simple-and-computer-assisted-olfactory-testing-for-mice

Simple and Computer-assisted Olfactory Testing for Mice

Olfaction is highly conserved among species and is required for reproduction and survival.
In humans, olfaction is also one of the senses that is affected ...

University of Fribourg

Phagosomal pH is thought to play an important role in the antimicrobial activity of polymorphonuclear leukocytes (PMNs). In this study, we set up a method for a rapid and accurate measurement of phagosomal pH in PMNs with the use of Candida albicans doubly labeled with a pH-insensitive and a pH-sensitive probe and flow cytometry.

Measurement of phagosomal pH of normal and CGD-like human neutrophils by dual fluorescence flow cytometry.

Midbrain dopaminergic neurons are the main source of dopamine in the mammalian central nervous system and are associated with one of the most prominent human neurological disorders, Parkinson's disease. During development, they are induced in the ventral midbrain by an interaction between two diffusible factors, SHH and FGF8. The local identity of this part of the midbrain is probably determined by the combinatorial expression of three transcription factors, Otx2, Pax2, and Pax5. After the last cell division, the neurons start to express transcription factors that control further differentiation and the manifestation of cellular properties characteristic for adult dopaminergic neurons of the substantia nigra compacta and the ventral tegmentum. The first to appear is the LIM-homeodomain transcription factor, Lmx1b. It is essential for the survival of these neurons, and it regulates the expression of another transcription factor, Pitx3, an activator of tyrosine hydroxylase. Lmx1b is followed by the orphan steroid receptor Nurr1. It is essential for the expression of the dopaminergic phenotype. Several genes involved in dopamine synthesis, transport, release, and reuptake are regulated by Nurr1. This requirement is specific to the midbrain dopaminergic neurons, since other populations of the same neurotransmitter phenotype develop normally in absence of the gene. A day after Nurr1, two homeodomain transcription factors, engrailed-1 and -2, are expressed. In animals deficient in the two genes, the midbrain dopaminergic neurons are generated, but then fail to differentiate and disappear very rapidly. Interestingly, alpha-synuclein, a gene recently linked to familial forms of Parkinson's disease, is regulated by engrailed-1 and -2.

Midbrain dopaminergic neurons: determination of their developmental fate by transcription factors.

The neuropathological hallmark of Parkinson's disease is the loss of dopaminergic neurons in the substantia nigra pars compacta, presumably mediated by apoptosis. The homeobox transcription factors engrailed 1 and engrailed 2 are expressed by this neuronal population from early in development to adulthood. Despite a large mid-hindbrain deletion in double mutants null for both genes, mesencephalic dopaminergic (mDA) neurons are induced, become postmitotic and acquire their neurotransmitter phenotype. However, at birth, no mDA neurons are left. We show that the entire population of these neurons is lost by E14 in the mutant animals, earlier than in any other described genetic model system for Parkinson's disease. This disappearance is caused by apoptosis revealed by the presence of activated caspase 3 in the dying tyrosine hydroxylase-positive mutant cells. Furthermore, using in vitro cell mixing experiments and RNA interference on primary cell culture of ventral midbrain we were able to show that the demise of mDA neurons in the mutant mice is due to a cell-autonomously requirement of the engrailed genes and not a result of the missing mid-hindbrain tissue. Gene silencing in the postmitotic neurons by RNA interference activates caspase 3 and induces apoptosis in less than 24 hours. This rapid induction of cell death in mDA neurons suggests that the engrailed genes participate directly in the regulation of apoptosis, a proposed mechanism for Parkinson's disease.

Engrailed genes are cell-autonomously required to prevent apoptosis in mesencephalic dopaminergic neurons.

As for any other cell population, the development, cell fate, and properties of mesencephalic dopaminergic (mesDA) neurons are ultimately controlled at the transcriptional level. The genes for two transcription factors Engrailed-1 ( En1) and Engrailed-2 ( En2) play an essential role in the development and maintenance of these cells. They belong to a family of genes that have been investigated in Drosophila for more than half a century. The products of these genes are all characterized by homeotic tissue transformation and a highly conserved protein sequence, the homeobox. En1 and En2 act upon at least two steps of the differentiation of mesDA neurons. They take part in the regionalization event, which gives rise to the neuroepithelium that provides the precursor cells in the ventral midbrain with the fibroblast growth factor 8 signal necessary for their induction. Additionally, these genes are required in postmitotic mesDA neurons in which they are expressed from embryonic day 12 continuously into adulthood. In mutant mice homozygous null for En1 and En2, the neurons are generated in the ventral midbrain, become postmitotic, and begin to express their neurotransmitter phenotype. However, thereafter, they rapidly die by apoptosis. Cell mixing experiments in vitro and in vivo have demonstrated that the engrailed requirement for the survival of mesDA neurons is cell-autonomous. The inactivation of engrailed by RNA interference induces apoptosis in less than 24 h. These data suggest that the engrailed genes control an essential mechanism for the survival of mesDA neurons.

Midbrain dopaminergic neurons: control of their cell fate by the engrailed transcription factors.

The homeobox transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic neurons in a cell-autonomous and gene-dose-dependent manner. Because of this requirement, the cells die by apoptosis when all four alleles of the Engrailed genes are genetically ablated (En1-/-;En2-/-). In the present study, we show that viable and fertile mice, heterozygous null for Engrailed-1 and homozygous null for Engrailed-2 (En1+/-;En2-/-), have an adult phenotype that resembles key pathological features of Parkinson's disease. Specifically, postnatal mutant mice exhibit a progressive degeneration of dopaminergic neurons in the substantia nigra during the first 3 mo of their lives, leading to diminished storage and release of dopamine in the caudate putamen, motor deficits similar to akinesia and bradykinesia, and a lower body weight. This genetic model may provide access to the molecular etiology for Parkinson's disease and could assist in the development of novel treatments for this neurodegenerative disorder.

Slow progressive degeneration of nigral dopaminergic neurons in postnatal Engrailed mutant mice.

Les bo&icirc;te hom&eacute;otique des facteurs de transcription Engrailed-1 et Engrailed-2 sont n&eacute;cessaires pour la survie des neurones dopaminergiques m&eacute;senc&eacute;phaliques d&#39;une mani&egrave;re autonome cellule et g&egrave;ne-dose-d&eacute;pendante. En raison de cette exigence, les cellules meurent par apoptose quand tous les quatre all&egrave;les des g&egrave;nes Engr&ecirc;l&eacute;s sont g&eacute;n&eacute;tiquement ablation (En1-/-;En2-/-). Dans la pr&eacute;sente &eacute;tude, nous montrons que viables et fertiles souris, null h&eacute;t&eacute;rozygote pour Engrailed-1 et null homozygote pour Engrailed-2 (En1 +/-;En2-/-), ont un ph&eacute;notype adult qui ressemble &agrave; des caract&eacute;ristiques pathologiques principales de la maladie de Parkinson. Plus pr&eacute;cis&eacute;ment, postnatals souris mutantes pr&eacute;sentent une d&eacute;g&eacute;n&eacute;rescence progressive des neurones dopaminergiques dans la substantia nigra pendant les 3 premiers mo de leur vie, conduisant &agrave; la diminution de stockage et la lib&eacute;ration de dopamine dans le noyau caud&eacute; putamen, automobiles de d&eacute;ficits semblables &agrave; l&#39;akin&eacute;sie et la bradykin&eacute;sie et un poids inf&eacute;rieur. Ce mod&egrave;le g&eacute;n&eacute;tique peut donner acc&egrave;s &agrave; l&#39;&eacute;tiologie mol&eacute;culaire pour la maladie de Parkinson et pourrait contribuer &agrave; l&#39;&eacute;laboration de nouveaux traitements pour cette maladie neurod&eacute;g&eacute;n&eacute;rative.

