stereotaxic-infusion-oligomeric-amyloid-beta-into-mouse

Stereotaxic Infusion of Oligomeric Amyloid-beta into the Mouse Hippocampus

Alzheimer&#8217;s disease is a neurodegenerative disease affecting the aging population. A key neuropathological feature of the disease is the ...

quantification-of-immunostained-caspase-9-in-retinal-tissue

Quantification of Immunostained Caspase-9 in Retinal Tissue

The family of caspases is known to mediate many cellular pathways beyond cell death, including cell differentiation, axonal pathfinding, and ...

Columbia University Medical Center

Columbia University

Columbia College

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&#x5185;&#x8033;&#x53D1;&#x5C55;&#x7684;&#x722A;&#x87FE;&#x7684;&#x4E09;&#x7EF4;&#x5F62;&#x6001;&#x3002;

The three-dimensional morphology of the membranous labyrinth of Xenopus laevis is presented from embryonic through late tadpole development (stages 28 to 52, inclusive). This was accomplished by paint-filling the endolymphatic spaces of Xenopus ears at a series of stages, beginning with the embryonic otic vesicle and ending with the complex ear of the late tadpole. At stage 52, the inner ear has expanded approximately 23-fold in its anterior/posterior dimension compared with stage 28 and it is a miniature of the adult form. The paint-filling technique illustrates the dramatic changes required to convert a simple ear vesicle into the elaborate form of the adult, including semicircular canal formation and genesis of vestibular and auditory organs, and it can serve as a basis for phenotype identification in experimentally or genetically manipulated ears.

Three-dimensional morphology of inner ear development in Xenopus laevis.

La morphologie tridimensionnelle du labyrinthe membraneux de Xenopus laevis est pr&#xE9;sent&#xE9; &#xE0; partir embryonnaire par le d&#xE9;veloppement t&#xEA;tard fin (&#xE9;tapes 28 &#xE0; 52, inclusivement). Cela a &#xE9;t&#xE9; accompli par la peinture de remplissage des espaces endolymphatique d&#x26;#39;oreilles de Xenopus &#xE0; une s&#xE9;rie d&#x26;#39;&#xE9;tapes, en commen&#xE7;ant par la v&#xE9;sicule embryonnaire otique et se terminant avec l&#x26;#39;oreille complexe du t&#xEA;tard en retard. A l&#x26;#39;&#xE9;tape 52, l&#x26;#39;oreille interne a &#xE9;largi d&#x26;#39;environ 23 fois dans sa dimension ant&#xE9;rieure / post&#xE9;rieure par rapport &#xE0; la phase 28 et il est une miniature de la forme adulte. La technique de peinture de remplissage illustre les changements dramatiques n&#xE9;cessaires pour convertir une v&#xE9;sicule oreille simple en forme &#xE9;labor&#xE9;e de l&#x26;#39;adulte, y compris la formation canal semi-circulaire et la gen&#xE8;se des organes vestibulaires et auditives, et il peut servir de base pour l&#x26;#39;identification du ph&#xE9;notype dans exp&#xE9;rimentalement ou g&#xE9;n&#xE9;tiquement manipul&#xE9; les oreilles.

Tridimensionnelle Morphologie du D&#xE9;veloppement oreille interne chez Xenopus laevis

Dreidimensionale Morphologie Innenohrentwicklung in Xenopus laevis.

La morfologia tridimensionale del labirinto membranoso di Xenopus laevis &egrave; presentata da embrionali attraverso tardo sviluppo girino (fasi 28 a 52, compreso). Questo &egrave; stato compiuto dalla vernice-riempimento degli spazi endolinfatico di Xenopus orecchie a una serie di fasi, inizio con la vescicola embrionale otic e termina con il complesso orecchio il girino tardo. In fase 52, l&#39;orecchio interno ha ampliato circa 23-fold nella sua dimensione anteriore/posteriore confrontato con tappa 28 ed &egrave; una miniatura della forma dell&#39;adulto. La tecnica di pittura-riempimento illustra i drammatici cambiamenti necessari per convertire una vescicola semplice orecchio in forma elaborata dell&#39;adulto, compreso formazione canale semicircolare e genesi degli organi vestibolari e uditivi, e pu&ograve; servire come base per l&#39;identificazione di fenotipo in orecchie sperimentalmente o geneticamente manipolate.

Morfologia tridimensionale dello sviluppo dell&#39;orecchio interno in Xenopus laevis.

&#x30A2;&#x30D5;&#x30EA;&#x30AB;&#x30C4;&#x30E1;&#x30AC;&#x30A8;&#x30EB;&#x306E;&#x819C;&#x8FF7;&#x8DEF;&#x306E;&#x4E09;&#x6B21;&#x5143;&#x5F62;&#x614B;&#x304C;&#x9045;&#x304F;&#x30AA;&#x30BF;&#x30DE;&#x30B8;&#x30E3;&#x30AF;&#x30B7;&#x306E;&#x958B;&#x767A;&#xFF08;&#x30B9;&#x30C6;&#x30FC;&#x30B8;28&#x304B;&#x3089;52&#x307E;&#x3067;&#x3001;&#x5305;&#x62EC;&#x7684;&#x306A;&#xFF09;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x80DA;&#x304B;&#x3089;&#x63D0;&#x793A;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x306F;&#x5F8C;&#x534A;&#x306B;&#x30AA;&#x30BF;&#x30DE;&#x30B8;&#x30E3;&#x30AF;&#x30B7;&#x306E;&#x8907;&#x96D1;&#x306A;&#x8033;&#x3067;&#x80DA;&#x306E;&#x8033;&#x80DE;&#x3067;&#x59CB;&#x307E;&#x308A;&#x3001;&#x7D42;&#x308F;&#x308B;&#x3001;&#x30B9;&#x30C6;&#x30FC;&#x30B8;&#x306E;&#x30B7;&#x30EA;&#x30FC;&#x30BA;&#x3067;&#x3001;&#x30A2;&#x30D5;&#x30EA;&#x30AB;&#x30C4;&#x30E1;&#x30AC;&#x30A8;&#x30EB;&#x306E;&#x8033;&#x306E;&#x5185;&#x30EA;&#x30F3;&#x30D1;&#x30B9;&#x30DA;&#x30FC;&#x30B9;&#x3092;&#x5857;&#x6599;&#x5145;&#x586B;&#x3059;&#x308B;&#x3053;&#x3068;&#x306B;&#x3088;&#x3063;&#x3066;&#x9054;&#x6210;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x30B9;&#x30C6;&#x30FC;&#x30B8;52&#x3067;&#x3001;&#x5185;&#x8033;&#x306B;&#x306F;&#x3001;&#x30B9;&#x30C6;&#x30FC;&#x30B8;28&#x3068;&#x6BD4;&#x8F03;&#x3057;&#x3066;&#x3001;&#x305D;&#x306E;&#x524D;&#x90E8;/&#x5F8C;&#x90E8;&#x6B21;&#x5143;&#x200B;&#x200B;&#x3067;&#x7D04;23&#x500D;&#x306B;&#x62E1;&#x5927;&#x3057;&#x3066;&#x3044;&#x308B;&#x3001;&#x305D;&#x308C;&#x306F;&#x5927;&#x4EBA;&#x306E;&#x5F62;&#x306E;&#x30DF;&#x30CB;&#x30C1;&#x30E5;&#x30A2;&#x3067;&#x3059;&#x3002;&#x5857;&#x6599;&#x306E;&#x5145;&#x586B;&#x6280;&#x8853;&#x306F;&#x3001;&#x534A;&#x898F;&#x7BA1;&#x306E;&#x5F62;&#x6210;&#x3068;&#x524D;&#x5EAD;&#x3001;&#x8074;&#x899A;&#x5668;&#x5B98;&#x306E;&#x8D77;&#x6E90;&#x3092;&#x542B;&#x3081;&#x3066;&#x3001;&#x5927;&#x4EBA;&#x306E;&#x624B;&#x306E;&#x8FBC;&#x3093;&#x3060;&#x5F62;&#x306B;&#x5358;&#x7D14;&#x306A;&#x8033;&#x5C0F;&#x80DE;&#x3092;&#x5909;&#x63DB;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x5FC5;&#x8981;&#x306A;&#x5287;&#x7684;&#x306A;&#x5909;&#x5316;&#x3092;&#x793A;&#x3057;&#x3001;&#x305D;&#x308C;&#x304C;&#x5B9F;&#x9A13;&#x7684;&#x307E;&#x305F;&#x306F;&#x907A;&#x4F1D;&#x7684;&#x306B;&#x8868;&#x73FE;&#x578B;&#x540C;&#x5B9A;&#x306E;&#x305F;&#x3081;&#x306E;&#x57FA;&#x790E;&#x3068;&#x3057;&#x3066;&#x5F79;&#x7ACB;&#x3064;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x308B;&#x8033;&#x3092;&#x64CD;&#x4F5C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3002;

