;&#x8BA4;&#x77E5;&#x969C;&#x788D;&#x7684;&#x7814;&#x7A76;&#xFF0C;&#x548C;&#x8D8B;&#x540C;&#x7684;&#x52A8;&#x7269;&#x7814;&#x7A76;&#x8868;&#x660E; SS14 &#x795E;&#x7ECF;&#x5143;&#x5DEE;&#x5F02;&#x8C03;&#x8282;&#x6D77;&#x9A6C;&#x548C;&#x7EB9;&#x72B6;&#x4F53;&#x4F9D;&#x8D56;&#x8BB0;&#x5FC6;&#x7684;&#x5F62;&#x6210;&#x3002;&#x56DB;&#x4E2A; SS14 &#x53D7;&#x4F53;&#x4E9A;&#x578B; (SSTR1-4&#xFF09; &#x8868;&#x793A;&#x5728;&#x6D77;&#x9A6C;&#xFF0C;&#x4F46;&#x5728;&#x8BB0;&#x5FC6;&#x8FC7;&#x7A0B;&#x4E2D;&#x5404;&#x81EA;&#x7684;&#x4F5C;&#x7528;&#x4ECD;&#x6709;&#x5F85;&#x786E;&#x5B9A;&#x3002;

&#x6D77;&#x9A6C; SSTR4 &#x751F;&#x957F;&#x6291;&#x7D20;&#x53D7;&#x4F53;&#x63A7;&#x5236;&#x7684;&#x8BB0;&#x5FC6;&#x7B56;&#x7565;&#x7684;&#x9009;&#x62E9;&#x3002;

Somatostatin (SS14) has been implicated in various cognitive disorders, and converging evidence from animal studies suggests that SS14 neurons differentially regulate hippocampal- and striatal-dependent memory formation. Four SS14 receptor subtypes (SSTR1-4) are expressed in the hippocampus, but their respective roles in memory processes remain to be determined.

Hippocampal SSTR4 somatostatin receptors control the selection of memory strategies.

La somatostatine (ES14) a &eacute;t&eacute; impliqu&eacute;e dans divers troubles cognitifs et convergentes des &eacute;tudes chez l&#39;animal sugg&egrave;rent que les neurones ES14 r&eacute;glementent diff&eacute;remment formation hippocampique et striatale-d&eacute;pendant de la m&eacute;moire. Quatre sous-types de r&eacute;cepteurs ES14 (SSTR1-4) sont exprim&eacute;es dans l&#39;hippocampe, mais leurs r&ocirc;les respectifs dans le processus de m&eacute;moire restent &agrave; d&eacute;terminer.

R&eacute;cepteurs de la somatostatine hippocampe SSTR4 contr&ocirc;lent le choix des strat&eacute;gies de m&eacute;moire.

Somatostatin (SS14) hat verwickelt wurden, bei verschiedenen kognitiven St&ouml;rungen und konvergierende Tier Forschungsergebnisse deuten darauf hin, dass SS14 Neuronen differentiell hippocampal - und Striatale-abh&auml;ngigen Ged&auml;chtnisbildung regulieren. Vier SS14-Rezeptor-Subtypen (SSTR1-4) werden im Hippocampus ausgedr&uuml;ckt, aber ihre jeweiligen Rollen im Speicher Prozesse m&uuml;ssen noch bestimmt werden.

Hippocampale SSTR4 Somatostatin-Rezeptoren steuern die Auswahl an Speicher Strategien.