Lente d&eacute;g&eacute;n&eacute;rescence progressive des neurones dopaminergiques INEF chez des souris mutantes Engr&ecirc;l&eacute;s postnatals.

I fattori di trascrizione homeobox Engrailed-1 ed Engrailed-2 sono necessari per la sopravvivenza dei neuroni dopaminergici mesencefaliche in maniera autonoma delle cellule e gene-dose-dipendente. A causa di questo requisito, le cellule muoiono per apoptosi quando tutti e quattro gli alleli dei geni Engrailed sono geneticamente ablazione (En1-/-;EN2-/-). Nel presente studio, mostriamo che vitale e fertili topi, null eterozigoti per Engrailed-1 e null omozigoti per Engrailed-2 (En1 +;EN2-/-), hanno un fenotipo adulto che assomiglia a chiave caratteristiche patologiche della malattia di Parkinson. In particolare, topi mutanti postnatali mostrano una progressiva degenerazione dei neuroni dopaminergici nella substantia nigra, durante i primi 3 mo della loro vita, portando a diminuita stoccaggio e rilascio di dopamina nel caudato putamen, motore deficit simili a acinesia e bradicinesia e un peso inferiore del corpo. Questo modello genetico pu&ograve; fornire l&#39;accesso all&#39;eziologia molecolare per il morbo di Parkinson e potrebbe aiutare nello sviluppo di nuovi trattamenti per questa malattia neurodegenerativa.

Lenta progressiva degenerazione dei neuroni dopaminergici nigral in topi mutanti Engrailed postnatali.

Los factores de transcripci&oacute;n homeobox Engrailed 1 y 2 de Engrailed son necesarios para la supervivencia de las neuronas dopamin&eacute;rgicas mesencef&aacute;licas de manera c&eacute;lula aut&oacute;noma y dependiente de la dosis g&eacute;nica. Debido a este requisito, las c&eacute;lulas mueren por apoptosis cuando todos cuatro alelos de los genes angrelados son gen&eacute;ticamente ablaci&oacute;n (En1-/-;En2-/-). En el presente estudio, mostramos que viable y f&eacute;rtiles ratones, null heterozig&oacute;tico para Engrailed 1 y null homocig&oacute;tica para Engrailed-2 (En1 + /;En2-/-), tienen un fenotipo adulto que se asemeja a principales caracter&iacute;sticas patol&oacute;gicas de la enfermedad de Parkinson. Concretamente, postnatales ratones mutantes presentan una degeneraci&oacute;n progresiva de las neuronas dopamin&eacute;rgicas en la sustancia negra durante los primero 3 meses de sus vidas, conduce a la disminuci&oacute;n del almacenamiento y la liberaci&oacute;n de dopamina en el putamen caudado, motor d&eacute;ficits similares a aquinesia y bradiquinesia y un menor peso corporal. Este modelo gen&eacute;tico puede proporcionar acceso a la etiolog&iacute;a molecular de la enfermedad de Parkinson y podr&iacute;a ayudar en el desarrollo de nuevos tratamientos para este trastorno neurodegenerativo.

Lenta degeneraci&oacute;n progresiva de las neuronas dopamin&eacute;rgicas de nigral en ratones mutantes angrelados postnatales.

Los factores de transcripci&oacute;n homeodomain Engrailed 1 y 2 de Engrailed son necesarios para la supervivencia de las neuronas dopamin&eacute;rgicas mesencef&aacute;licas (mesDA) en una manera c&eacute;lula aut&oacute;noma y dependiente de la dosis g&eacute;nica. Ratones mutantes de homocigoto, deficientes de ambos genes (En1-/-;En2-/-), mueren al nacer y exhiben una p&eacute;rdida de todas las neuronas mesDA por mid-gestation. En los animales heterocigotos (En1 + /;En2-/-), que son viables y f&eacute;rtil, postnatal del mantenimiento del sistema dopamin&eacute;rgico nigrostriatal se aflige, conduce a una progresiva degeneraci&oacute;n espec&iacute;fica de esta subpoblaci&oacute;n y d&eacute;ficits moleculares y de comportamiento como la enfermedad de Parkinson.

Expresi&oacute;n elevada de P75NTR causa la muerte de las neuronas dopamin&eacute;rgicas de midbrain angrelado deficiente por la supresi&oacute;n de Erk1/2.

The homeodomain transcription factors Engrailed-1 and Engrailed-2 are required for the survival of mesencephalic dopaminergic (mesDA) neurons in a cell-autonomous and gene-dose-dependent manner. Homozygote mutant mice, deficient of both genes (En1-/-;En2-/-), die at birth and exhibit a loss of all mesDA neurons by mid-gestation. In heterozygote animals (En1+/-;En2-/-), which are viable and fertile, postnatal maintenance of the nigrostriatal dopaminergic system is afflicted, leading to a progressive degeneration specific to this subpopulation and Parkinson's disease-like molecular and behavioral deficits.

Elevated P75NTR expression causes death of engrailed-deficient midbrain dopaminergic neurons by Erk1/2 suppression.

L&#39;hom&eacute;odomaine des facteurs de transcription Engrailed-1 et Engrailed-2 sont n&eacute;cessaires pour la survie des neurones dopaminergiques m&eacute;senc&eacute;phaliques (mesDA) d&#39;une mani&egrave;re autonome cellule et g&egrave;ne-dose-d&eacute;pendante. Les souris mutantes homozygote, d&eacute;ficientes des deux g&egrave;nes (En1-/-;En2-/-), meurent &agrave; la naissance et pr&eacute;sentent une perte de neurones de mesDA tous par le milieu. Chez les animaux h&eacute;t&eacute;rozygotes (En1 +/-;En2-/-), qui sont viables et fertile, postnatal de maintenance du syst&egrave;me dopaminergique sont est afflig&eacute;, conduisant &agrave; une d&eacute;g&eacute;n&eacute;rescence progressive sp&eacute;cifique &agrave; cette sous-population et la maladie de Parkinson-comme les d&eacute;ficits mol&eacute;culaires et comportements.

Expression P75NTR &eacute;lev&eacute;e provoque la mort des neurones dopaminergiques m&eacute;senc&eacute;phale engr&ecirc;l&eacute; d&eacute;ficient par suppression de Erk1/2.

L&#39;homeodomain transcription factors Engrailed-1 ed Engrailed-2 sono necessari per la sopravvivenza dei neuroni dopaminergici mesencefaliche (mesDA) in maniera autonoma delle cellule e gene-dose-dipendente. Topi mutanti omozigote, carenti di entrambi i geni (En1-/-;EN2-/-), muoiono alla nascita e mostrano una perdita di tutti i neuroni mesDA da mid-gestation. Negli animali eterozigote (En1 +;EN2-/-), che sono vitali e fertili, postnatale manutenzione del sistema dopaminergico Sonografia &egrave; afflitto, portando ad una progressiva degenerazione specifica per questa sottopopolazione e morbo di Parkinson-come Deficit molecolare e comportamentale.