&#x30A2;&#x30D5;&#x30EA;&#x30AB;&#x30C4;&#x30E1;&#x30AC;&#x30A8;&#x30EB;&#x306B;&#x304A;&#x3051;&#x308B;&#x5185;&#x8033;&#x306E;&#x958B;&#x767A;&#x306E;&#x4E09;&#x6B21;&#x5143;&#x5F62;&#x614B;

Xenopus laevis&#xC758; membranous &#xBBF8;&#xB85C;&#xC758; 3 &#xCC28;&#xC6D0; &#xD615;&#xD0DC;&#xB294; &#xB2A6;&#xC740; &#xC62C;&#xCC59;&#xC774; &#xAC1C;&#xBC1C; (&#xB2E8;&#xACC4; &#xD3EC;&#xD568; 52 &#xD558; 28)&#xC744; &#xD1B5;&#xD574; &#xBC30;&#xC544;&#xC5D0;&#xC11C; &#xC81C;&#xACF5; &#xB429;&#xB2C8;&#xB2E4;. &#xC774;&#xAC83;&#xC740; &#xD398;&#xC778;&#xD2B8; &#xCC44;&#xC6B0;&#xAE30; &#xB2E8;&#xACC4; &#xC2DC;&#xB9AC;&#xC988; Xenopus &#xADC0; endolymphatic &#xACF5;&#xAC04;, &#xBC30;&#xC544; otic &#xC18C;&#xD3EC;&#xC640; &#xC2DC;&#xC791;&#xACFC; &#xB05D; &#xD6C4;&#xBC18; &#xC62C;&#xCC59;&#xC774;&#xC758; &#xBCF5;&#xC7A1; &#xD55C; &#xADC0;&#xC5D0; &#xC758;&#xD574; &#xB2EC;&#xC131; &#xD588;&#xC2B5;&#xB2C8;&#xB2E4;. 52 &#xB2E8;&#xACC4;&#xC5D0;&#xC11C; &#xB0B4;&#xAC00; &#xC55E;&#xCABD; &#xC5D0;/&#xD6C4;&#xBD80; &#xCC28;&#xC6D0; &#xBB34;&#xB300; 28&#xC5D0; &#xBE44;&#xD574; &#xC57D; 23-fold &#xD655;&#xC7A5; &#xADF8;&#xB9AC;&#xACE0; &#xC131;&#xC778; &#xD3FC;&#xC758; &#xBBF8;&#xB2C8;&#xC5B4;&#xCC98;. &#xD398;&#xC778;&#xD2B8; &#xCC44;&#xC6B0;&#xAE30; &#xAE30;&#xC220;&#xC740; &#xC815;&#xAD50;&#xD55C; &#xD615;&#xD0DC;&#xC758; &#xBC18;&#xC6D0;&#xC758; &#xC6B4;&#xD558; &#xD615;&#xC131;&#xACFC; vestibular &#xCCAD;&#xAC01; &#xAE30;&#xAD00;&#xC758; &#xCC3D;&#xC138;&#xAE30;&#xB97C; &#xD3EC;&#xD568; &#xD558; &#xC5EC; &#xC131;&#xC778;&#xC73C;&#xB85C; &#xAC04;&#xB2E8;&#xD55C; &#xADC0; &#xAE30;&#xB97C; &#xBCC0;&#xD658; &#xD558;&#xB294; &#xB370; &#xD544;&#xC694;&#xD55C; &#xADF9;&#xC801;&#xC778; &#xBCC0;&#xD654; &#xC774;&#xBA70; &#xC2E4;&#xD5D8;&#xC801;&#xC73C;&#xB85C; &#xB610;&#xB294; &#xC720;&#xC804;&#xC790; &#xC870;&#xC791; &#xADC0;&#xC5D0;&#xC11C; &#xD615; &#xC2DD;&#xBCC4;&#xC744; &#xC704;&#xD55C; &#xAE30;&#xBC18;&#xC73C;&#xB85C; &#xC0AC;&#xC6A9;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

Xenopus laevis&#xC758; &#xB0B4;&#xAC00; &#xAC1C;&#xBC1C;&#xC758; 3 &#xCC28;&#xC6D0; &#xD615;&#xD0DC;.

La morfolog&#xED;a en tres dimensiones del laberinto membranoso de Xenopus laevis se presenta a partir de embriones a trav&#xE9;s del desarrollo de renacuajos tard&#xED;a (etapas 28 a 52, ambos inclusive). Esto se logr&#xF3; mediante pintura de llenado de los espacios endolinf&#xE1;tico de orejas de Xenopus en una serie de etapas, comenzando con la ves&#xED;cula &#xF3;tica embrionario y terminando con la oreja del complejo renacuajo tarde. En la etapa 52, el o&#xED;do interno se ha expandido aproximadamente 23 veces en su dimensi&#xF3;n anterior / posterior en comparaci&#xF3;n con la etapa 28 y es una miniatura de la forma adulta. La t&#xE9;cnica de pintura llenado ilustra los cambios dram&#xE1;ticos necesarias para convertir una ves&#xED;cula oreja simple en la forma elaborada del adulto, incluyendo la formaci&#xF3;n del canal semicircular y la g&#xE9;nesis de &#xF3;rganos vestibulares y auditivas, y que puede servir como una base para la identificaci&#xF3;n fenotipo en experimentalmente o gen&#xE9;ticamente manipulado orejas.

Tridimensional Morfolog&#xED;a del desarrollo del o&#xED;do interno en Xenopus laevis

A key neurotrophin responsible for the survival and function of basal forebrain (BF) cholinergic neurons is brain-derived neurotrophic factor (BDNF). A number of studies now indicate that a source of this factor may be BF astrocytes. This study was designed to define the role of BF-astrocyte-derived BDNF on cholinergic neurons. Moreover, it investigated regulatory events that modulate BDNF content and release. In initial work BDNF derived from BF-astrocyte-conditioned medium (ACM) was found to increase both numbers of BF acetylcholinesterase (AChE+) cholinergic neurons and the cholinergic synthetic enzyme choline acetyltransferase (ChAT). Western blots, immunocytochemistry and pharmacological inhibition studies revealed that glutamate, through group I metabotropic glutamate receptors (mGluR), increases the intracellular levels of BDNF in BF astrocytes in culture, as well as its release. Furthermore, the release of BDNF is mediated by the actions of PLC, IP3 and internal stores of Ca2+. These results suggest that BF astrocytes serve as local sources of BDNF for cholinergic neurons, and that they may be regulated as such by the neuronal signal, glutamate, through the mediation of group I metabotropic receptors and the PLC pathway.

Glutamate elicits release of BDNF from basal forebrain astrocytes in a process dependent on metabotropic receptors and the PLC pathway.