(Sst) &#x6D77;&#x9A6C;&#x751F;&#x957F;&#x6291;&#x7D20;&#x53D7;&#x4F53;&#x4E9A;&#x578B; 4 &#xFF08;sst(4)) &#x8C03;&#x5236;&#x7684;&#x63D0;&#x9AD8;&#x4F9D;&#x8D56;&#x4E8E;&#x7EB9;&#x72B6;&#x4F53;&#x7684;&#x884C;&#x4E3A;&#x540C;&#x65F6;&#x51CF;&#x5C11;&#x57FA;&#x4E8E;&#x6D77;&#x9A6C;&#x7684;&#x7A7A;&#x95F4;&#x529F;&#x80FD;&#x7684;&#x8BB0;&#x5FC6;&#x7684;&#x5F62;&#x6210;&#x3002;(4) sst-&#x4ECB;&#x5BFC;&#x7684;&#x6CD5;&#x89C4;&#x5BF9;&#x6D77;&#x9A6C;&#x795E;&#x7ECF;&#x5143;&#x6D3B;&#x6027;&#x7684;&#x51FA;&#x73B0;&#x53D6;&#x51B3;&#x4E8E;&#x7ADE;&#x4E89;&#x4E0E;&#x5408;&#x4F5C;&#x4E0E;&#x4E92;&#x52A8; sst &#x53D7;&#x4F53;&#x4E9A;&#x578B; 2 &#xFF08;sst(2))&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x8C03;&#x67E5;&#x4E0E; sst(2) &#x53D7;&#x4F53;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x662F;&#x5426;&#x9700;&#x8981; sst (4)-&#x4ECB;&#x5BFC;&#x6D77;&#x9A6C;&#x4F9D;&#x8D56;&#x7A7A;&#x95F4;&#x8BB0;&#x5FC6;&#x548C;&#x4F9D;&#x8D56;&#x4E8E;&#x7EB9;&#x72B6;&#x4F53;&#x7684;&#x6807;&#x8BB0;&#x7684;&#x5185;&#x5B58;&#x5728;&#x6C34;&#x8FF7;&#x5BAB;&#x8303;&#x5F0F;&#x7684;&#x5F71;&#x54CD;&#x3002;&#x7ADE;&#x4E89;&#x5728;&#x5C0F;&#x9F20;&#x6D77;&#x9A6C;&#x6CE8;&#x5C04; sst(2) &#x53D7;&#x4F53;&#x6FC0;&#x52A8;&#x5242; &#xFF08;L-779,976 &#x6216;&#x66F2;&#xFF09; sst(4) &#x6FC0;&#x52A8;&#x5242; L-803,087 &#x5355;&#x72EC;&#x6216;&#x8054;&#x5408;&#x8BC4;&#x4F30;&#x3002;&#x5728; sst(2) &#x57FA;&#x56E0;&#x6572;&#x9664;&#x5C0F;&#x9F20;&#xFF0C;&#x8BC4;&#x4F30;&#x53D7;&#x4F53;&#x5408;&#x4F5C;&#xFF0C;&#x8FD8;&#x6D4B;&#x8BD5;&#x4E86; L 803,087 &#x7684;&#x5F71;&#x54CD;&#x3002;&#x6700;&#x540E;&#xFF0C;&#x901A;&#x8FC7;&#x514D;&#x75AB;&#x7EC4;&#x7EC7;&#x5316;&#x5B66;&#x5206;&#x6790;&#x4E86;&#x6D77;&#x9A6C;&#x5206;&#x533A;&#x57DF;&#x5185;&#x7684; sst(2a) &#x548C; sst(4) &#x4F9B;&#x9500;&#x548C; sst(2a) &#x548C; sst(2b) &#x7684;&#x8868;&#x8FBE;&#x6C34;&#x5E73;&#x91CF;&#x5316;&#x7684;&#x5B9E;&#x65F6; qPCR&#x3002;&#x6D77;&#x9A6C;&#x6CE8;&#x5C04; L 803,087 &#x7684;&#x7A7A;&#x95F4;&#x8BB0;&#x5FC6;&#x53D7;&#x635F;&#xFF0C;&#x4F46;&#x589E;&#x5F3A;&#x6807;&#x8BB0;&#x7684;&#x5185;&#x5B58;&#x3002;&#x540E;&#x8005;&#x6548;&#x679C;&#x8FF7;&#x5931;&#x4E0D;&#x53EA;&#x5728; sst(2) &#x57FA;&#x56E0;&#x6572;&#x9664;&#x5C0F;&#x9F20;&#xFF0C;&#x4F46;&#x4E5F;&#x5B58;&#x5728; sst(2) &#x53D7;&#x4F53;&#x6FC0;&#x52A8;&#x5242;&#xFF0C;&#x800C;&#x4ECD;&#x7136;&#x53D7; sst(2) &#x53D7;&#x4F53;&#x6FC0;&#x52A8;&#x5242;&#x6216;&#x57FA;&#x56E0;&#x7F3A;&#x5931;&#x5BF9;&#x524D;&#x8005;&#x7684;&#x5F71;&#x54CD;&#x3002;&#x5965;&#x66F2;&#x80BD;&#x548C; L 779,976 &#x4E0D;&#x4F1A;&#x4EA7;&#x751F;&#x8BB0;&#x5FC6;&#x6548;&#x5E94;&#xFF0C;&#x4F46;&#x51CF;&#x5C11;&#x6574;&#x4E2A;&#x91C7;&#x96C6;&#x5BA1;&#x5224;&#x6697;&#x793A; sst(2) &#x523A;&#x6FC0;&#x5F71;&#x54CD;&#x52A8;&#x673A;&#x548C;/&#x6216;&#x7126;&#x8651;&#x7684;&#x6E38;&#x6CF3;&#x901F;&#x5EA6;&#x3002;sst(2a) &#x548C; sst(4) &#x5206;&#x522B;&#x68C0;&#x6D4B;&#x5230;&#x5728;&#x6D77;&#x9A6C;&#x9F7F;&#x72B6;&#x56DE; (DG) &#x548C;&#x6697;&#x793A;&#x5176;&#x529F;&#x80FD;&#x4E0A;&#x7684;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x4E0D;&#x4ECB;&#x5BFC;&#x76F4;&#x63A5;&#x53D7;&#x4F53;&#x8026;&#x5408;&#x7684; CA1 &#x5B50;&#x5B57;&#x6BB5;&#x3002;&#x6D77;&#x9A6C; sst(2a) &#x8868;&#x8FBE;&#x5F0F;&#x662F;&#x6BD4; sst(2b) 36-fold &#x9AD8;&#x3002;&#x53EF;&#x80FD;&#x7684;&#x795E;&#x7ECF;&#x673A;&#x5236;&#x548C;&#x529F;&#x80FD;&#x610F;&#x4E49;&#x5173;&#x7CFB;&#x5728;&#x6D77;&#x9A6C;&#x7684;&#x529F;&#x80FD;&#x5E94;&#x6FC0;&#x53D8;&#x5316;&#x4E0E;&#x5185;&#x5B58;&#x7CFB;&#x7EDF;&#x4E4B;&#x95F4;&#x7684;&#x4E92;&#x52A8;&#x8BA8;&#x8BBA;&#x3002;

&#x6D77;&#x9A6C;&#x751F;&#x957F;&#x6291;&#x7D20;&#x53D7;&#x4F53;&#x5B50; 4 &#x548C; 2 &#x4E4B;&#x95F4;&#x7684;&#x5408;&#x4F5C;&#xFF1A; &#x4E2D;&#x7684;&#x4EA4;&#x4E92;&#x8BB0;&#x5FC6;&#x7CFB;&#x7EDF;&#x7684;&#x529F;&#x80FD;&#x76F8;&#x5173;&#x3002;

The hippocampal somatostatin (sst) receptor subtype 4 (sst(4)) modulates memory formation by diminishing hippocampus-based spatial function while enhancing striatum-dependent behaviors. sst(4)-mediated regulations on neuronal activity in the hippocampus appear to depend on both competitive and cooperative interactions with sst receptor subtype 2 (sst(2)). Here, we investigated whether interactions with sst(2) receptors are required for sst(4)-mediated effects on hippocampus-dependent spatial memory and striatum-dependent cued memory in a water maze paradigm. Competition was assessed in mice by intrahippocampal injections of the sst(4) agonist L-803,087 alone or combined with sst(2) agonists (L-779,976 or octreotide). Effects of L-803,087 were also tested in sst(2) knockout mice to assess for receptor cooperation. Finally, sst(2a) and sst(4) localizations within hippocampal subregions were analyzed by immunohistochemistry and expression levels of sst(2a) and sst(2b) were quantified by real-time qPCR. Hippocampal injections of L-803,087 impaired spatial memory but enhanced cued memory. The latter effect was lost not only in sst(2) knockout mice but also in the presence of sst(2) agonists, whereas the former effect remained unaffected by sst(2) agonists or gene deletion. Octreotide and L-779,976 did not yield memory effects but reduced swim velocity throughout the acquisition trials suggesting that stimulation of sst(2) affected motivation and/or anxiety. sst(2a) and sst(4) were respectively detected in the dentate gyrus (DG) and the CA1 subfield suggesting that their functional interactions are not mediated by direct receptor coupling. Hippocampus sst(2a) expression was 36-fold higher than sst(2b). Possible neural mechanisms and functional significances for interaction between memory systems in relationship with stress-induced changes in hippocampal functions are discussed.

Cooperation between hippocampal somatostatin receptor subtypes 4 and 2: functional relevance in interactive memory systems.