Elevata espressione P75NTR causa morte dei neuroni dopaminergici engrailed-carenti mesencefalo dalla soppressione di Erk1/2.

R&#xE9;cepteurs Notch (1-4) sont des prot&#xE9;ines membranaires qui, sur stilumation ligand, lib&#xE8;rent leurs domaines cytoplasmique &#xE0; servir en tant que facteurs de transcription. Notch-2 favorise la prolif&#xE9;ration &#xE0; la fois au cours du d&#xE9;veloppement et cancer, mais son r&#xF4;le dans la r&#xE9;ponse &#xE0; une l&#xE9;sion isch&#xE9;mique est moins bien compris. Le but de cette &#xE9;tude &#xE9;tait de comprendre si Notch-2 est induite apr&#xE8;s un AVC n&#xE9;onatal et d&#x26;#39;enqu&#xEA;ter sur sa pertinence fonctionnelle.

Course n&#xE9;onatale chez la souris provoque &#xE0; long terme des changements dans neuronale Notch-2 expression qui peut contribuer &#xE0; la l&#xE9;sion prolong&#xE9;e

Kerbe-Rezeptoren (1-4) sind Membranproteine, die auf Ligand Stilumation, lassen Sie ihre zytoplasmatischen Dom&auml;nen als Transkriptionsfaktoren dienen. Kerbe-2 f&ouml;rdert die Verbreitung sowohl w&auml;hrend der Entwicklung und Krebs, aber seine Rolle als Reaktion auf isch&auml;mische Verletzung ist weniger gut verstanden. Der Zweck dieser Studie war zu erkennen, ob Notch-2 nach neonataler Schlaganfall hervorgerufen wird und seine funktionelle Bedeutung zu untersuchen.

Neonatale Strich in den M&auml;usen verursacht langfristige Ver&auml;nderungen in neuronalen Notch-2-Ausdruck, der zu l&auml;ngeren Verletzungen beitragen kann.

Recettori tacca (1-4) sono proteine di membrana che il ligando stilumation, rilasciare i loro domini citoplasmatici a servire come fattori di trascrizione. Tacca-2 promuove la proliferazione sia durante lo sviluppo e il cancro, ma il ruolo in risposta alla lesione ischemica &egrave; meno ben inteso. Lo scopo di questo studio era di capire se la tacca-2 &egrave; indotta dopo stroke neonatale e di indagare la sua rilevanza funzionale.

Stroke neonatale nei topi provoca cambiamenti a lungo termine nell&#39;espressione di Notch-2 neuronali che possa contribuire al danno prolungato.

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Notch receptors (1-4) are membrane proteins that, on ligand stilumation, release their cytoplasmic domains to serve as transcription factors. Notch-2 promotes proliferation both during development and cancer, but its role in response to ischemic injury is less well understood. The purpose of this study was to understand whether Notch-2 is induced after neonatal stroke and to investigate its functional relevance.

Neonatal stroke in mice causes long-term changes in neuronal Notch-2 expression that may contribute to prolonged injury.

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&#xB178;&#xCE58; &#xC218;&#xC6A9; &#xCCB4; (1-4)&#xB294; &#xADF8; ligand stilumation&#xC5D0; &#xACF5;&#xAC1C; &#xB179;&#xC74C; &#xBC29;&#xC1A1; &#xC694;&#xC778;&#xC73C;&#xB85C; &#xADF8;&#xB4E4;&#xC758; &#xC138;&#xD3EC;&#xC9C8; &#xB3C4;&#xBA54;&#xC778; &#xB9C9; &#xB2E8;&#xBC31;&#xC9C8;. &#xB178;&#xCE58;-2 &#xAC1C;&#xBC1C; &#xBC0F; &#xC554;, &#xB3C4;&#xC911; &#xD655;&#xC0B0;&#xC744; &#xCD09;&#xC9C4; &#xD558;&#xC9C0;&#xB9CC; &#xD5C8; &#xD608; &#xC131; &#xC190;&#xC0C1;&#xC5D0; &#xB300; &#xD55C; &#xC751;&#xB2F5;&#xC5D0;&#xC11C;&#xC758; &#xC5ED;&#xD560;&#xC740; &#xB35C; &#xC798; &#xC774;&#xD574; &#xD569;&#xB2C8;&#xB2E4;. &#xC774; &#xC5F0;&#xAD6C;&#xC758; &#xBAA9;&#xC801;&#xC740; &#xB178;&#xCE58; 2 &#xC2E0;&#xC0DD;&#xC544; &#xB1CC;&#xC878;&#xC911; &#xD6C4; &#xC720;&#xBC1C; &#xC5EC;&#xBD80;&#xB97C; &#xC774;&#xD574; &#xD558; &#xACE0; &#xADF8;&#xAC83;&#xC758; &#xAE30;&#xB2A5;&#xC801; &#xAD00;&#xB828;&#xC131;&#xC744; &#xC870;&#xC0AC; &#xD588;&#xB2E4;.

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Receptores muesca (1-4) son prote&#xED;nas de membrana que, en stilumation ligando, liberan sus dominios citopl&#xE1;smicos de servir como factores de transcripci&#xF3;n. Notch-2 promueve la proliferaci&#xF3;n tanto durante el desarrollo y el c&#xE1;ncer, pero su papel en la respuesta a la lesi&#xF3;n isqu&#xE9;mica se entiende tan bien. El prop&#xF3;sito de este estudio fue conocer si Notch-2 se induce despu&#xE9;s del accidente cerebrovascular neonatal y para investigar su relevancia funcional.

Carrera neonatal en ratones provoca cambios a largo plazo en neuronal Notch-2 de expresi&#xF3;n que pueden contribuir a la lesi&#xF3;n de larga duraci&#xF3;n