&#x6700;&#x8FD1;&#x7684;&#x7814;&#x7A76;&#x8868;&#x660E;&#x795E;&#x7ECF;&#x80BD; VGF (nonacronymic) &#x53D7;&#x6D77;&#x9A6C;&#x6297;&#x6291;&#x90C1;&#x836F;&#x7269;&#x7597;&#x6CD5;&#x548C;&#x6291;&#x90C1;&#x75C7;&#x52A8;&#x7269;&#x6A21;&#x578B;&#x7684;&#x548C; VGF &#x6CBB;&#x7597;&#x6025;&#x6027;&#x52A8;&#x7269;&#x8303;&#x5F0F;&#x4E2D;&#x5177;&#x6709;&#x7C7B;&#x4F3C;&#x6297;&#x6291;&#x90C1;&#x5242;&#x7684;&#x6D3B;&#x6027;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x5728;&#x4EBA;&#x7C7B;&#x7684;&#x7CBE;&#x795E;&#x7D0A;&#x4E71;&#x7684; VGF &#x4F5C;&#x7528;&#x672A;&#x77E5;&#x3002;&#x6211;&#x4EEC;&#x73B0;&#x5728;&#x6F14;&#x793A;&#x4F7F;&#x7528;&#x539F;&#x4F4D;&#x6742;&#x4EA4; VGF &#x662F;&#x5728;&#x8E81;&#x90C1;&#x75C7;&#x7684;&#x6D77;&#x9A6C;&#x548C;&#x524D;&#x989D;&#x53F6;&#x76AE;&#x5C42;&#x533A; 9 Brodmann &#x7684; CA &#x5730;&#x533A;&#x7F16;&#x7801;&#x3002;&#x63A2;&#x8BA8;&#x4E86; VGF &#x4E0E;&#x6C2F;&#x5316;&#x9502;&#x7684;&#x673A;&#x5236;&#x3002;&#x8FD9;&#x4E24;&#x4E2A;&#x6C2F;&#x5316;&#x9502;&#x8179;&#x8154; VGF &#x4FA7;&#x8111;&#x5BA4;&#x51CF;&#x5C11;&#x5EF6;&#x8FDF;&#x6709;&#x559D;&#x9152;&#x7684;&#x65B0;&#x5947;&#x8BF1;&#x5BFC;&#x7684; hypophagia &#x548C;&#x6C2F;&#x5316;&#x9502;&#x5E76;&#x975E;&#x6709;&#x6548; VGF(+/-) &#x5C0F;&#x9F20;&#xFF0C;&#x6697;&#x793A; VGF &#x53EF;&#x80FD;&#x6709;&#x52A9;&#x4E8E;&#x6B64;&#x54CD;&#x5E94;&#x6162;&#x6027;&#x6297;&#x6291;&#x90C1;&#x6CBB;&#x7597;&#x7684;&#x884C;&#x4E3A;&#x8FC7;&#x7A0B;&#x4E2D;&#x6C2F;&#x5316;&#x9502;&#x7684;&#x5F71;&#x54CD;&#x3002;&#x6D77;&#x9A6C;&#x6CE8;&#x5C04; VGF &#x4E5F;&#x66FE;&#x65B0;&#x578B;&#x6D3B;&#x52A8;&#x4E2D;&#x82EF;&#x4E19;&#x80FA;&#x8BF1;&#x5BFC; hyperlocomotion &#x6D4B;&#x5B9A;&#xFF0C;&#x56E0;&#x6B64;&#x6A21;&#x4EFF;&#x6C2F;&#x5316;&#x9502;&#x7684;&#x884C;&#x52A8;&#x8179;&#x8154;&#x6CE8;&#x5C04;&#x7CFB;&#x7EDF;&#x4E2D;&#xFF0C;phenocopies &#x8E81;&#x72C2;&#x7B49;&#x884C;&#x4E3A;&#x3002;&#x6B64;&#x5916;&#xFF0C;VGF(+/-) &#x5C0F;&#x9F20;&#x82EF;&#x4E19;&#x80FA;&#x6CBB;&#x7597;&#x540E;&#x5C55;&#x51FA;&#x589E;&#x52A0;&#x7684;&#x8FD0;&#x52A8;&#x548C;&#x6CA1;&#x6709;&#x56DE;&#x5E94;&#x6C2F;&#x5316;&#x9502;&#xFF0C;&#x6697;&#x793A; VGF &#x6C2F;&#x5316;&#x9502;&#x7684;&#x5F71;&#x54CD;&#x9700;&#x5728;&#x904F;&#x5236;&#x5BF9;&#x82EF;&#x4E19;&#x80FA;&#x7684;&#x53CD;&#x5E94;&#x3002;&#x6700;&#x540E;&#xFF0C;VGF &#x4EA4;&#x4ED8;&#x4F53;&#x5185;&#x4FA7;&#x8111;&#x5BA4;&#x6C2F;&#x5316;&#x9502;&#x4F5C;&#x4E3A;&#x76F8;&#x540C;&#x7684;&#x4FE1;&#x53F7;&#x901A;&#x8DEF;&#x7684;&#x6FC0;&#x6D3B;&#xFF0C;&#x6709;&#x5FC5;&#x8981;&#x4E3A;&#x8BF1;&#x5BFC;&#x4E1D;&#x88C2;&#x7D20;&#x6D3B;&#x5316;&#x86CB;&#x767D;&#x6FC0;&#x9176;&#x548C; Akt &#x7684;&#x6C2F;&#x5316;&#x9502;&#xFF0C;&#x56E0;&#x6B64;&#x8D37;&#x6B3E;&#x6D1E;&#x5BDF;&#x57FA;&#x7840;&#x7684; VGF &#x884C;&#x52A8;&#x7684;&#x5206;&#x5B50;&#x673A;&#x5236;&#x3002;&#x8E81;&#x90C1;&#x75C7;&#x7684; VGF &#x5931;&#x8C03;&#x4EE5;&#x53CA;&#x884C;&#x4E3A;&#x7C7B;&#x4F3C;&#x4E8E;&#x6C2F;&#x5316;&#x9502;&#x7684;&#x795E;&#x7ECF;&#x80BD;&#x7684;&#x5F71;&#x54CD;&#x8868;&#x660E; VGF &#x53EF;&#x80FD;&#x4F5C;&#x4E3A;&#x57FA;&#x7840;&#x7684;&#x8E81;&#x90C1;&#x75C7;&#x75C5;&#x7406;&#x751F;&#x7406;&#x5B66;&#x3002;

&#x795E;&#x7ECF;&#x80BD; VGF &#x4E24;&#x6781;&#x4E8B;&#x540E;&#x4EBA;&#x8111;&#x5728;&#x51CF;&#x5C11;&#xFF0C;&#x5E76;&#x6709;&#x52A9;&#x4E8E;&#x4E00;&#x4E9B;&#x884C;&#x4E3A;&#x548C;&#x5206;&#x5B50;&#x5F71;&#x54CD;&#x7684;&#x9502;&#x3002;

Recent studies demonstrate that the neuropeptide VGF (nonacronymic) is regulated in the hippocampus by antidepressant therapies and animal models of depression and that acute VGF treatment has antidepressant-like activity in animal paradigms. However, the role of VGF in human psychiatric disorders is unknown. We now demonstrate using in situ hybridization that VGF is downregulated in bipolar disorder in the CA region of the hippocampus and Brodmann's area 9 of the prefrontal cortex. The mechanism of VGF in relation to LiCl was explored. Both LiCl intraperitoneally and VGF intracerebroventricularly reduced latency to drink in novelty-induced hypophagia, and LiCl was not effective in VGF(+/-) mice, suggesting that VGF may contribute to the effects of LiCl in this behavioral procedure that responds to chronic antidepressant treatment. VGF by intrahippocampal injection also had novel activity in an amphetamine-induced hyperlocomotion assay, thus mimicking the actions of LiCl injected intraperitoneally in a system that phenocopies manic-like behavior. Moreover, VGF(+/-) mice exhibited increased locomotion after amphetamine treatment and did not respond to LiCl, suggesting that VGF is required for the effects of LiCl in curbing the response to amphetamine. Finally, VGF delivered intracerebroventricularly in vivo activated the same signaling pathways as LiCl and is necessary for the induction of mitogen-activated protein kinase and Akt by LiCl, thus lending insight into the molecular mechanisms underlying the actions of VGF. The dysregulation of VGF in bipolar disorder as well as the behavioral effects of the neuropeptide similar to LiCl suggests that VGF may underlie the pathophysiology of bipolar disorder.