Le sous-type de r&eacute;cepteur de somatostatin hippocampe (sst) 4 (sst(4)) module de formation de la m&eacute;moire en diminuant la fonction spatiale ax&eacute;e sur l&#39;hippocampe tout en am&eacute;liorant les comportements striatum-d&eacute;pendante. SST (4)-R&egrave;glement par m&eacute;diation sur l&#39;activit&eacute; neuronale dans l&#39;hippocampe semble d&eacute;pendre de la fois comp&eacute;titives et coop&eacute;ratives des interactions avec le sous-type de r&eacute;cepteur de sst 2 (sst(2)). Ici, nous avons examin&eacute; si les interactions avec les r&eacute;cepteurs sst(2) sont n&eacute;cessaires pour la sst (4)-m&eacute;diation des effets sur la m&eacute;moire spatiale hippocampe-d&eacute;pendantes et d&eacute;pendantes striatum indic&eacute;e m&eacute;moire dans un paradigme de labyrinthe de l&#39;eau. La concurrence a &eacute;t&eacute; &eacute;valu&eacute;e chez des souris par des injections d&#39;intrahippocampal de l&#39;agoniste sst(4) L-803 087 seul ou combin&eacute; avec des agonistes sst(2) (L-779 976 ou octr&eacute;otide). Effets de la L-803 087 ont aussi &eacute;t&eacute; test&eacute;s chez les souris knock-out sst(2) pour &eacute;valuer la coop&eacute;ration des r&eacute;cepteurs. Enfin, sst(2a) et sst(4) des localisations dans les sous-r&eacute;gions hippocampe ont &eacute;t&eacute; analys&eacute;es par immunohistochimie et niveaux d&#39;expression des sst(2a) et sst(2b) ont &eacute;t&eacute; quantifi&eacute;s par qPCR en temps r&eacute;el. Hippocampe injections de L-803 087 r&eacute;duite de la m&eacute;moire spatiale mais une m&eacute;moire indic&eacute;. Ce dernier effet a &eacute;t&eacute; perdu non seulement dans les souris knock-out sst(2) mais aussi en pr&eacute;sence d&#39;agonistes de la sst(2), alors que l&#39;effet ancien demeure inchang&eacute; par sst(2) agonistes ou d&eacute;l&eacute;tion du g&egrave;ne. L&#39;octr&eacute;otide et L-779 976 n&#39;ont pas donn&eacute; les effets de m&eacute;moire, mais r&eacute;duit la vitesse de nage tout au long des essais d&#39;acquisition sugg&eacute;rant que la stimulation de sst(2) affect&eacute;e motivation et/ou d&#39;anxi&eacute;t&eacute;. SST(2a) et sst(4) ont &eacute;t&eacute; d&eacute;tect&eacute;s respectivement dans le gyrus dent&eacute; (DG) et le sous-champ CA1, sugg&eacute;rant que leurs interactions fonctionnelles ne sont pas v&eacute;hicul&eacute;es par un couplage du r&eacute;cepteur direct. Expression sst(2a) hippocampe d&eacute;passait 36 sst(2b). Les m&eacute;canismes neurones possibles et significations fonctionnelles pour l&#39;interaction entre les syst&egrave;mes de m&eacute;moire en relation avec les changements provoqu&eacute;s par le stress dans les fonctions de l&#39;hippocampe sont discut&eacute;es.

Coop&eacute;ration entre la somatostatine hippocampe sous-types de r&eacute;cepteurs 4 et 2: pertinence fonctionnelle dans les syst&egrave;mes de m&eacute;moire interactive.

Der hippocampal Somatostatin (sst)-Rezeptor-Subtyp 4 (sst(4)) moduliert Ged&auml;chtnisbildung von abnehmender Hippokampus-basierte r&auml;umliche Funktion bei verbesserter Striatum-abh&auml;ngigen Verhaltensweisen. SST (4)-vermittelte Verordnungen &uuml;ber die neuronale Aktivit&auml;t im Hippocampus erscheinen h&auml;ngt sowohl Wettbewerb als auch kooperative Interaktionen mit sst-Rezeptor-Subtyp 2 (sst(2)). Hier wir gepr&uuml;ft, ob Wechselwirkungen mit sst(2)-Rezeptoren f&uuml;r sst (4) erforderlich sind-vermittelte Wirkungen auf Hippokampus-abh&auml;ngigen und die Striatum-abh&auml;ngige Stichnoten Erinnerung in einem Wasser-Labyrinth-Paradigma. Wettbewerb wurde in den M&auml;usen von Intrahippocampal Injektionen von den sst(4)-Agonisten L-803.087 allein oder in Kombination mit sst(2)-Agonisten (L-779.976 oder Octreotid) bewertet. Wirkung von L-803.087 wurden in sst(2) Knockout-M&auml;use f&uuml;r Rezeptor Zusammenarbeit bewerten auch getestet. Schlie&szlig;lich wurden sst(2a) und sst(4) Lokalisierungen in hippocampal Subregionen von Immunohistochemistry analysiert und Stufen der sst(2a) und sst(2b) wurden durch Echtzeit-qPCR quantifiziert. Hippocampale Injektionen von L-803.087 r&auml;umliches Ged&auml;chtnis beeintr&auml;chtigt aber Stichnoten Speicher erweitert. Die letztere Wirkung wurde nicht nur in sst(2)-Knockout-M&auml;use sondern auch in Gegenwart von sst(2)-Agonisten, verloren, w&auml;hrend die ehemalige Wirkung von sst(2)-Agonisten oder gen L&ouml;schung unber&uuml;hrt blieben. Octreotid und L-779.976 Memory-Effekt nicht nachgeben, aber reduziert Schwimmen Geschwindigkeit w&auml;hrend der Akquisition-Studien, die darauf hindeutet, dass die Stimulation des sst(2) Motivation und/oder Angst betroffen. SST(2a) und sst(4) wurden jeweils in den Gyrus dentatus (DG) und das CA1-Unterfeld, die darauf hindeutet, dass ihre funktionalen Wechselwirkungen nicht durch direkte Rezeptor Kupplung vermittelt werden erkannt. Hippocampus sst(2a) Ausdruck 36-fold h&ouml;her war als sst(2b). M&ouml;gliche neurale Mechanismen und funktionale Bedeutungen f&uuml;r die Interaktion zwischen Memory-Systemen in Beziehung mit Spannung induziert Ver&auml;nderungen in hippocampal Funktionen werden erl&auml;utert.

Zusammenarbeit zwischen hippocampal Somatostatin-Rezeptor-Subtypen 4 und 2: funktionelle Relevanz im interaktiven Memory-Systeme.