Notch &#x5728;&#x4E2D;&#x67A2;&#x795E;&#x7ECF;&#x7CFB;&#x7EDF;&#x4E2D;&#x6700;&#x4E13;&#x653B;&#x7EC6;&#x80DE;&#x547D;&#x8FD0;&#x89C4;&#x8303;&#x7684;&#x4E0A;&#x4E0B;&#x6587;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x8BB8;&#x591A;&#x7814;&#x7A76;&#x8868;&#x660E;&#x7F3A;&#x53E3;&#x8FD8;&#x8C03;&#x8282;&#x795E;&#x7ECF;&#x5143;&#x7684;&#x5F62;&#x6001;&#x3001; &#x7A81;&#x89E6;&#x53EF;&#x5851;&#x6027;&#x3001; &#x5B66;&#x4E60;&#x548C;&#x8BB0;&#x5FC6;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x5C55;&#x793A; Notch1 &#x548C; Jagged1 &#x53CA;&#x5176;&#x914D;&#x4F53;&#x5728;&#x51FA;&#x5E2D;&#x7A81;&#x89E6;&#x540E;&#xFF0C;&#x548C;&#x8FD9; Notch &#x4FE1;&#x53F7;&#x5728;&#x795E;&#x7ECF;&#x5143;&#x7A81;&#x89E6;&#x6D3B;&#x52A8;&#x54CD;&#x5E94;&#x53D1;&#x751F;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x795E;&#x7ECF;&#x5143; Notch &#x4FE1;&#x53F7;&#x79EF;&#x6781;&#x5F27;/Arg3.1&#xFF0C;&#x8BF1;&#x5BFC;&#x6D3B;&#x6027;&#x7684;&#x57FA;&#x56E0;&#xFF0C;&#x6240;&#x9700;&#x7684;&#x7A81;&#x89E6;&#x53EF;&#x5851;&#x6027;&#x7684;&#x8C03;&#x8282;&#x3002;&#x5F27;/Arg3.1 &#x7A81;&#x53D8;&#x4F53;&#x795E;&#x7ECF;&#x5143;&#x86CB;&#x767D;&#x6C34;&#x89E3;&#x6D3B;&#x5316;&#x7684; Notch1 &#x88AB;&#x6270;&#x4E71;&#x4F53;&#x5185;&#x548C;&#x4F53;&#x5916;&#x3002;Notch1 &#x4EA7;&#x540E;&#x6D77;&#x9A6C;&#x7684;&#x6761;&#x4EF6;&#x5220;&#x9664;&#x4E2D;&#x65AD;&#x957F;&#x65F6;&#x7A0B;&#x589E;&#x5F3A; (LTP) &#x548C;&#x957F;&#x671F;&#x8427;&#x6761; (&#x6709;&#x9650;&#x516C;&#x53F8;) &#x548C;&#x5BFC;&#x81F4;&#x8D64;&#x5B57;&#x5728;&#x5B66;&#x4E60;&#x548C;&#x77ED;&#x671F;&#x8BB0;&#x5FC6;&#x3002;&#x56E0;&#x6B64;&#xFF0C;Notch &#x4FE1;&#x53F7;&#x52A8;&#x6001;&#x8C03;&#x8282;&#x795E;&#x7ECF;&#x5143;&#x6D3B;&#x52A8;&#x54CD;&#x5E94;&#x3001; &#x5F27;/Arg3.1 &#x662F;&#x4E0A;&#x4E0B;&#x6587;&#x76F8;&#x5173;&#x7684;&#x69FD;&#x53E3;&#x8C03;&#x538B;&#x5668;&#xFF0C;&#x548C; Notch1 &#x662F;&#x6709;&#x52A9;&#x4E8E;&#x8BB0;&#x5FC6;&#x5F62;&#x6210;&#x7684;&#x7A81;&#x89E6;&#x53EF;&#x5851;&#x6027;&#x7684;&#x5FC5;&#x8981;&#x6761;&#x4EF6;&#x3002;

&#x6D3B;&#x52A8;&#x8BF1;&#x5BFC;&#x795E;&#x7ECF;&#x5143; Notch &#x4FE1;&#x53F7;&#x9700;&#x8981;&#x5F27;/Arg3.1&#xFF0C;&#x5E76;&#x4E14;&#x662F;&#x5728;&#x7F51;&#x7EDC;&#x4E2D;&#x6D77;&#x9A6C;&#x7A81;&#x89E6;&#x53EF;&#x5851;&#x6027;&#x7684;&#x5FC5;&#x8981;&#x6761;&#x4EF6;&#x3002;

Notch signaling in the nervous system has been most studied in the context of cell fate specification. However, numerous studies have suggested that Notch also regulates neuronal morphology, synaptic plasticity, learning, and memory. Here we show that Notch1 and its ligand Jagged1 are present at the synapse, and that Notch signaling in neurons occurs in response to synaptic activity. In addition, neuronal Notch signaling is positively regulated by Arc/Arg3.1, an activity-induced gene required for synaptic plasticity. In Arc/Arg3.1 mutant neurons, the proteolytic activation of Notch1 is disrupted both in vivo and in vitro. Conditional deletion of Notch1 in the postnatal hippocampus disrupted both long-term potentiation (LTP) and long-term depression (LTD), and led to deficits in learning and short-term memory. Thus, Notch signaling is dynamically regulated in response to neuronal activity, Arc/Arg3.1 is a context-dependent Notch regulator, and Notch1 is required for the synaptic plasticity that contributes to memory formation.

Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks.

De signalisation Notch dans le syst&#xE8;me nerveux a &#xE9;t&#xE9; le plus &#xE9;tudi&#xE9; dans le cadre de la sp&#xE9;cification du destin cellulaire. Cependant, de nombreuses &#xE9;tudes ont sugg&#xE9;r&#xE9; que Notch r&#xE9;gule &#xE9;galement la morphologie neuronale, la plasticit&#xE9; synaptique, l&#x26;#39;apprentissage et la m&#xE9;moire. Ici, nous montrons que Notch1 et ses Jagged1 ligands sont pr&#xE9;sents &#xE0; la synapse, et que la signalisation Notch dans les neurones se produit en r&#xE9;ponse &#xE0; l&#x26;#39;activit&#xE9; synaptique. En outre, la signalisation Notch neuronale est r&#xE9;gul&#xE9;e positivement par Arc/Arg3.1, un g&#xE8;ne induit par l&#x26;#39;activit&#xE9;-requis pour la plasticit&#xE9; synaptique. En Arc/Arg3.1 neurones mutantes, l&#x26;#39;activation prot&#xE9;olytique de Notch1 est perturb&#xE9; &#xE0; la fois in vivo et in vitro. Suppression conditionnelle de Notch1 dans l&#x26;#39;hippocampe postnatale perturb&#xE9;e &#xE0; la fois potentialisation &#xE0; long terme (LTP) et d&#xE9;pression &#xE0; long terme (LTD), et a conduit &#xE0; des d&#xE9;ficits dans l&#x26;#39;apprentissage et m&#xE9;moire &#xE0; court terme. Ainsi, Notch est dynamiquement r&#xE9;gul&#xE9;e en r&#xE9;ponse &#xE0; l&#x26;#39;activit&#xE9; neuronale, Arc/Arg3.1 est un r&#xE9;gulateur de Notch d&#xE9;pendant du contexte, et Notch1 est n&#xE9;cessaire pour la plasticit&#xE9; synaptique qui contribue &#xE0; la formation de la m&#xE9;moire.

Signalisation Notch activit&#xE9; induite dans les neurones N&#xE9;cessite Arc/Arg3.1 et est essentiel pour la plasticit&#xE9; synaptique dans l&#x26;#39;hippocampe Networks

Kerbe, die Signalisierung im Nervensystem ist am meisten im Zusammenhang mit der Zelle-Schicksal-Spezifikation studiert worden. Allerdings haben zahlreiche Studien vorgeschlagen, dass Notch auch neuronale Morphologie, synaptische Plastizit&auml;t, lernen und Ged&auml;chtnis reguliert. Hier zeigen wir, dass Notch1 und seine Ligand Jagged1 an der Synapse sind und diese Kerbe signalisieren in den Neuronen als Reaktion auf synaptische Aktivit&auml;t wird. Neuronale Notch-Signalisierung wird dar&uuml;ber hinaus durch Arc/Arg3.1, eine Aktivit&auml;t induziert-gen f&uuml;r die synaptische Plastizit&auml;t positiv geregelt. In Arc/Arg3.1 mutant Neuronen ist die proteolytische Aktivierung des Notch1 sowohl in-vivo und in vitro gest&ouml;rt. Bedingte L&ouml;schung von Notch1 in der postnatalen Hippocampus gest&ouml;rt, langfristige Erm&ouml;glichung (LTP) und langfristige Depression (LTD) und f&uuml;hrte zu Defiziten im Lern- und kurzfristige Speicher. Also Notch Signalisierung wird dynamisch geregelt, als Reaktion auf die neuronale Aktivit&auml;t, Arc/Arg3.1 ist ein kontextabh&auml;ngig Notch-Regulator und Notch1 ist erforderlich f&uuml;r die synaptische Plastizit&auml;t, die zur Ged&auml;chtnisbildung beitr&auml;gt.