The neuropeptide VGF is reduced in human bipolar postmortem brain and contributes to some of the behavioral and molecular effects of lithium.

Des &#xE9;tudes r&#xE9;centes d&#xE9;montrent que le VGF neuropeptide (nonacronymic) est r&#xE9;glement&#xE9;e dans l&#x26;#39;hippocampe par les th&#xE9;rapies antid&#xE9;pressives et des mod&#xE8;les animaux de d&#xE9;pression et que le traitement aigu VGF a antid&#xE9;presseur-comme l&#x26;#39;activit&#xE9; dans les paradigmes des animaux. Cependant, le r&#xF4;le de VGF dans les troubles psychiatriques de l&#x26;#39;homme est inconnu. Nous maintenant d&#xE9;montrer en utilisant l&#x26;#39;hybridation in situ qui VGF est diminu&#xE9;e dans le trouble bipolaire dans la r&#xE9;gion CA de l&#x26;#39;hippocampe et la zone de Brodmann 9 de la cortex pr&#xE9;frontal. Le m&#xE9;canisme de VGF dans le cadre de LiCl a &#xE9;t&#xE9; explor&#xE9;e. Les deux LiCl par voie intrap&#xE9;riton&#xE9;ale et VGF intrac&#xE9;r&#xE9;broventriculaire r&#xE9;duction de la latence &#xE0; boire dans la nouveaut&#xE9; induite par hypophagie, et LiCl n&#x26;#39;&#xE9;tait pas efficace pour VGF (+ / -) chez la souris, ce qui sugg&#xE8;re que VGF peut contribuer aux effets de LiCl dans cette proc&#xE9;dure de comportement qui r&#xE9;pond &#xE0; un traitement antid&#xE9;presseur chronique . VGF par injection intra-hippocampique ont eu une activit&#xE9; nouvelle dans un dosage hyperlocomotion amph&#xE9;tamines induite, imitant ainsi les actions de LiCl inject&#xE9; par voie intrap&#xE9;riton&#xE9;ale dans un syst&#xE8;me qui ph&#xE9;nocopies maniaco-comme le comportement. En outre, VGF (+ / -) des souris expos&#xE9;es locomotion augment&#xE9; apr&#xE8;s le traitement d&#x26;#39;amph&#xE9;tamine et de ne pas r&#xE9;pondre &#xE0; LiCl, ce qui sugg&#xE8;re que VGF est n&#xE9;cessaire pour les effets de LiCl dans la lutte contre la r&#xE9;ponse &#xE0; l&#x26;#39;amph&#xE9;tamine. Enfin, l&#x26;#39;AGV livr&#xE9; intrac&#xE9;r&#xE9;broventriculaire in vivo activ&#xE9; les voies de signalisation m&#xEA;mes que LiCl et est n&#xE9;cessaire pour l&#x26;#39;induction de la prot&#xE9;ine kinase activ&#xE9;e par le mitog&#xE8;ne et Akt par LiCl, donnant ainsi un aper&#xE7;u sur les m&#xE9;canismes mol&#xE9;culaires qui sous-tendent les actions de VGF. Le d&#xE9;r&#xE8;glement de la VGF dans le trouble bipolaire ainsi que les effets comportementaux de l&#x26;#39;neuropeptide similaire &#xE0; LiCl sugg&#xE8;re que VGF peut expliquer la physiopathologie du trouble bipolaire.

Le VGF neuropeptide est r&#xE9;duite dans le cerveau post-mortem humain bipolaire et contribue &#xE0; certains des effets comportementaux et mol&#xE9;culaires de la lithium

Neuere Studien zeigen, dass das Neuropeptid VGF (Nonacronymic) im Hippocampus durch antidepressive Therapien und Tiermodellen f&uuml;r Depression Regeln und VGF Akutbehandlung Antidepressivum viren&auml;hnliche Tier Paradigmenwechsel hat. Die Rolle der VGF in psychiatrischen St&ouml;rungen des Menschen ist jedoch unbekannt. Wir zeigen jetzt in situ-Hybridisierung, dass VGF Downregulated in bipolaren St&ouml;rung in der CA-Region des Hippocampus und Brodmanns-Areal 9 des pr&auml;frontalen Cortex ist. Der Mechanismus der VGF in Bezug auf LiCl wurde erforscht. Beide LiCl intraperitoneal VGF Intracerebroventricularly reduzierte Latenz Neuheit-induzierte Hypophagia zu trinken und LiCl war nicht wirksam bei VGF(+/-) M&auml;use, was darauf hindeutet, dass VGF auf die Auswirkungen der LiCl in diesem verhaltensbasierten Verfahren beitragen kann, die auf chronische antidepressiven Behandlung reagiert. VGF durch Intrahippocampal Injektion hatte auch neuartige Aktivit&auml;t in ein Amphetamin-induzierte Hyperlocomotion-Assay, so imitiert die Aktionen der LiCl injiziert intraperitoneal in einem System, dass Ph&auml;nokopien manisch-&auml;hnliches Verhalten. Dar&uuml;ber hinaus VGF(+/-) M&auml;use erh&ouml;hte Fortbewegung nach Amphetamin Behandlung ausgestellt und reagierte nicht auf LiCl, darauf hindeutet, dass die VGF f&uuml;r die Auswirkungen der LiCl erforderlich ist, die Reaktion auf Amphetamine einzuschr&auml;nken. Schlie&szlig;lich VGF geliefert Intracerebroventricularly in-vivo aktiviert die gleichen Signalwege als LiCl und ist notwendig f&uuml;r die Induktion von Mitogen-aktivierte Proteinkinase und Akt von LiCl, somit Einblick in die molekularen Mechanismen der Aktionen der VGF Kreditvergabe. Die Dysregulation der VGF in bipolaren St&ouml;rung sowie die verhaltensbasierten Auswirkungen das Neuropeptid LiCl &auml;hnlich zufolge VGF die Pathophysiologie der bipolaren St&ouml;rung zugrunde liegen k&ouml;nnten.

Das Neuropeptid VGF bipolar Post-mortem Gehirn reduziert ist und tr&auml;gt zur die Verhaltens- und Molekulare Effekte von Lithium.

Recenti studi dimostrano che il neuropeptide VGF (nonacronymic) &egrave; regolata nell&#39;ippocampo terapie antidepressivo e modelli animali di depressione e che trattamento acuto VGF ha antidepressivo-come attivit&agrave; in paradigmi di animali. Tuttavia, il ruolo del VGF in disturbi psichiatrici umane &egrave; sconosciuto. Abbiamo ora dimostrare tramite l&#39;ibridazione in situ che VGF &egrave; downregolata nel disturbo bipolare nella regione CA dell&#39;ippocampo e dell&#39;area di Brodmann 9 della corteccia prefrontale. Il meccanismo di VGF in relazione LiCl &egrave; stato esplorato. Entrambi LiCl intraperitoneale VGF intracerebroventricularly ridotta latenza a bere in hypophagia novit&agrave;-indotta e LiCl non era efficace nei topi VGF(+/-), suggerendo che VGF pu&ograve; contribuire agli effetti di LiCl in questa procedura comportamentale che risponde al trattamento antidepressivo cronica. VGF intrahippocampal iniezione aveva anche attivit&agrave; romanzo in un&#39;analisi hyperlocomotion indotta da Amfetamina, imitando cos&igrave; le azioni di LiCl iniettato per via intraperitoneale in un sistema che comportamento maniacale come fenocopie. Inoltre, VGF(+/-) topi esposti locomozione aumentata dopo il trattamento di anfetamine e non hanno risposto a LiCl, suggerendo che VGF &egrave; richiesta per gli effetti di LiCl nel frenare la risposta di anfetamine. Infine, VGF consegnato intracerebroventricularly in vivo attivato lo stessi segnalazione percorsi come LiCl ed &egrave; necessario per l&#39;induzione della chinasi di proteina mitogene-attivata e Akt di LiCl, prestito cos&igrave; approfondita i meccanismi molecolari sottostanti le azioni del VGF. La disregolazione del VGF nel disturbo bipolare, cos&igrave; come gli effetti del comportamento del neuropeptide simile a LiCl suggeriscono che VGF pu&ograve; essere alla base della fisiopatologia del disturbo bipolare.