Il sottotipo di recettore hippocampal somatostatina (sst) 4 (sst(4)) modula la formazione di memoria diminuendo la funzione spaziale basata su ippocampo mentre migliorando comportamenti striato-dipendente. SST (4)-mediati regolamenti sull&#39;attivit&agrave; neuronale nell&#39;ippocampo sembrano dipendono dalle interazioni competitive e cooperative con sottotipo di recettore sst 2 (sst(2)). Qui, abbiamo indagato se le interazioni con i recettori sst(2) sono necessarie per la sst (4)-mediata effetti sulla memoria spaziale ippocampo-dipendente e striato-dipendente attirare in un paradigma di labirinto d&#39;acqua. Concorrenza &egrave; stato valutato nei topi da iniezioni di intrahippocampal dell&#39;agonista sst(4) L-803.087 da solo o in combinazione con sst(2) agonisti (L-779.976 o octreotide). Effetti di L-803.087 sono stati testati anche in topi knockout sst(2) per valutare la cooperazione del recettore. Infine, sst(2a) e sst(4) localizzazioni all&#39;interno dell&#39;ippocampo sottoregioni sono stati analizzati da immunohistochemistry e livelli di espressione di sst(2a) e sst(2b) sono stati quantificati da qPCR in tempo reale. Iniezioni di hippocampal di L-803.087 con problemi di memoria spaziale ma migliorata attirare memoria. L&#39;effetto di quest&#39;ultimo &egrave; stato perso non solo nei topi knockout sst(2) ma anche in presenza di sst(2) agonisti, considerando che l&#39;effetto ex &egrave; rimasto inalterato da sst(2) agonisti o delezione di un gene. Octreotide e L-779.976 non ha dato effetti di memoria ma ridotta velocit&agrave; di nuotata durante i processi di acquisizione, suggerendo che la stimolazione del sst(2) interessato motivazione e/o ansia. SST(2a) e sst(4) sono stati rilevati rispettivamente il giro dentato (DG) e il sottocampo CA1 suggerendo che loro interazioni funzionali non sono mediati da accoppiamento diretto del recettore. Espressione sst(2a) ippocampo era 36-fold superiore a sst(2b). Vengono discussi i possibili meccanismi neurali e significati funzionali per l&#39;interazione tra sistemi di memoria in relazione con i cambiamenti indotti dallo stress nelle funzioni dell&#39;ippocampo.

Cooperazione tra somatostatina hippocampal recettore sottotipi 4 e 2: rilevanza funzionale nei sistemi interattivi di memoria.