Aktivit&auml;t induziert Notch signalisieren in Neuronen erfordert Arc/Arg3.1 und essentiell f&uuml;r synaptische Plastizit&auml;t in hippocampale Netzwerke.

Tacca di segnalazione nel sistema nervoso &egrave; stato pi&ugrave; studiato nell&#39;ambito della specifica di destino delle cellule. Tuttavia, numerosi studi hanno suggerito che la tacca anche regola morfologia neuronale, plasticit&agrave; sinaptica, apprendimento e memoria. Qui vi mostriamo che Notch1 e suo ligando Jagged1 sono presenti presso le sinapsi, e tale segnalazione Notch in neuroni si verifica in risposta all&#39;attivit&agrave; sinaptica. Inoltre, segnalazione Notch neuronale positivamente &egrave; regolata da Arc/Arg3.1, un gene indotta da attivit&agrave; necessario per la plasticit&agrave; sinaptica. Nei neuroni mutanti Arc/Arg3.1, l&#39;attivazione proteolitica di Notch1 &egrave; perturbato in vivo e in vitro. Eliminazione condizionale di Notch1 nell&#39;ippocampo postnatale perturbato sia potenziamento a lungo termine (LTP) e depressione a lungo termine (LTD) e ha portato a deficit nella memoria a breve termine e apprendimento. Cos&igrave;, segnalazione Notch &egrave; regolata dinamicamente in risposta all&#39;attivit&agrave; neuronale, Arc/Arg3.1 &egrave; un regolatore di tacca dipendente dal contesto e Notch1 &egrave; richiesto per la plasticit&agrave; sinaptica che contribuisce alla formazione della memoria.

Indotta da attivit&agrave; Notch segnalazione in neuroni richiede Arc/Arg3.1 ed &egrave; essenziale per plasticit&agrave; sinaptica in reti hippocampal.

&#x795E;&#x7D4C;&#x7CFB;&#x306B;&#x304A;&#x3051;&#x308B;Notch&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x306E;&#x5F79;&#x5272;&#x306F;&#x3001;&#x307B;&#x3068;&#x3093;&#x3069;&#x306E;&#x7D30;&#x80DE;&#x306E;&#x904B;&#x547D;&#x4ED5;&#x69D8;&#x306E;&#x6587;&#x8108;&#x3067;&#x691C;&#x8A0E;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x591A;&#x304F;&#x306E;&#x7814;&#x7A76;&#x306F;&#x3001;&#x30CE;&#x30C3;&#x30C1;&#x3082;&#x795E;&#x7D4C;&#x5F62;&#x614B;&#x3001;&#x30B7;&#x30CA;&#x30D7;&#x30B9;&#x53EF;&#x5851;&#x6027;&#x3001;&#x5B66;&#x7FD2;&#x3001;&#x8A18;&#x61B6;&#x3092;&#x8ABF;&#x7BC0;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x793A;&#x5506;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x305F;Notch1&#x3068;&#x305D;&#x306E;&#x30EA;&#x30AC;&#x30F3;&#x30C9;Jagged1&#x306F;&#x30B7;&#x30CA;&#x30D7;&#x30B9;&#x306B;&#x5B58;&#x5728;&#x3059;&#x308B;&#x3068;&#x3001;&#x795E;&#x7D4C;&#x7D30;&#x80DE;&#x306E;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x305D;&#x306E;&#x30CE;&#x30C3;&#x30C1;&#x306F;&#x3001;&#x30B7;&#x30CA;&#x30D7;&#x30B9;&#x6D3B;&#x52D5;&#x306B;&#x5FDC;&#x7B54;&#x3057;&#x3066;&#x767A;&#x751F;&#x3057;&#x305F;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;&#x795E;&#x7D4C;&#x7D30;&#x80DE;&#x306E;Notch&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x3092;&#x7A4D;&#x6975;&#x7684;&#x306B;Arc/Arg3.1&#x3001;&#x30B7;&#x30CA;&#x30D7;&#x30B9;&#x53EF;&#x5851;&#x6027;&#x306B;&#x5FC5;&#x8981;&#x306A;&#x6D3B;&#x52D5;&#x306B;&#x3088;&#x3063;&#x3066;&#x8A98;&#x767A;&#x3055;&#x308C;&#x308B;&#x907A;&#x4F1D;&#x5B50;&#x306B;&#x3088;&#x3063;&#x3066;&#x898F;&#x5236;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002; Arc/Arg3.1&#x5909;&#x7570;&#x4F53;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x3067;&#x306F;&#x3001;Notch1&#x306E;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x5206;&#x89E3;&#x6D3B;&#x6027;&#x306F;&#x3001;in vivo&#x304A;&#x3088;&#x3073;in vitro&#x306E;&#x4E21;&#x65B9;&#x3067;&#x4E2D;&#x65AD;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x751F;&#x5F8C;&#x6D77;&#x99AC;&#x306B;&#x304A;&#x3051;&#x308B;Notch1&#x306E;&#x6761;&#x4EF6;&#x524A;&#x9664;&#x306F;&#x3001;&#x9577;&#x671F;&#x5897;&#x5F37;&#xFF08;LTP&#xFF09;&#x3068;&#x9577;&#x671F;&#x6291;&#x5727;&#xFF08;LTD&#xFF09;&#x306E;&#x4E21;&#x65B9;&#x3092;&#x7834;&#x58CA;&#x3057;&#x3001;&#x5B66;&#x7FD2;&#x3068;&#x77ED;&#x671F;&#x8A18;&#x61B6;&#x306E;&#x8D64;&#x5B57;&#x306B;&#x3064;&#x306A;&#x304C;&#x3063;&#x305F;&#x3002;&#x3057;&#x305F;&#x304C;&#x3063;&#x3066;&#x3001;Notch&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x306F;&#x795E;&#x7D4C;&#x6D3B;&#x52D5;&#x306B;&#x5FDC;&#x3058;&#x3066;&#x52D5;&#x7684;&#x306B;&#x8ABF;&#x6574;&#x3055;&#x308C;&#x3001;Arc/Arg3.1&#x306F;&#x3001;&#x30B3;&#x30F3;&#x30C6;&#x30AD;&#x30B9;&#x30C8;&#x4F9D;&#x5B58;&#x306E;&#x30CE;&#x30C3;&#x30C1;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30BF;&#x3067;&#x3059;&#x3001;&#x3068;Notch1&#x306F;&#x8A18;&#x61B6;&#x5F62;&#x6210;&#x306B;&#x5BC4;&#x4E0E;&#x3057;&#x3066;&#x30B7;&#x30CA;&#x30D7;&#x30B9;&#x53EF;&#x5851;&#x6027;&#x306B;&#x5FC5;&#x8981;&#x3068;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;