Il neuropeptide VGF &egrave; ridotto nel cervello post-mortem bipolare umano e contribuisce ad alcuni degli effetti comportamentali e molecolari di litio.

&#x6700;&#x8FD1;&#x306E;&#x7814;&#x7A76;&#x3067;&#x306F;&#x3001;&#x795E;&#x7D4C;&#x30DA;&#x30D7;&#x30C1;&#x30C9;VGF&#xFF08;nonacronymic&#xFF09;&#x306F;&#x3046;&#x3064;&#x75C5;&#x306E;&#x6297;&#x3046;&#x3064;&#x85AC;&#x6CBB;&#x7642;&#x3068;&#x52D5;&#x7269;&#x30E2;&#x30C7;&#x30EB;&#x306B;&#x3088;&#x308B;&#x6D77;&#x99AC;&#x3067;&#x898F;&#x5236;&#x3057;&#x3001;&#x305D;&#x306E;&#x6025;&#x6027;VGF&#x6CBB;&#x7642;&#x306F;&#x52D5;&#x7269;&#x306E;&#x30D1;&#x30E9;&#x30C0;&#x30A4;&#x30E0;&#x3067;&#x306F;&#x6297;&#x3046;&#x3064;&#x69D8;&#x6D3B;&#x6027;&#x3092;&#x6709;&#x3057;&#x3066;&#x3044;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x30D2;&#x30C8;&#x306E;&#x7CBE;&#x795E;&#x75BE;&#x60A3;&#x306E;VGF&#x306E;&#x5F79;&#x5272;&#x306F;&#x4E0D;&#x660E;&#x3067;&#x3042;&#x308B;&#x3002;&#x6211;&#x3005;&#x306F;&#x4ECA;&#x3001;VGF&#x306F;&#x3001;&#x6D77;&#x99AC;&#x3068;&#x524D;&#x982D;&#x524D;&#x91CE;&#x306E;&#x30D6;&#x30ED;&#x30FC;&#x30C9;&#x30DE;&#x30F3;&#x306E;&#x9818;&#x57DF;9&#x306E;CA&#x9818;&#x57DF;&#x3067;&#x53CC;&#x6975;&#x6027;&#x969C;&#x5BB3;&#x3067;&#x30C0;&#x30A6;&#x30F3;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30C8;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3053;&#x3068;&#x3092;in situ&#x30CF;&#x30A4;&#x30D6;&#x30EA;&#x30C0;&#x30A4;&#x30BC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x3067;&#x306E;&#x4F7F;&#x7528;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002; LiCl&#x3068;&#x306E;&#x95A2;&#x4FC2;&#x3067;VGF&#x306E;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x304C;&#x691C;&#x8A0E;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002; LiCl&#x3092;&#x8179;&#x8154;&#x5185;&#x6295;&#x4E0E;&#x3068;VGF&#x306F;&#x4E21;&#x65B9;&#x3068;&#x3082;&#x8133;&#x5BA4;&#x5185;&#x30CE;&#x30D9;&#x30EB;&#x30C6;&#x30A3;&#x8A98;&#x8D77;hypophagia&#x306B;&#x98F2;&#x3080;&#x3088;&#x3046;&#x306B;&#x30EC;&#x30A4;&#x30C6;&#x30F3;&#x30B7;&#x3092;&#x6E1B;&#x5C11;&#x3057;&#x3001;&#x5869;&#x5316;&#x30EA;&#x30C1;&#x30A6;&#x30E0;&#x306F;&#x3001;VGF&#x306B;&#x52B9;&#x679C;&#x7684;&#x3067;&#x306F;&#x306A;&#x304B;&#x3063;&#x305F;&#xFF08;+ /  - &#xFF09;&#x30DE;&#x30A6;&#x30B9;&#x3067;&#x306F;&#x3001;VGF&#x306F;&#x3001;&#x6162;&#x6027;&#x6297;&#x3046;&#x3064;&#x85AC;&#x6CBB;&#x7642;&#x306B;&#x5FDC;&#x7B54;&#x3057;&#x3001;&#x3053;&#x306E;&#x884C;&#x52D5;&#x306E;&#x624B;&#x9806;&#x3067;LiCl&#x306E;&#x52B9;&#x679C;&#x306B;&#x8CA2;&#x732E;&#x3059;&#x308B;&#x304B;&#x3082;&#x3057;&#x308C;&#x306A;&#x3044;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;&#x6D77;&#x99AC;&#x5185;&#x6CE8;&#x5165;&#x306B;&#x3088;&#x308B;VGF&#x306F;&#x307E;&#x305F;&#x3001;&#x3053;&#x306E;&#x3088;&#x3046;&#x306B;&#x8E81;&#x306E;&#x3088;&#x3046;&#x306A;&#x52D5;&#x4F5C;&#x3092;phenocopies&#x30B7;&#x30B9;&#x30C6;&#x30E0;&#x306B;LiCl&#x3092;&#x8179;&#x8154;&#x5185;&#x6CE8;&#x5C04;&#x306E;&#x884C;&#x52D5;&#x3092;&#x6A21;&#x5023;&#x3057;&#x3001;&#x30A2;&#x30F3;&#x30D5;&#x30A7;&#x30BF;&#x30DF;&#x30F3;&#x8A98;&#x767A;&#x6027;hyperlocomotion&#x30A2;&#x30C3;&#x30BB;&#x30A4;&#x306B;&#x304A;&#x3051;&#x308B;&#x65B0;&#x898F;&#x6D3B;&#x6027;&#x3092;&#x6709;&#x3057;&#x3066;&#x3044;&#x305F;&#x3002;&#x307E;&#x305F;&#x3001;VGF&#xFF08;+ /  - &#xFF09;&#x30DE;&#x30A6;&#x30B9;&#x306F;&#x3001;&#x30A2;&#x30F3;&#x30D5;&#x30A7;&#x30BF;&#x30DF;&#x30F3;&#x306E;&#x6CBB;&#x7642;&#x5F8C;&#x306B;&#x5897;&#x52A0;&#x3057;&#x305F;&#x904B;&#x52D5;&#x3092;&#x793A;&#x3057;&#x3001;VGF&#x306F;&#x30A2;&#x30F3;&#x30D5;&#x30A7;&#x30BF;&#x30DF;&#x30F3;&#x3078;&#x306E;&#x5FDC;&#x7B54;&#x3092;&#x6291;&#x5236;&#x3059;&#x308B;&#x306B;&#x306F;LiCl&#x306E;&#x52B9;&#x679C;&#x306E;&#x305F;&#x3081;&#x306B;&#x5FC5;&#x8981;&#x3068;&#x3055;&#x308C;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3001;LiCl&#x306E;&#x306B;&#x5FDC;&#x7B54;&#x3057;&#x307E;&#x305B;&#x3093;&#x3067;&#x3057;&#x305F;&#x3002;&#x6700;&#x5F8C;&#x306B;&#x3001;VGF&#x306F;LiCl&#x3092;&#x540C;&#x3058;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x7D4C;&#x8DEF;&#x3092;&#x6D3B;&#x6027;&#x5316;&#x3057;&#x3001;in vivo&#x3067;&#x8133;&#x5BA4;&#x5185;&#x914D;&#x4FE1;&#x30DE;&#x30A4;&#x30C8;&#x30B8;&#x30A7;&#x30F3;&#x6D3B;&#x6027;&#x5316;&#x30D7;&#x30ED;&#x30C6;&#x30A4;&#x30F3;&#x30AD;&#x30CA;&#x30FC;&#x30BC;&#x304A;&#x3088;&#x3073;LiCl&#x306B;&#x3088;&#x308B;Akt&#x306E;&#x8A98;&#x5C0E;&#x306B;&#x5FC5;&#x8981;&#x3067;&#x3042;&#x308A;&#x3001;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;VGF&#x306E;&#x884C;&#x52D5;&#x306E;&#x6839;&#x5E95;&#x306B;&#x3042;&#x308B;&#x5206;&#x5B50;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3078;&#x306E;&#x6D1E;&#x5BDF;&#x3092;&#x8CB8;&#x3059;&#x3002;&#x53CC;&#x6975;&#x6027;&#x969C;&#x5BB3;&#x306B;&#x304A;&#x3051;&#x308B;VGF&#x306E;&#x8ABF;&#x7BC0;&#x4E0D;&#x5168;&#x3068;&#x540C;&#x69D8;&#x306B;&#x5869;&#x5316;&#x30EA;&#x30C1;&#x30A6;&#x30E0;&#x306B;&#x4F3C;&#x3066;&#x795E;&#x7D4C;&#x30DA;&#x30D7;&#x30C1;&#x30C9;&#x306E;&#x884C;&#x52D5;&#x3078;&#x306E;&#x5F71;&#x97FF;&#x306F;&#x3001;VGF&#x306F;&#x3001;&#x53CC;&#x6975;&#x6027;&#x969C;&#x5BB3;&#x306E;&#x75C5;&#x614B;&#x306E;&#x6839;&#x5E95;&#x306B;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