&#x6D77;&#x99AC;&#x30BD;&#x30DE;&#x30C8;&#x30B9;&#x30BF;&#x30C1;&#x30F3; (sst) &#x53D7;&#x5BB9;&#x4F53;&#x30B5;&#x30D6;&#x30BF;&#x30A4;&#x30D7; 4 (sst(4)) &#x8A18;&#x61B6;&#x5F62;&#x6210;&#x7DDA;&#x6761;&#x4F53;&#x306B;&#x4F9D;&#x5B58;&#x3057;&#x305F;&#x884C;&#x52D5;&#x3092;&#x5F37;&#x5316;&#x3057;&#x306A;&#x304C;&#x3089;&#x6D77;&#x99AC;&#x306B;&#x57FA;&#x3065;&#x3044;&#x3066;&#x7A7A;&#x9593;&#x95A2;&#x6570;&#x3092;&#x6E1B;&#x5C11;&#x3092;&#x5909;&#x8ABF;&#x3057;&#x307E;&#x3059;&#x3002;sst (4)-&#x6D77;&#x99AC;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x6D3B;&#x52D5;&#x306E;&#x4EF2;&#x4ECB;&#x3055;&#x308C;&#x305F;&#x898F;&#x5236;&#x3092;&#x8868;&#x793A;&#x7AF6;&#x4E89;&#x3068;&#x5354;&#x529B;&#x3068;&#x306E;&#x76F8;&#x4E92;&#x4F5C;&#x7528; sst &#x53D7;&#x5BB9;&#x4F53;&#x30B5;&#x30D6;&#x30BF;&#x30A4;&#x30D7; 2 (sst(2)) &#x4F9D;&#x5B58;&#x3059;&#x308B;&#x306B;&#x306F;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x6211;&#x3005; &#x306F; sst(2) &#x53D7;&#x5BB9;&#x4F53;&#x3068;&#x306E;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x304C; sst (4) &#x304C;&#x5FC5;&#x8981;&#x304B;&#x3069;&#x3046;&#x304B;&#x3092;&#x8ABF;&#x3079;&#x305F;-&#x3092;&#x4ECB;&#x3057;&#x305F;&#x6D77;&#x99AC;&#x4F9D;&#x5B58;&#x7684;&#x7A7A;&#x9593;&#x8A18;&#x61B6;&#x3068;&#x7DDA;&#x6761;&#x4F53;&#x306B;&#x4F9D;&#x5B58;&#x3059;&#x308B;&#x30AD;&#x30E5;&#x30FC;&#x8A18;&#x61B6;&#x6C34;&#x8FF7;&#x8DEF;&#x30D1;&#x30E9;&#x30C0;&#x30A4;&#x30E0;&#x306B;&#x5F71;&#x97FF;&#x3057;&#x307E;&#x3059;&#x3002;&#x7AF6;&#x4E89;&#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x6D77;&#x99AC;&#x5185;&#x6CE8;&#x5C04; sst(2) &#x30A2;&#x30B4;&#x30CB;&#x30B9;&#x30C8; &#xFF08;L 779,976 &#x307E;&#x305F;&#x306F;&#x30AA;&#x30AF;&#x30C8;&#x30EC;&#x30AA;&#x30C1;&#x30C9;&#xFF09; &#x3068; sst(4) &#x30A2;&#x30B4;&#x30CB;&#x30B9;&#x30C8; L 803,087 &#x5358;&#x72EC;&#x307E;&#x305F;&#x306F;&#x4F75;&#x7528;&#x306B;&#x3088;&#x3063;&#x3066;&#x8A55;&#x4FA1;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;L 803,087 &#x306E;&#x52B9;&#x679C;&#x306F; sst(2) &#x30CE;&#x30C3;&#x30AF;&#x30A2;&#x30A6;&#x30C8; &#x30DE;&#x30A6;&#x30B9;&#x53D7;&#x5BB9;&#x4F53;&#x306E;&#x5354;&#x529B;&#x3092;&#x8A55;&#x4FA1;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x307E;&#x305F;&#x8A66;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x6700;&#x5F8C;&#x306B;&#x3001;sst(2a) &#x3068; sst(4) &#x306E;&#x30ED;&#x30FC;&#x30AB;&#x30E9;&#x30A4;&#x30BA;&#x6D77;&#x99AC;&#x306E;&#x30B5;&#x30D6;&#x9818;&#x57DF;&#x5185;&#x514D;&#x75AB;&#x67D3;&#x8272;&#x306B;&#x3088;&#x308A;&#x89E3;&#x6790;&#x3057;&#x305F;&#x3057;&#x3001;sst(2a) &#x3068; sst(2b) &#x306E;&#x767A;&#x73FE;&#x91CF;&#x306B;&#x3088;&#x3063;&#x3066;&#x30EA;&#x30A2;&#x30EB;&#x30BF;&#x30A4;&#x30E0; qPCR &#x5B9A;&#x91CF;&#x5316;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x6D77;&#x99AC;&#x6CE8;&#x5C04; L 803,087 &#x306E;&#x7A7A;&#x9593;&#x8A18;&#x61B6;&#x969C;&#x5BB3;&#x8005;&#x304C;&#x3001;&#x30AD;&#x30E5;&#x30FC;&#x306E;&#x30E1;&#x30E2;&#x30EA;&#x3092;&#x5897;&#x5F37;&#x3057;&#x307E;&#x3059;&#x3002;Sst(2) &#x4F5C;&#x52D5;&#x85AC;&#x307E;&#x305F;&#x306F;&#x907A;&#x4F1D;&#x5B50;&#x6B20;&#x5931;&#x306B;&#x3088;&#x3063;&#x3066;&#x5143;&#x306E;&#x5F71;&#x97FF;&#x3092;&#x53D7;&#x3051;&#x306A;&#x304B;&#x3063;&#x305F;&#x306B;&#x5BFE;&#x3057;&#x5F8C;&#x8005;&#x306E;&#x52B9;&#x679C;&#x3060;&#x3051;&#x3067;&#x306A;&#x304F; sst(2) &#x30CE;&#x30C3;&#x30AF;&#x30A2;&#x30A6;&#x30C8; &#x30DE;&#x30A6;&#x30B9;&#x3082; sst(2) &#x30A2;&#x30B4;&#x30CB;&#x30B9;&#x30C8;&#x5B58;&#x5728;&#x4E0B;&#x3067;&#x5931;&#x308F;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x30AA;&#x30AF;&#x30C8;&#x30EC;&#x30AA;&#x30C1;&#x30C9;&#x3068; L 779,976 &#x30E1;&#x30E2;&#x30EA;&#x52B9;&#x679C;&#x3092;&#x3082;&#x305F;&#x3089;&#x3059;&#x306A;&#x3044;&#x304C;&#x6CF3;&#x3050;&#x901F;&#x5EA6;&#x523A;&#x6FC0; sst(2) &#x306E;&#x52D5;&#x6A5F;&#x3084;&#x4E0D;&#x5B89;&#x306E;&#x5F71;&#x97FF;&#x3092;&#x53D7;&#x3051;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x53D6;&#x5F97;&#x8A66;&#x9A13;&#x5168;&#x4F53;&#x3092;&#x524A;&#x6E1B;&#x3057;&#x307E;&#x3059;&#x3002;sst(2a) &#x3068; sst(4) &#x306F;&#x305D;&#x308C;&#x305E;&#x308C;&#x6B6F;&#x72B6;&#x56DE; &#xFF08;DG&#xFF09; &#x3068;&#x305D;&#x308C;&#x3089;&#x306E;&#x6A5F;&#x80FD;&#x7684;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x76F4;&#x63A5;&#x53D7;&#x5BB9;&#x4F53;&#x7D50;&#x5408;&#x306B;&#x3088;&#x3063;&#x3066;&#x5A92;&#x4ECB;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x305B;&#x3093;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506; CA1 &#x30B5;&#x30D6;&#x30D5;&#x30A3;&#x30FC;&#x30EB;&#x30C9;&#x304C;&#x691C;&#x51FA;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x6D77;&#x99AC; sst(2a) &#x5F0F;&#x306F; 36-fold sst(2b) &#x3088;&#x308A;&#x3082;&#x9AD8;&#x304B;&#x3063;&#x305F;.&#x53EF;&#x80FD;&#x306A;&#x795E;&#x7D4C;&#x6A5F;&#x69CB;&#x3068;&#x5FDC;&#x529B;&#x8A98;&#x8D77;&#x6D77;&#x99AC;&#x6A5F;&#x80FD;&#x306E;&#x5909;&#x5316;&#x3068;&#x306E;&#x95A2;&#x4FC2;&#x3067;&#x30E1;&#x30E2;&#x30EA; &#x30B7;&#x30B9;&#x30C6;&#x30E0;&#x9593;&#x306E;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x306E;&#x6A5F;&#x80FD;&#x7684;&#x610F;&#x7FA9;&#x3092;&#x8AAC;&#x660E;&#x3057;&#x307E;&#x3059;&#x3002;

&#x6D77;&#x99AC;&#x30BD;&#x30DE;&#x30C8;&#x30B9;&#x30BF;&#x30C1;&#x30F3;&#x53D7;&#x5BB9;&#x4F53;&#x30B5;&#x30D6;&#x30BF;&#x30A4;&#x30D7; 4 &#x3068; 2 &#x306E;&#x9593;&#x306E;&#x5354;&#x529B;&#xFF1A; &#x5BFE;&#x8A71;&#x578B;&#x30E1;&#x30E2;&#x30EA; &#x30B7;&#x30B9;&#x30C6;&#x30E0;&#x306B;&#x304A;&#x3051;&#x308B;&#x6A5F;&#x80FD;&#x7684;&#x95A2;&#x9023;&#x6027;&#x3002;