&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306E;&#x6D3B;&#x52D5;&#x306B;&#x3088;&#x3063;&#x3066;&#x8A98;&#x767A;&#x3055;&#x308C;&#x308B;Notch&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x306F;Arc/Arg3.1&#x3092;&#x5FC5;&#x8981;&#x3068;&#x3057;&#x3001;&#x6D77;&#x99AC;&#x30CD;&#x30C3;&#x30C8;&#x30EF;&#x30FC;&#x30AF;&#x306B;&#x304A;&#x3051;&#x308B;&#x30B7;&#x30CA;&#x30D7;&#x30B9;&#x53EF;&#x5851;&#x6027;&#x306B;&#x5FC5;&#x9808;&#x3067;&#x3042;&#x308B;

&#xB178;&#xCE58; &#xC2E0; &#xACBD;&#xACC4;&#xC5D0; &#xC2E0;&#xD638; &#xC138;&#xD3EC; &#xC6B4;&#xBA85; &#xADDC;&#xACA9;&#xC758; &#xB9E5;&#xB77D;&#xC5D0;&#xC11C; &#xAC00;&#xC7A5; &#xACF5;&#xBD80; &#xD558;&#xACE0;&#xC788;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, &#xB2E4; &#xC218;&#xC758; &#xC5F0;&#xAD6C;&#xB294; &#xB178;&#xCE58; &#xB610;&#xD55C; &#xC2E0;&#xACBD; &#xD615;&#xD0DC;&#xD559;, &#xC2DC; &#xB0C5; &#xC2A4;&#xAC00; &#xC18C;&#xC131;, &#xD559;&#xC2B5; &#xBC0F; &#xBA54;&#xBAA8;&#xB9AC; &#xC870;&#xC808; &#xAC74;&#xC758; &#xD588;&#xB2E4;. &#xC5EC;&#xAE30; &#xC6B0;&#xB9AC;&#xB294; Notch1 &#xBC0F; jagged1&#xC758; &#xB9AC;&#xAC04;&#xB4DC;&#xB97C; &#xB0C5;&#xC5D0; &#xC788;&#xB294;&#xC9C0; &#xADF8;&#xB9AC;&#xACE0; &#xC2DC; &#xB0C5; &#xC2A4; &#xD65C;&#xB3D9;&#xC5D0; &#xB300; &#xD55C; &#xC751;&#xB2F5;&#xC73C;&#xB85C; &#xBC1C;&#xC0DD; &#xD569;&#xB2C8;&#xB2E4; &#xADF8; &#xB178;&#xCE58; &#xC2E0;&#xACBD; &#xC138;&#xD3EC;&#xC5D0; &#xC2E0;&#xD638;&#xB97C; &#xBCF4;&#xC5EC;&#xC90D;&#xB2C8;&#xB2E4;. &#xB610;&#xD55C;, &#xC2E0;&#xACBD; &#xB178;&#xCE58; &#xC2E0;&#xD638;&#xB294; &#xAE0D;&#xC815;&#xC801;&#xC73C;&#xB85C; &#xD638;/Arg3.1, &#xC2DC; &#xB0C5; &#xC2A4;&#xAC00; &#xC18C;&#xC131;&#xC5D0; &#xD544;&#xC694;&#xD55C; &#xD65C;&#xB3D9; &#xC720;&#xBC1C; &#xC720;&#xC804;&#xC790;&#xB294;&#xC5D0; &#xC758;&#xD574; &#xADDC;&#xC81C; &#xB429;&#xB2C8;&#xB2E4;. &#xD638;/Arg3.1 &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xC2E0;&#xACBD; &#xC138;&#xD3EC;, &#xC0DD;&#xCCB4; &#xC870;&#xAC74; &#xBC0F; &#xC0DD;&#xCCB4; &#xC678;&#xC5D0;&#xC11C; notch1&#xC758; &#xB2E8;&#xBC31;&#xC9C8; &#xD65C;&#xC131;&#xD654;&#xB294; &#xC911;&#xB2E8; &#xB429;&#xB2C8;&#xB2E4;. &#xC0B0; &#xD6C4; &#xD574; &#xB9C8;&#xC5D0;&#xC11C; notch1&#xC758; &#xC870;&#xAC74;&#xBD80; &#xC0AD;&#xC81C; &#xC7A5;&#xAE30; potentiation (LTP)&#xC640; &#xC7A5;&#xAE30; &#xBD88;&#xD669; (&#xACF5;&#xC0AC;), &#xC911;&#xB2E8; &#xACE0; &#xD559;&#xC2B5;&#xACFC; &#xB2E8;&#xAE30; &#xBA54;&#xBAA8;&#xB9AC;&#xC5D0; &#xC801;&#xC790;. &#xB530;&#xB77C;&#xC11C;, &#xC2E0;&#xACBD; &#xD65C;&#xB3D9;&#xC5D0; &#xB300; &#xD55C; &#xC751;&#xB2F5;&#xC73C;&#xB85C; &#xB3D9;&#xC801;&#xC73C;&#xB85C; &#xADDC;&#xC81C;&#xB294; &#xB178;&#xCE58; &#xC2E0;&#xD638;, &#xC544;&#xD06C;/arg3.1&#xC740; &#xB9DE;&#xB294; &#xC218;&#xC900;&#xC758; &#xB808; &#xADE4; &#xB808;&#xC774; &#xD130;&#xB294; &#xBC0F; notch1&#xC740; &#xBA54;&#xBAA8;&#xB9AC; &#xD615;&#xC131;&#xC5D0; &#xAE30;&#xC5EC; &#xD558;&#xB294; &#xC2DC; &#xB0C5; &#xC2A4;&#xAC00; &#xC18C;&#xC131;&#xC5D0; &#xB300; &#xD55C; &#xD544;&#xC694;.

&#xC2E0;&#xACBD;&#xC5D0; &#xC788;&#xB294; &#xB178;&#xCE58; &#xC2E0;&#xD638; &#xD65C;&#xB3D9; &#xC720;&#xB3C4; &#xD638;/Arg3.1 &#xD544;&#xC694; &#xD558;&#xBA70; hippocampal &#xB124;&#xD2B8;&#xC6CC;&#xD06C;&#xC5D0;&#xC11C; &#xC2DC; &#xB0C5; &#xC2A4;&#xAC00; &#xC18C;&#xC131;&#xC5D0; &#xD544;&#xC218;&#xC801; &#xC774;&#xB2E4;.