&#x30CB;&#x30E5;&#x30FC;&#x30ED;VGF&#x306F;&#x3001;&#x30D2;&#x30E5;&#x30FC;&#x30DE;&#x30F3;&#xB7;&#x30D0;&#x30A4;&#x30DD;&#x30FC;&#x30E9;&#x6B7B;&#x5F8C;&#x8133;&#x3067;&#x6E1B;&#x5C11;&#x3057;&#x3001;&#x30EA;&#x30C1;&#x30A6;&#x30E0;&#x306E;&#x884C;&#x52D5;&#x304A;&#x3088;&#x3073;&#x5206;&#x5B50;&#x52B9;&#x679C;&#x306E;&#x4E00;&#x90E8;&#x306B;&#x5BC4;&#x4E0E;&#x3059;&#x308B;

&#xCD5C;&#xADFC; &#xC5F0;&#xAD6C; &#xBCF4;&#xC5EC; neuropeptide VGF (nonacronymic)&#xC740; &#xD56D;&#xC6B0;&#xC6B8;&#xC81C; &#xCE58;&#xB8CC;&#xC640; &#xC6B0;&#xC6B8;&#xC99D;&#xC758; &#xB3D9;&#xBB3C; &#xBAA8;&#xB378;&#xC5D0; &#xC758;&#xD574; &#xD574; &#xB9C8;&#xC5D0;&#xC11C; &#xADDC;&#xC81C; &#xD558; &#xACE0; &#xAE09;&#xC131; VGF &#xCE58;&#xB8CC; &#xB3D9;&#xBB3C; &#xD328;&#xB7EC;&#xB2E4;&#xC784;&#xC5D0;&#xC11C; &#xD56D;&#xC6B0;&#xC6B8;&#xC81C; &#xAC19;&#xC740; &#xD65C;&#xB3D9;&#xC744; &#xD588;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, &#xC778;&#xAC04;&#xC758; &#xC815;&#xC2E0; &#xC7A5;&#xC560; VGF&#xC758; &#xC5ED;&#xD560;&#xC744; &#xC54C; &#xC218; &#xC788;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; &#xC9C0;&#xAE08; &#xC81C;&#xC790;&#xB9AC; &#xAD50; &#xC7A1; VGF&#xC740; &#xD574; &#xB9C8;&#xC640; &#xC804; &#xB450; &#xC5FD; &#xD53C; &#xC9C8;&#xC758; Brodmann&#xC758; &#xC601;&#xC5ED; 9&#xC758; &#xCE98;&#xB9AC;&#xD3EC;&#xB2C8;&#xC544; &#xC9C0;&#xC5ED;&#xC5D0; &#xC788;&#xB294; &#xC591;&#xADF9;&#xC131; &#xC9C8;&#xD658;&#xC5D0; &#xC788;&#xB294; downregulated&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xBCF4;&#xC5EC; &#xC90D;&#xB2C8;&#xB2E4;. VGF LiCl &#xAD00;&#xACC4; &#xBA54;&#xCEE4;&#xB2C8;&#xC998; &#xD0D0;&#xD5D8; &#xD588;&#xB2E4;. &#xB450; LiCl intraperitoneally VGF intracerebroventricularly &#xCC38;&#xC2E0; &#xC720;&#xB3C4; hypophagia&#xC5D0;&#xC11C; &#xB9C8;&#xC2DC;&#xB294; &#xB300;&#xAE30; &#xC2DC;&#xAC04; &#xAC10;&#xC18C;&#xC640; LiCl VGF &#xB9CC;&#xC131; &#xD56D;&#xC6B0;&#xC6B8;&#xC81C; &#xCE58;&#xB8CC;&#xC5D0; &#xC751;&#xB2F5; &#xD558;&#xB294;&#xC774; &#xD589;&#xB3D9; &#xC808;&#xCC28;&#xC5D0; Licl&#xC758; &#xD6A8;&#xACFC;&#xC5D0; &#xAE30;&#xC5EC;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xC81C;&#xC548; VGF(+/-) &#xB9C8;&#xC6B0;&#xC2A4;&#xC5D0; &#xD6A8;&#xACFC;&#xC801; &#xC774;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. VGF intrahippocampal &#xC8FC;&#xC785; &#xD558; &#xC5EC;&#xB3C4; &#xC554;&#xD398;&#xD0C0;&#xBBFC; &#xC720;&#xBC1C; hyperlocomotion &#xBD84;&#xC11D; &#xACB0;&#xACFC;&#xC5D0; &#xC18C;&#xC124; &#xD65C;&#xB3D9;&#xC744; &#xD588;&#xB2E4;, &#xB530;&#xB77C;&#xC11C; Licl&#xC758; &#xD589;&#xB3D9;&#xC744; &#xD749;&#xB0B4; &#xB0B8; intraperitoneally&#xC5D0; &#xC8FC;&#xC785; &#xD558;&#xB294; &#xC2DC;&#xC2A4;&#xD15C; phenocopies &#xC870; &#xBCD1;-&#xAC19;&#xC740; &#xB3D9;&#xC791;&#xC744; &#xD569;&#xB2C8;&#xB2E4;. &#xB610;&#xD55C;, VGF(+/-) &#xB9C8;&#xC6B0;&#xC2A4; &#xC554;&#xD398;&#xD0C0;&#xBBFC; &#xCE58;&#xB8CC; &#xD6C4; &#xC99D;&#xAC00; &#xC6B4;&#xB3D9;&#xC744; &#xC804;&#xC2DC; &#xD558; &#xACE0; LiCl VGF &#xC554;&#xD398;&#xD0C0;&#xBBFC;&#xC5D0; &#xB300; &#xD55C; &#xC751;&#xB2F5;&#xC774; &#xC5B5;&#xC81C;&#xC5D0; Licl&#xC758; &#xD6A8;&#xACFC; &#xB300; &#xD55C; &#xD544;&#xC694; &#xD558;&#xB2E4;&#xB294; &#xC81C;&#xC548;&#xC5D0; &#xC751;&#xB2F5; &#xD558;&#xC9C0; &#xC54A;&#xC558;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB9C8;&#xC9C0;&#xB9C9;&#xC73C;&#xB85C;, VGF intracerebroventricularly vivo&#xC5D0;&#xC11C; &#xBC30;&#xB2EC; Licl&#xB85C; &#xB3D9;&#xC77C;&#xD55C; &#xC2E0;&#xD638; &#xACBD;&#xB85C; &#xD65C;&#xC131;&#xD654; &#xD558; &#xACE0; &#xBB3C;&#xC9C8; &#xD65C;&#xC131;&#xD654; &#xD55C; &#xB2E8;&#xBC31;&#xC9C8; &#xD0A4; &#xB2C8; &#xC544; &#xC81C; &#xBC0F; Akt LiCl, &#xB530;&#xB77C;&#xC11C; VGF &#xC791;&#xC5C5; &#xAE30;&#xBCF8; &#xBD84;&#xC790; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC5D0; &#xB300; &#xD55C; &#xD1B5;&#xCC30;&#xB825;&#xC744; &#xB300;&#xCD9C; &#xD558; &#xC5EC; &#xC720;&#xB3C4;&#xC5D0; &#xD544;&#xC694;&#xD55C;. &#xC591;&#xADF9;&#xC131; &#xC7A5;&#xC560;&#xC5D0;&#xC11C; VGF dysregulation &#xBFD0;&#xB9CC; &#xC544;&#xB2C8;&#xB77C; &#xBE44;&#xC2B7;&#xD55C; LiCl neuropeptide&#xC758; &#xD589;&#xB3D9; &#xD6A8;&#xACFC; VGF &#xC591;&#xADF9;&#xC131; &#xC9C8;&#xD658;&#xC758; &#xC774;&#xC0C1; &#xAE30;&#xCD08; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xC81C;&#xC548; &#xD569;&#xB2C8;&#xB2E4;.