Hippocampal somatostatin (sst) &#xC218;&#xC6A9; &#xCCB4; &#xD558;&#xC704; 4 (sst(4))&#xAC00; &#xC885;&#xC18D; &#xB3D9;&#xC791;&#xC744; &#xAC15;&#xD654; &#xD558;&#xBA74;&#xC11C; &#xD574; &#xB9C8; &#xAE30;&#xBC18; &#xACF5;&#xAC04; &#xAE30;&#xB2A5; &#xAC10;&#xC18C;&#xC5D0; &#xC758;&#xD574; &#xAE30;&#xC5B5; &#xD615;&#xC131;&#xC744; &#xBCC0;&#xC870; &#xD55C;&#xB2E4;. sst (4)-&#xD574; &#xB9C8;&#xC758; &#xC2E0;&#xACBD; &#xD65C;&#xB3D9;&#xC5D0; &#xB300; &#xD55C; &#xC911;&#xC7AC; &#xADDC;&#xC815; &#xACBD;&#xC7C1; &#xBC0F; &#xD611;&#xB825; &#xC0C1;&#xD638; sst &#xC218;&#xC6A9; &#xCCB4;&#xC758; &#xD558;&#xC704; 2 (sst(2))&#xC5D0; &#xB530;&#xB77C; &#xD45C;&#xC2DC;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC; sst(2) &#xC218;&#xC6A9; &#xCCB4;&#xC640;&#xC758; &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC740; sst (4) &#xD544;&#xC694; &#xC5EC;&#xBD80; &#xC870;&#xC0AC;-&#xC911;&#xC7AC;&#xAC00; &#xC885;&#xC18D; &#xBB38;&#xC7A5;&#xC744;&#xB41C; &#xBA54;&#xBAA8;&#xB9AC; &#xBB3C; &#xBBF8;&#xB85C; &#xD328;&#xB7EC;&#xB2E4;&#xC784;&#xC5D0;&#xC11C; &#xD574; &#xB9C8;&#xC5D0; &#xC885;&#xC18D;&#xC801;&#xC778; &#xACF5;&#xAC04; &#xBA54;&#xBAA8;&#xB9AC;&#xC5D0; &#xB300; &#xD55C; &#xD6A8;&#xACFC;. &#xACBD;&#xC7C1;&#xC758; &#xAE38; &#xD56D;&#xC740; sst(4) &#xC81C; &#xD328;-803,087 &#xD63C;&#xC790; &#xB610;&#xB294; &#xACB0;&#xD569; &#xB41C; sst(2) agonists (L 779,976 &#xB610;&#xB294; octreotide)&#xC640; intrahippocampal &#xC8FC;&#xC0AC;&#xC5D0; &#xC758;&#xD574; &#xC950;&#xC5D0;&#xC11C; &#xD3C9;&#xAC00; &#xB418;&#xC5C8;&#xB2E4;. L-803,087&#xC758; &#xD6A8;&#xACFC; &#xB610;&#xD55C; sst(2) &#xB179;&#xC544;&#xC6C3; &#xC0DD;&#xC950; &#xC218;&#xC6A9; &#xCCB4; &#xD611;&#xB825;&#xC5D0; &#xB300; &#xD55C; &#xD3C9;&#xAC00;&#xC5D0;&#xC11C; &#xD14C;&#xC2A4;&#xD2B8; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB9C8;&#xC9C0;&#xB9C9;&#xC73C;&#xB85C; hippocampal &#xAD6C;&#xC5ED; &#xB0B4;&#xC5D0;&#xC11C; sst(2a) &#xBC0F; sst(4) &#xC9C0;&#xC5ED;&#xD654; &#xAE30;&#xC220;&#xC5D0; &#xC758;&#xD574; &#xBD84;&#xC11D; &#xBC0F; &#xC2DD; &#xC218;&#xC900;&#xC758; sst(2a) &#xBC0F; sst(2b) &#xC2E4;&#xC2DC;&#xAC04; Qpcr&#xB85C; &#xACC4;&#xB7C9; &#xD588;&#xB2E4;. L-803,087&#xC758; hippocampal &#xC8FC;&#xC0AC; &#xACF5;&#xAC04; &#xBA54;&#xBAA8;&#xB9AC; &#xC190;&#xC0C1; &#xD558;&#xC9C0;&#xB9CC; &#xBB38;&#xC7A5;&#xC744;&#xB41C; &#xBA54;&#xBAA8;&#xB9AC; &#xD5A5;&#xC0C1;. &#xD6C4;&#xC790;&#xC758; &#xD6A8;&#xACFC; &#xC804; &#xD6A8;&#xACFC; &#xC720;&#xC9C0; sst(2) agonists &#xB610;&#xB294; &#xC720;&#xC804;&#xC790; &#xC0AD;&#xC81C;&#xC5D0; &#xC758;&#xD574; &#xC601;&#xD5A5;&#xC744; &#xBC1B;&#xC9C0; &#xC54A;&#xB294; &#xBC18;&#xBA74; sst(2) &#xB179;&#xC544;&#xC6C3; &#xC0DD;&#xC950; sst(2) agonists&#xC758; &#xC874;&#xC7AC; &#xBFD0;&#xB9CC; &#xC544;&#xB2C8;&#xB77C;&#xC5D0;&#xC11C; &#xBFD0;&#xB9CC; &#xC544;&#xB2C8;&#xB77C; &#xC190;&#xC2E4; &#xB429;&#xB2C8;&#xB2E4;. Octreotide &#xBC0F; L-779,976 &#xBA54;&#xBAA8;&#xB9AC; &#xD6A8;&#xACFC; &#xC591;&#xBCF4;&#xB97C; &#xD558;&#xC9C0; &#xC54A;&#xC558;&#xB2E4; &#xADF8;&#xB7EC;&#xB098; sst(2)&#xC758; &#xC790;&#xADF9; &#xB3D9;&#xAE30; &#xBD80;&#xC5EC; &#xBC0F; &#xBD88;&#xC548; &#xC601;&#xD5A5;&#xC744; &#xC81C;&#xC548; &#xC218;&#xC9D1; &#xC7AC;&#xD310; &#xB0B4;&#xB0B4; &#xC218;&#xC601; &#xC18D;&#xB3C4; &#xAC10;&#xC18C;. sst(2a)&#xC640; sst(4) &#xAC01;&#xAC01; (DG)&#xAC00; &#xB1CC;&#xC758; &#xAE30;&#xB2A5;&#xC801; &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC740; &#xC9C1;&#xC811; &#xC218;&#xC6A9; &#xCCB4; &#xACB0;&#xD569;&#xC5D0; &#xC758;&#xD574; &#xC911;&#xC7AC; &#xD558;&#xC9C0; &#xC81C;&#xC548; CA1 &#xD558;&#xC704; &#xD544;&#xB4DC;&#xC5D0;&#xC11C; &#xBC1C;&#xACAC; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xD574; &#xB9C8; sst(2a) &#xC2DD; 36-fold sst(2b) &#xBCF4;&#xB2E4; &#xB192;&#xC558;&#xB2E4;&#xC785;&#xB2C8;&#xB2E4;. &#xAC00;&#xB2A5;&#xD55C; &#xC2E0;&#xACBD; &#xBA54;&#xCEE4;&#xB2C8;&#xC998; &#xBC0F; &#xAE30;&#xB2A5;&#xC801; significances hippocampal &#xD568;&#xC218;&#xC5D0;&#xC11C; &#xBCC0;&#xD654; &#xC2A4;&#xD2B8;&#xB808;&#xC2A4; &#xC720;&#xBC1C; &#xAD00;&#xACC4;&#xC5D0;&#xC11C; &#xBA54;&#xBAA8;&#xB9AC; &#xC2DC;&#xC2A4;&#xD15C; &#xAC04;&#xC758; &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC5D0; &#xB300; &#xD55C; &#xC124;&#xBA85; &#xD569;&#xB2C8;&#xB2E4;.