De se&#xF1;alizaci&#xF3;n Notch en el sistema nervioso ha sido m&#xE1;s estudiado en el contexto de la especificaci&#xF3;n del destino celular. Sin embargo, numerosos estudios han sugerido que Notch regula tambi&#xE9;n la morfolog&#xED;a neuronal, la plasticidad sin&#xE1;ptica, el aprendizaje y la memoria. Aqu&#xED; nos muestran que Notch1 y sus ligandos Jagged1 est&#xE1;n presentes en la sinapsis, y que la se&#xF1;alizaci&#xF3;n Notch en las neuronas se produce en respuesta a la actividad sin&#xE1;ptica. Adem&#xE1;s, la se&#xF1;alizaci&#xF3;n de Notch neuronal est&#xE1; regulado positivamente por Arc/Arg3.1, un gen inducido por la actividad requerida para la plasticidad sin&#xE1;ptica. En Arc/Arg3.1 neuronas mutantes, la activaci&#xF3;n proteol&#xED;tica de Notch1 se interrumpe tanto in vivo como in vitro. La eliminaci&#xF3;n condicional de Notch1 en el hipocampo despu&#xE9;s del parto interrumpe tanto potenciaci&#xF3;n a largo plazo (LTP) y depresi&#xF3;n a largo plazo (LTD), y llev&#xF3; a los d&#xE9;ficits en el aprendizaje y la memoria a corto plazo. As&#xED;, la muesca de se&#xF1;alizaci&#xF3;n es regulado din&#xE1;micamente en respuesta a la actividad neuronal, Arc/Arg3.1 es un regulador de muesca dependiente del contexto, y Notch1 se requiere para la plasticidad sin&#xE1;ptica que contribuye a la formaci&#xF3;n de la memoria.

Actividad inducida por la se&#xF1;alizaci&#xF3;n de Notch en las neuronas requiere Arc/Arg3.1 y es esencial para la plasticidad sin&#xE1;ptica en hipocampo Redes

&#x51F9;&#x69FD;&#x901A;&#x8DEF;&#x662F;&#x8C03;&#x8282;&#x795E;&#x7ECF;&#x53D1;&#x80B2;&#x5728;&#x810A;&#x690E;&#x52A8;&#x7269;&#x4E2D;&#x7684;&#x5DF2;&#x77E5;&#x7684;&#x7A81;&#x51FA;&#x3002;&#x69FD;&#x53E3;&#x53D7;&#x4F53;&#x6FC0;&#x6D3B;&#x53EF;&#x4EE5;&#x6291;&#x5236;&#x795E;&#x7ECF;&#x518D;&#x751F;&#x3001; &#x7EF4;&#x6301;&#x795E;&#x7ECF;&#x524D;&#x4F53;&#x7EC6;&#x80DE;&#x7684;&#x5B57;&#x7B26;&#xFF0C;&#x548C;&#x5728;&#x67D0;&#x4E9B;&#x60C5;&#x51B5;&#x4E0B;&#x4FC3;&#x8FDB; gliogenesis &#x548C;&#x9A71;&#x52A8;&#x5668;&#x4E8C;&#x8FDB;&#x5236;&#x547D;&#x8FD0;&#x9009;&#x62E9;&#x3002;&#x6700;&#x8FD1;&#xFF0C;&#x4E00;&#x6CE2;&#x4EE4;&#x4EBA;&#x5174;&#x594B;&#x7684;&#x7814;&#x7A76;&#x51FA;&#x73B0;&#x4E86;&#xFF0C;&#x8FD9;&#x5DF2;&#x56FA;&#x5316;&#x4EE5;&#x524D;&#x4E3E;&#x884C;&#x7684;&#x65AD;&#x8A00;&#x548C;&#x6269;&#x5927;&#x6211;&#x4EEC;&#x7684;&#x7406;&#x89E3;&#x7684;&#x69FD;&#x53E3;&#x529F;&#x80FD;&#x795E;&#x7ECF;&#x53D1;&#x751F;&#x671F;&#x95F4;&#x6210;&#x4EBA;&#x5927;&#x8111;&#x4E2D;&#x3002;&#x8FD9;&#x4E9B;&#x7814;&#x7A76;&#x5BA1;&#x67E5;&#x4E86;&#x901A;&#x8DEF;&#x76D1;&#x7BA1;&#x673A;&#x6784;&#x548C;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#xFF0C;&#x4EE5;&#x53CA;&#x901A;&#x8DEF;&#x52A8;&#x529B;&#x5B66;&#x3001; &#x57FA;&#x56E0;&#x8868;&#x8FBE;&#x548C;&#x7EC6;&#x80DE;&#x4FE1;&#x53F7;&#x8F6C;&#x5BFC;&#x4E24;&#x65B9;&#x9762;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x91CD;&#x70B9;&#x4E3B;&#x8981;&#x810A;&#x690E;&#x52A8;&#x7269;&#xFF0C;&#x6211;&#x4EEC;&#x5F53;&#x524D;&#x6587;&#x5B66;&#x7814;&#x7A76;&#x8FDB;&#x5C55;&#x69FD;&#x53E3;&#x4FE1;&#x53F7;&#x5728;&#x4E2D;&#x67A2;&#x795E;&#x7ECF;&#x7CFB;&#x7EDF;&#x4E2D;&#xFF0C;&#x5E76;&#x7A81;&#x51FA;&#x663E;&#x793A;&#x8BB8;&#x591A;&#x6700;&#x8FD1;&#x7684;&#x7814;&#x7A76;&#x4EA7;&#x751F;&#x4E86;&#x6709;&#x8DA3;&#x548C;&#x610F;&#x60F3;&#x4E0D;&#x5230;&#x7684;&#x8FDB;&#x5C55;&#x3002;

&#x810A;&#x690E;&#x52A8;&#x7269;&#x7684;&#x4E2D;&#x67A2;&#x795E;&#x7ECF;&#x7CFB;&#x7EDF;&#x4E2D;&#x7684;&#x69FD;&#x53E3;: &#x8001;&#x72D7;&#x65B0;&#x628A;&#x620F;&#x3002;

The Notch pathway is prominent among those known to regulate neural development in vertebrates. Notch receptor activation can inhibit neurogenesis, maintain neural progenitor character, and in some contexts promote gliogenesis and drive binary fate choices. Recently, a wave of exciting studies has emerged, which has both solidified previously held assertions and expanded our understanding of Notch function during neurogenesis and in the adult brain. These studies have examined pathway regulators and interactions, as well as pathway dynamics, with respect to both gene expression and cell-cell signaling. Here, focusing primarily on vertebrates, we review the current literature on Notch signaling in the nervous system, and highlight numerous recent studies that have generated interesting and unexpected advances.

Notch in the vertebrate nervous system: an old dog with new tricks.

La voie Notch est importante parmi ceux connus pour r&#xE9;guler le d&#xE9;veloppement neuronal chez les vert&#xE9;br&#xE9;s. L&#x26;#39;activation du r&#xE9;cepteur Notch peut inhiber la neurogen&#xE8;se, de maintenir les caract&#xE9;ristiques prog&#xE9;nitrices neurales, et, dans certains contextes et des choix de promouvoir gliog&#xE9;n&#xE8;se entra&#xEE;nement binaires sort. R&#xE9;cemment, une vague d&#x26;#39;&#xE9;tudes passionnantes a &#xE9;merg&#xE9;, qui poss&#xE8;de &#xE0; la fois solidifi&#xE9; affirmations pr&#xE9;c&#xE9;demment d&#xE9;tenues et &#xE9;largi notre compr&#xE9;hension de la fonction Notch cours de la neurogen&#xE8;se et dans le cerveau adulte. Ces &#xE9;tudes ont examin&#xE9; les r&#xE9;gulateurs de la voie et les interactions, ainsi que la dynamique de la voie, &#xE0; l&#x26;#39;&#xE9;gard de l&#x26;#39;expression des g&#xE8;nes &#xE0; la fois de cellules et de la signalisation cellulaire. Ici, se concentrant principalement sur les vert&#xE9;br&#xE9;s, nous passons en revue la litt&#xE9;rature actuelle sur la signalisation Notch dans le syst&#xE8;me nerveux, et mettre en &#xE9;vidence de nombreuses &#xE9;tudes r&#xE9;centes qui ont g&#xE9;n&#xE9;r&#xE9; des avanc&#xE9;es int&#xE9;ressantes et inattendues.