Neuropeptide VGF &#xC778;&#xAC04;&#xC758; &#xC591;&#xADF9; &#xC0AC;&#xD6C4; &#xB1CC;&#xC5D0;&#xC11C; &#xAC10;&#xC18C; &#xD558; &#xACE0; &#xB9AC;&#xD2AC;&#xC758; &#xD589;&#xB3D9; &#xBC0F; &#xBD84;&#xC790; &#xD6A8;&#xACFC; &#xC911; &#xC77C;&#xBD80;&#xC5D0; &#xAE30;&#xC5EC; &#xD55C;&#xB2E4;.

Estudios recientes demuestran que la alimentaci&#xF3;n de grupos vulnerables neurop&#xE9;ptido (nonacronymic) est&#xE1; regulada en el hipocampo de los tratamientos antidepresivos y los modelos animales de depresi&#xF3;n y que el tratamiento agudo de alimentaci&#xF3;n de grupos vulnerables tiene actividad antidepresiva en los paradigmas de los animales. Sin embargo, el papel de VGF en humanos trastornos psiqui&#xE1;tricos es desconocida. Ahora muestran el uso de la hibridaci&#xF3;n in situ que VGF es downregulated en el trastorno bipolar en la regi&#xF3;n CA del hipocampo y el &#xE1;rea de Brodmann 9 de la corteza prefrontal. El mecanismo de VGF en relaci&#xF3;n con LiCl fue explorada. Tanto LiCl intraperitonealmente y VGF intracerebroventricularmente reduce la latencia para beber en la novedad inducida hipofagia, y LiCl no era eficaz en VGF (+ / -) ratones, lo que sugiere que VGF puede contribuir a los efectos de LiCl en este procedimiento de comportamiento que responde al tratamiento antidepresivo cr&#xF3;nico . Alimentaci&#xF3;n de grupos vulnerables mediante la inyecci&#xF3;n intrahipocampal tambi&#xE9;n tuvo actividad novedosa en un ensayo hyperlocomotion inducida por las anfetaminas, imitando las acciones de v&#xED;a intraperitoneal de LiCl inyectado en un sistema que fenocopias man&#xED;aco-como comportamiento. Adem&#xE1;s, VGF (+ / -) ratones expuestos locomoci&#xF3;n aument&#xF3; despu&#xE9;s de tratamiento con anfetaminas y no respondi&#xF3; a LiCl, lo que sugiere que VGF es necesario para los efectos de LiCl en la reducci&#xF3;n de la respuesta a la anfetamina. Por &#xFA;ltimo, VGF entrega intracerebroventricular en vivo activa las mismas v&#xED;as de se&#xF1;alizaci&#xF3;n como LiCl y es necesaria para la inducci&#xF3;n de la prote&#xED;na quinasa activada por mit&#xF3;genos y Akt por LiCl, lo cual proporciona informaci&#xF3;n sobre los mecanismos moleculares que subyacen a las acciones de alimentaci&#xF3;n de grupos vulnerables. La desregulaci&#xF3;n de la alimentaci&#xF3;n de grupos vulnerables en el trastorno bipolar, as&#xED; como los efectos sobre el comportamiento del neurop&#xE9;ptido similar a LiCl sugiere que la alimentaci&#xF3;n de grupos vulnerables puede ser la base de la fisiopatolog&#xED;a del trastorno bipolar.

El AGV es la reducci&#xF3;n de neurop&#xE9;ptido en el cerebro humano postmortem bipolar y contribuye a que muchos de los efectos conductuales y moleculares de litio

Caspases, initially identified as a family of proteases regulating cell death, have been found to have nonapoptotic functions as well. Some family members are critical for mediating programmed cell death in development. After development, caspases are downregulated in the nervous system, but continue to perform important nonapoptotic functions relevant for neurogenesis and synaptic plasticity. In neurodegenerative diseases, where aberrant neuronal death is an outstanding feature, there is an increase in caspase activity. The specific caspase death pathways leading to dysfunction and death have still not been fully clarified, despite the plethora of scientific literature addressing these issues. In this chapter, we will present the current knowledge of caspase activation and activity pathways, the current tools for examining caspases, and functions of caspases in the nervous system in health and in disease. Alzheimer's Disease, the most common neurodegenerative disorder, and cerebral ischemia, the most common cause of neurologic death, are used to illustrate our current understanding of death signaling in neurodegenerative diseases. A better understanding of how caspases function in health and disease would provide appropriate specific targets for the development of therapeutic interventions for these diseases. Life and death are exquisitely regulated at the cellular level from development through maturity. During development, neuronal death is the major factor shaping the nervous system. This death is mainly caspase-mediated apoptosis. Once the waves of developmental death have passed (death occurs at different times in different parts of the nervous system), there is downregulation of the death machinery, as the postmitotic neurons should live for the life of the organism. Aberrant neuronal death is a major part of neurodegenerative disorders, but there is still no clear understanding of the processes leading to the phenotypes of the various diseases. Even the type of death that occurs continues to be debated, whether it is apoptotic, necrotic, or autophagic, or some combination of these death mechanisms. Here, we will discuss the role that the caspases play in neuronal function, dysfunction, and death. First, we will discuss the regulation of caspase activation and activity. We will examine the current understanding of caspase function in developmental neuronal death and then illustrate the role of caspases in neuronal death in disease employing two diseases of neuronal loss, Alzheimer's Disease (AD), which is the most common chronic neurodegenerative disorder, and cerebral ischemia/stroke, the third most common cause of death in Western society, which is an acute neuronal disorder with chronic sequelae.

Regulation of caspases in the nervous system implications for functions in health and disease.

Caspase 2 was initially identified as a neuronally expressed developmentally down-regulated gene (HUGO gene nomenclature CASP2) and has been shown to be required for neuronal death induced by several stimuli, including NGF (nerve growth factor) deprivation and Aβ (β-amyloid). In non-neuronal cells the PIDDosome, composed of caspase 2 and two death adaptor proteins, PIDD (p53-inducible protein with a death domain) and RAIDD {RIP (receptor-interacting protein)-associated ICH-1 [ICE (interleukin-1β-converting enzyme)/CED-3 (cell-death determining 3) homologue 1] protein with a death domain}, has been proposed as the caspase 2 activation complex, although the absolute requirement for the PIDDosome is not clear. To investigate the requirement for the PIDDosome in caspase-2-dependent neuronal death, we have examined the necessity for each component in induction of active caspase 2 and in execution of caspase-2-dependent neuronal death. We find that both NGF deprivation and Aβ treatment of neurons induce active caspase 2 and that induction of this activity depends on expression of RAIDD, but is independent of PIDD expression. We show that treatment of wild-type or PIDD-null neurons with Aβ or NGF deprivation induces formation of a complex of caspase 2 and RAIDD. We also show that caspase-2-dependent execution of neurons requires RAIDD, not PIDD. Caspase 2 activity can be induced in neurons from PIDD-null mice, and NGF deprivation or Aβ use caspase 2 and RAIDD to execute death of these neurons.