&#xD611;&#xB825; hippocampal somatostatin &#xC218;&#xC6A9; &#xCCB4; &#xD558;&#xC704; 4&#xC640; 2: &#xC778;&#xD130;&#xB799;&#xD2F0;&#xBE0C; &#xBA54;&#xBAA8;&#xB9AC; &#xC2DC;&#xC2A4;&#xD15C;&#xC758; &#xAE30;&#xB2A5;&#xC801; &#xAD00;&#xB828;&#xC131;.

El subtipo de receptores de hipocampo somatostatina (sst) 4 (sst(4)) modula la formaci&oacute;n de la memoria disminuyendo la funci&oacute;n espacial basado en hipocampo incrementar comportamientos estriado-dependiente. SST (4)-mediadas regulaciones sobre la actividad neuronal en el hipocampo parecen depender de la interacci&oacute;n competitiva y cooperativa con subtipo de receptores de sst 2 (sst(2)). Aqu&iacute;, hemos investigado si las interacciones con los receptores sst(2) son necesarias para sst (4)-efectos dependiente del hipocampo memoria espacial y la memoria de localizaci&oacute;n de estriado-dependiente en un paradigma de laberinto de agua de mediaci&oacute;n. Competencia se evalu&oacute; en ratones por las inyecciones de intrahippocampal del agonista sst(4) L-803.087 solos o en combinaci&oacute;n con agonistas sst(2) (L-779.976 o octreotide). En ratones knockout de sst(2) evaluar la cooperaci&oacute;n del receptor tambi&eacute;n se probaron los efectos de L-803.087. Finalmente, sst(2a) y sst(4) localizaciones dentro de subregiones hipocampales se analizaron mediante inmunohistoqu&iacute;mica y niveles de la expresi&oacute;n de sst(2a) y sst(2b) fueron cuantificados mediante qPCR en tiempo real. Hippocampal inyecciones de L-803.087 deterioraron memoria espacial pero hab&iacute;a mejorado la localizaci&oacute;n de la memoria. El efecto de este &uacute;ltimo se perdi&oacute; no s&oacute;lo en ratones knockout de sst(2) sino tambi&eacute;n en presencia de agonistas sst(2), mientras que el efecto anterior segu&iacute;a siendo inafectado por sst(2) agonistas o canceladura del gene. Octreotide y L-779.976 no di&oacute; a efectos de memoria pero reducci&oacute;n la velocidad de nado a lo largo de los ensayos de adquisici&oacute;n, lo que sugiere que la estimulaci&oacute;n de sst(2) afectados motivaci&oacute;n y/o ansiedad. SST(2A) y sst(4) respectivamente fueron detectados en el giro dentado (DG) y el subcampo CA1, sugiriendo que sus interacciones funcionales no est&aacute;n mediadas por acoplamiento directo del receptor. Expresi&oacute;n de hipocampo sst(2a) fue 36-fold superior de sst(2b). Se discuten los posibles mecanismos neuronales y significados funcionales para la interacci&oacute;n entre los sistemas de memoria en relaci&oacute;n con cambios inducidos por estr&eacute;s en funciones hippocampal.

Cooperaci&oacute;n entre somatostatina hippocampal subtipos del receptor 4 y 2: relevancia funcional en sistemas interactivos de la memoria.

The multiple memory systems hypothesis posits that different neural circuits function in parallel and may compete for information processing and storage. For example, instrumental conditioning would depend on the striatum, whereas spatial memory may be mediated by a circuit centered on the hippocampus. However, the nature of the task itself is not sufficient to select durably one system over the other. In this study, we investigated the effects of natural and pharmacological rewards on the selection of a particular memory system during learning. We compared the effects of food- or drug-induced activation of the reward system on cue-guided versus spatial learning using a Y-maze discrimination task. Drug-induced reward severely impaired the acquisition of a spatial discrimination task but spared the cued version of the task. Immunohistochemical analysis of the phosphorylated form of the cAMP response element binding (CREB) protein and c-Fos expression induced by behavioral testing revealed that the spatial deficit was associated with a decrease of both markers within the hippocampus and the prefrontal cortex. In contrast, drug reward potentiated the cued learning-induced CREB phosphorylation within the dorsal striatum. Administration of the protein kinase A inhibitor 8-Bromo-adenosine-3',5'-cyclic monophosphorothioate Rp isomer (Rp-cAMPS) into the dorsal striatum before training completely reversed the drug-induced spatial deficit and restored CREB phosphorylation levels within the hippocampus and the prefrontal cortex. Therefore, drug-induced striatal hyperactivity may underlie the declarative memory deficit reported here. This mechanism could represent an important early step toward the development of addictive behaviors by promoting conditioning to the detriment of more flexible forms of memory.

Disrupting effect of drug-induced reward on spatial but not cue-guided learning: implication of the striatal protein kinase A/cAMP response element-binding protein pathway.

Chromatin modifications, especially histone acetylation, are critically involved in gene regulation required for long-term memory processes. Increasing histone acetylation via administration of histone deacetylase inhibitors before or after a learning experience enhances memory consolidation for hippocampus-dependent tasks and rescues age-related memory impairments. Whether acutely and locally enhancing histone acetylation during early consolidation processes can operate as a switch between multiple memory systems is less clear. This study examined the short- and long-term behavioral consequences of acute intra-CA1 administration of the histone deacetylase inhibitor Trichostatin A (TSA) on cue versus place learning strategy selection after a cue-guided water maze task and competition testing performed 1 or 24 h later in mice. Here, we show that intra-CA1 TSA infusion administrated immediately post-training biased young mice away from striatum-dependent cue strategy toward hippocampus-dependent place strategy under training condition that normally promotes cue strategy in vehicle controls. However, concomitant infusions of TSA with either PKA inhibitor, Rp-cAMPS, into CA1 or cAMP analog, 8Br-cAMP, into dorsal striatum failed to bias young mice to place strategy use. Behavioral and immunohistochemical analyses further indicated that post-training TSA infusion in aged mice rescued aging-associated deregulation of H4 acetylation in the CA1 but failed to reverse phosphorylated CREB deficits and to produce strategy bias on the 24 h probe test. These findings suggest that post-training intra-CA1 TSA infusion promotes dynamic shift from striatum toward the hippocampal system in young but not aged animals, and support the possibility of a role for CREB in the TSA-mediated switch between these two memory systems.

HDAC inhibition facilitates the switch between memory systems in young but not aged mice.