Neuronal caspase 2 activity and function requires RAIDD, but not PIDD.

Neuronal apoptotic death generally requires de novo transcription, and activation of the transcription factor c-Jun has been shown to be necessary in multiple neuronal death paradigms. Caspase-2 has been implicated in death of neuronal and non-neuronal cells, but its relationship to transcriptional activation has not been clearly elucidated. In the present study, using two different neuronal apoptotic paradigms, β-amyloid treatment and NGF (nerve growth factor) withdrawal, we examined the hierarchical role of caspase-2 activation in the transcriptional control of neuron death. Both paradigms induce rapid activation of caspase-2 as well as activation of the transcription factor c-Jun and subsequent induction of the pro-apoptotic BH3 (Bcl-homology domain 3)-only protein Bim (Bcl-2-interacting mediator of cell death). Caspase-2 activation is dependent on the adaptor protein RAIDD {RIP (receptor-interacting protein)-associated ICH-1 [ICE (interleukin-1β-converting enzyme)/CED-3 (cell-death determining 3) homologue 1] protein with a death domain}, and both caspase-2 and RAIDD are required for c-Jun activation and Bim induction. The present study thus shows that rapid caspase-2 activation is essential for c-Jun activation and Bim induction in neurons subjected to apoptotic stimuli. This places caspase-2 at an apical position in the apoptotic cascade and demonstrates for the first time that caspase-2 can regulate transcription.

Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death.

In Alzheimer's disease (AD) brain, exposure of axons to Aβ causes pathogenic changes that spread retrogradely by unknown mechanisms, affecting the entire neuron. We found that locally applied Aβ1-42 initiates axonal synthesis of a defined set of proteins including the transcription factor ATF4. Inhibition of local translation and retrograde transport or knockdown of axonal Atf4 mRNA abolished Aβ-induced ATF4 transcriptional activity and cell loss. Aβ1-42 injection into the dentate gyrus (DG) of mice caused loss of forebrain neurons whose axons project to the DG. Protein synthesis and Atf4 mRNA were upregulated in these axons, and coinjection of Atf4 siRNA into the DG reduced the effects of Aβ1-42 in the forebrain. ATF4 protein and transcripts were found with greater frequency in axons in the brain of AD patients. These results reveal an active role for intra-axonal translation in neurodegeneration and identify ATF4 as a mediator for the spread of AD pathology.

Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions.

Specific therapies for neurologic diseases such as Alzheimer's disease provide the potential for better clinical outcomes. Expression of caspases in the brain is developmentally regulated, and dysregulated in neurologic disease, supporting that caspases may be therapeutic targets. The activity of caspases is carefully regulated via binding partners, cleavage, or endogenous inhibitors to prevent spontaneous activation, which could lead to aberrant cell death. This review serves as a brief examination of the current understanding of the regulation and function of caspases, and approaches to specifically target aberrant caspase activity. The use of proper tools to investigate individual caspases is addressed. Moreover, it summarizes the reports of various caspases in Alzheimer's disease studies. A better understanding of specific caspase pathways in heath and neurodegenerative disease is crucial for identifying specific targets for the development of therapeutic interventions.

Caspases: therapeutic targets in neurologic disease.

Lissencephaly is a malformation of cortical development typically caused by deficient neuronal migration resulting in cortical thickening and reduced gyration. Here we describe a "thin" lissencephaly (TLIS) variant characterized by megalencephaly, frontal predominant pachygyria, intellectual disability, and seizures. Trio-based whole-exome sequencing and targeted re-sequencing identified recessive mutations of CRADD in six individuals with TLIS from four unrelated families of diverse ethnic backgrounds. CRADD (also known as RAIDD) is a death-domain-containing adaptor protein that oligomerizes with PIDD and caspase-2 to initiate apoptosis. TLIS variants cluster in the CRADD death domain, a platform for interaction with other death-domain-containing proteins including PIDD. Although caspase-2 is expressed in the developing mammalian brain, little is known about its role in cortical development. CRADD/caspase-2 signaling is implicated in neurotrophic factor withdrawal- and amyloid-β-induced dendritic spine collapse and neuronal apoptosis, suggesting a role in cortical sculpting and plasticity. TLIS-associated CRADD variants do not disrupt interactions with caspase-2 or PIDD in co-immunoprecipitation assays, but still abolish CRADD's ability to activate caspase-2, resulting in reduced neuronal apoptosis in vitro. Homozygous Cradd knockout mice display megalencephaly and seizures without obvious defects in cortical lamination, supporting a role for CRADD/caspase-2 signaling in mammalian brain development. Megalencephaly and lissencephaly associated with defective programmed cell death from loss of CRADD function in humans implicate reduced apoptosis as an important pathophysiological mechanism of cortical malformation. Our data suggest that CRADD/caspase-2 signaling is critical for normal gyration of the developing human neocortex and for normal cognitive ability.

Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant.

Central nervous system ischemic injury features neuronal dysfunction, inflammation and breakdown of vascular integrity. Here we show that activation of endothelial caspase-9 after hypoxia-ischemia is a critical event in subsequent dysfunction of the blood-retina barrier, using a panel of interrelated ophthalmic in vivo imaging measures in a mouse model of retinal vein occlusion (RVO). Rapid nonapoptotic activation of caspase-9 and its downstream effector caspase-7 in endothelial cells promotes capillary ischemia and retinal neurodegeneration. Topical eye-drop delivery of a highly selective caspase-9 inhibitor provides morphological and functional retinal protection. Inducible endothelial-specific caspase-9 deletion phenocopies this protection, with attenuated retinal edema, reduced inflammation and preserved neuroretinal morphology and function following RVO. These results reveal a non-apoptotic function of endothelial caspase-9 which regulates blood-retina barrier integrity and neuronal survival, and identify caspase-9 as a therapeutic target in neurovascular disease.

Endothelial activation of caspase-9 promotes neurovascular injury in retinal vein occlusion.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ArticleTotal : 2	Year
Publication title Cited by 40	2015
Publication title Cited by 4	2022

Article	Year
Three-dimensional morphology of inner ear development in Xenopus laevis. Developmental dynamics : an official publication of the American Association of Anatomists\| PubMed ID: 12815629	2003
Glutamate elicits release of BDNF from basal forebrain astrocytes in a process dependent on metabotropic receptors and the PLC pathway. Neuron glia biology\| PubMed ID: 19267952	2008
The neuropeptide VGF is reduced in human bipolar postmortem brain and contributes to some of the behavioral and molecular effects of lithium. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 20631166	2010
Regulation of caspases in the nervous system implications for functions in health and disease. Progress in molecular biology and translational science\| PubMed ID: 21238939	2011
Neuronal caspase 2 activity and function requires RAIDD, but not PIDD. The Biochemical journal\| PubMed ID: 22515271	2012
Caspase-2 is essential for c-Jun transcriptional activation and Bim induction in neuron death. The Biochemical journal\| PubMed ID: 23815625	2013
Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell\| PubMed ID: 25171414	2014
Caspases: therapeutic targets in neurologic disease. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics\| PubMed ID: 25339539	2015
Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant. American journal of human genetics\| PubMed ID: 27773430	2016
Endothelial activation of caspase-9 promotes neurovascular injury in retinal vein occlusion. Nature communications\| PubMed ID: 32576823	2020
Author Correction: Endothelial activation of caspase-9 promotes neurovascular injury in retinal vein occlusion. Nature communications\| PubMed ID: 32647109	2020

Ying Y. Jean

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