Altered brain somatostatin functions recently appeared as key elements for the pathogenesis of stress-related neuropsychiatric disorders. The hippocampus exerts an inhibitory feedback on stress but the mechanisms involved remain unclear. We investigated herein the role of hippocampal somatostatin receptor subtypes in both stress response and behavioral emotionality using C57BL/6, wild type and sst or sst knockout mice. Inhibitory effects of hippocampal infusions of somatostatin agonists on stress-induced hypothalamo-pituitary-adrenal axis (HPA) activity were tested by monitoring peripheral blood and local hippocampus corticosterone levels, the latter by using microdialysis. Anxiolytic and antidepressant-like effects were determined in the elevated-plus maze, open field, forced swimming, and stress-sensitive beam walking tests. Hippocampal injections of somatostatin analogs and sst or sst but not sst or sst receptor agonists produced rapid and sustained inhibition of HPA axis. sst agonists selectively produced anxiolytic-like behaviors whereas both sst and sst agonists had antidepressant-like effects. Consistent with these findings, high corticosterone levels and anxiety were found in sstKO mice and depressive-like behaviors observed in both sstKO and sstKO strains. Both hippocampal sst and sst receptors selectively inhibit stress-induced HPA axis activation but mediate anxiolytic and antidepressive effects through distinct mechanisms. Such results are to be accounted for in development of pathway-specific somatostatin receptor agents in the treatment of hypercortisolism (Cushing's disease) and stress-related neuropsychiatric disorders.

Roles of Hippocampal Somatostatin Receptor Subtypes in Stress Response and Emotionality.

This study investigated whether sst2 gene deletion interacts with age and chronic stress exposure to produce exacerbated emotional and cognitive ageing. Middle-aged (10-12 month) sst2 knockout (sst2KO) and wild-type (WT) mice underwent an unpredictable chronic mild stress (UCMS) procedure for 6 weeks or no stress for control groups. This was followed by a battery of tests to assess emotional and cognitive functions and neuroendocrine status (CORT level). A re-evaluation was performed 6 months later (i.e. with 18-month-old mice). UCMS reproduced neuroendocrine and behavioral features of stress-related disorders such as elevated circulating CORT levels, physical deteriorations, increased anxiety- and depressive-like behaviors and working memory impairments. sst2KO mice displayed behavioral alterations which were similar to stressed WT and exhibited exacerbated changes following UCMS exposure. The evaluations performed in the older mice showed significant long-term effects of UCMS exposure. Old sst2KO mice previously exposed to UCMS exhibited spatial learning and memory accuracy impairments and high levels of anxiety-like behaviors which drastically added to the effects of normal ageing. Spatial abilities and emotionality scores (mean z-scores) measured both at the UCMS outcome and 6 months later were correlated with the initially measured CORT levels in middle-age. The present findings indicate that the deletion of the sst2 receptor gene produces chronic hypercorticosteronemia and exacerbates sensitivity to stressors which over time, have consequences on ageing brain function processes.

sst-receptor gene deletion exacerbates chronic stress-induced deficits: Consequences for emotional and cognitive ageing.

Exposure to prolonged, unpredictable stress leads to glucocorticoids-mediated long-lasting neuroendocrine abnormalities associated with emotional and cognitive impairments. Excessive levels of serum glucocorticoids (cortisol in humans, corticosterone in rodents) contribute notably to deficits in working memory (WM), a task which heavily relies on functional interactions between the medial prefrontal cortex (PFC) and the dorsal hippocampus (dHPC). However, it is unknown whether stress-induced increases in plasma corticosterone mirror corticosterone levels in specific brain regions critical for WM. After a 6 week- exposure, C57BL/6 J male mice exhibited increased anxiety- and depressive-like behaviors when measured one week later and displayed WM impairments timely associated with increased plasma corticosterone response. In chronically stressed mice, basal phosphorylated/activated CREB (pCREB) was markedly increased in the PFC and the CA1 area of the dHPC and WM testing did not elicit any further increase in pCREB in the two regions. Using microdialysis samples from freely-moving mice, we found that WM testing co-occurred with a rapid and sustained increase in corticosterone response in the PFC while there was a late, non-significant rise of corticosterone in the dHPC. The results also show that non-stressed mice injected with corticosterone (2 mg/kg i.p.) before WM testing displayed behavioral and molecular alterations similar to those observed in stressed animals while a pre-WM testing metyrapone injection (35 mg/kg i.p.), a corticosterone synthesis inhibitor, prevented the effects of  exposure. Overall, the abnormal regional increase of corticosterone concentrations mainly in the PFC emerges as a key factor of enduring WM dysfunctions in -treated animals.

Sustained corticosterone rise in the prefrontal cortex is a key factor for chronic stress-induced working memory deficits in mice.

The G9a/G9a-like protein (GLP) histone lysine dimethyltransferase complex and downstream histone H3 lysine 9 dimethylation (H3K9me2) repressive mark have recently emerged as key transcriptional regulators of gene expression programs necessary for long-term memory (LTM) formation in the dorsal hippocampus. However, the role for hippocampal G9a/GLP complex in mediating the consolidation of spatial LTM remains largely unknown. Using a water maze competition task in which both dorsal hippocampus-dependent spatial and striatum-dependent cue navigation strategies are effective to solve the maze, we found that pharmacological inhibition of G9a/GLP activity immediately after learning disrupts long-term consolidation of previously learned spatial information in male mice, hence producing cue bias on the competition test performed 24 h later. Importantly, the inhibition of hippocampal G9a/GLP did not disrupt short-term memory retention. Immunohistochemical analyses revealed increases in global levels of permissive histone H3K9 acetylation in the dorsal hippocampus and dorsal striatum at 1 h post-training, which persisted up to 24 h in the hippocampus. Conversely, H3K9me2 levels were either unchanged in the dorsal hippocampus or transiently decreased at 15 min post-training in the dorsal striatum. Finally, the inhibition of G9a/GLP activity further increased global levels of H3K9 acetylation while decreasing H3K9me2 in the hippocampus at 1 h post-training. However, both marks returned to vehicle control levels at 24 h. Together, these findings support the possibility that G9a/GLP in the dorsal hippocampus is required for the transcriptional switch from short-term to long-term spatial memory formation.

Jean-Louis Guillou

Centre National de la Recherche Scientifique,
UMR 5287,
Institut de Neurosciences Cognitives et Intégratives d'Aquitaine,
Centre National de la Recherche Scientifique, UMR 5287, Institut de Neurosciences Cognitives et Intégratives d'Aquitaine

Université de Bordeaux

Handling Techniques to Reduce Stress in Mice