Notch dans le syst&#xE8;me nerveux des vert&#xE9;br&#xE9;s: un vieux chien avec New Tricks

Der Notch-Signalweg ist prominent unter die bekannten neuralen Entwicklung bei Wirbeltieren zu regulieren. Notch-Rezeptor-Aktivierung kann hemmen Neurogenese, neuronalen Vorl&auml;uferzellen Charakter beizubehalten und in manchen Kontexten f&ouml;rdern Gliogenesis und mit dem bin&auml;ren Schicksal Entscheidungen. Vor kurzem hat eine Welle von spannenden Studien entstanden, die sowohl zuvor gehaltene Assertionen verfestigt und erweitert unser Verst&auml;ndnis von Notch-Funktion w&auml;hrend der Neurogenese und im erwachsenen Gehirn. Diese Studien haben Weg Regulierungsbeh&ouml;rden sowie Interaktionen und Weg-Dynamik, in Bezug auf die Genexpression und Zell-Zell-Signalisierung gepr&uuml;ft. Hier konzentrieren sich haupts&auml;chlich auf Wirbeltiere, wir &uuml;berpr&uuml;fen die aktuelle Literatur auf Notch im Nervensystem signalisieren, und markieren Sie zahlreiche aktuelle Studien, die interessante und unerwartete Fortschritte generiert haben.

Kerbe in der Wirbeltiere Nervensystem: ein alter Hund mit neuen Tricks.

Il pathway di Notch &egrave; prominente tra quelli noti per regolare lo sviluppo neurale nei vertebrati. Attivazione del recettore notch pu&ograve; inibire la neurogenesi, mantenere carattere progenitrici neurali e in alcuni contesti promuovere scelte binarie destino gliogenesis e unit&agrave;. Recentemente, &egrave; emersa un&#39;ondata di interessanti studi, che ha sia solidificato precedentemente tenute asserzioni e ampliato la nostra comprensione della funzione di tacca durante la neurogenesi e nel cervello adulto. Questi studi hanno esaminato pathway regolatori e interazioni, nonch&eacute; dinamiche di percorso, per quanto riguarda sia l&#39;espressione di gene e segnalazione della cellula-cellula. Qui, concentrandosi principalmente sui vertebrati, esaminiamo la letteratura corrente sulla tacca di segnalazione nel sistema nervoso ed evidenziare i numerosi studi recenti che hanno generato i progressi interessanti e inaspettati.

Tacca vertebrati del sistema nervoso: un vecchio cane con nuovi trucchi.

Notch&#x7D4C;&#x8DEF;&#x306F;&#x3001;&#x810A;&#x690E;&#x52D5;&#x7269;&#x306E;&#x795E;&#x7D4C;&#x767A;&#x751F;&#x3092;&#x8ABF;&#x7BC0;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x77E5;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#x3082;&#x306E;&#x306E;&#x9593;&#x3067;&#x9855;&#x8457;&#x3067;&#x3042;&#x308B;&#x3002; Notch&#x53D7;&#x5BB9;&#x4F53;&#x6D3B;&#x6027;&#x5316;&#x306F;&#x3001;&#x795E;&#x7D4C;&#x65B0;&#x751F;&#x3092;&#x6291;&#x5236;&#x3059;&#x308B;&#x795E;&#x7D4C;&#x524D;&#x99C6;&#x7D30;&#x80DE;&#x306E;&#x7279;&#x5FB4;&#x3092;&#x7DAD;&#x6301;&#x3057;&#x3001;&#x3044;&#x304F;&#x3064;&#x304B;&#x306E;&#x6587;&#x8108;&#x3067;gliogenesis&#x3068;&#x30C9;&#x30E9;&#x30A4;&#x30D6;&#x306E;&#x30D0;&#x30A4;&#x30CA;&#x30EA;&#x904B;&#x547D;&#x306E;&#x9078;&#x629E;&#x3092;&#x4FC3;&#x9032;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3002;&#x6700;&#x8FD1;&#x3067;&#x306F;&#x3001;&#x30A8;&#x30AD;&#x30B5;&#x30A4;&#x30C6;&#x30A3;&#x30F3;&#x30B0;&#x306A;&#x7814;&#x7A76;&#x306E;&#x6CE2;&#x306F;&#x3001;&#x4EE5;&#x524D;&#x306B;&#x958B;&#x50AC;&#x3055;&#x308C;&#x305F;&#x30A2;&#x30B5;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x3092;&#x56FA;&#x5316;&#x3057;&#x3066;&#x795E;&#x7D4C;&#x4E2D;&#x304A;&#x3088;&#x3073;&#x6210;&#x4F53;&#x8133;&#x306B;&#x304A;&#x3051;&#x308B;Notch&#x306E;&#x6A5F;&#x80FD;&#x306E;&#x7406;&#x89E3;&#x3092;&#x62E1;&#x5927;&#x3057;&#x3066;&#x3044;&#x308B;&#x3069;&#x3061;&#x3089;&#x3082;&#x3001;&#x6D6E;&#x4E0A;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x7814;&#x7A76;&#x306F;&#x3001;&#x907A;&#x4F1D;&#x5B50;&#x767A;&#x73FE;&#x3068;&#x7D30;&#x80DE;&#x9593;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x306E;&#x4E21;&#x65B9;&#x306B;&#x95A2;&#x3057;&#x3066;&#x3001;&#x7D4C;&#x8DEF;&#x306E;&#x898F;&#x5236;&#x5F53;&#x5C40;&#x3068;&#x306E;&#x76F8;&#x4E92;&#x4F5C;&#x7528;&#x3068;&#x540C;&#x69D8;&#x306B;&#x3001;&#x7D4C;&#x8DEF;&#x306E;&#x30C0;&#x30A4;&#x30CA;&#x30DF;&#x30AF;&#x30B9;&#x3092;&#x691C;&#x8A0E;&#x3057;&#x305F;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x4E3B;&#x306B;&#x810A;&#x690E;&#x52D5;&#x7269;&#x306B;&#x7126;&#x70B9;&#x3092;&#x5F53;&#x3066;&#x3001;&#x6211;&#x3005;&#x306F;&#x795E;&#x7D4C;&#x7CFB;&#x306B;&#x304A;&#x3051;&#x308B;Notch&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x306E;&#x73FE;&#x5728;&#x306E;&#x6587;&#x732E;&#x3092;&#x78BA;&#x8A8D;&#x3057;&#x3001;&#x9762;&#x767D;&#x3044;&#x3068;&#x4E88;&#x671F;&#x305B;&#x306C;&#x9032;&#x6B69;&#x3092;&#x751F;&#x6210;&#x3057;&#x305F;&#x591A;&#x6570;&#x306E;&#x6700;&#x8FD1;&#x306E;&#x7814;&#x7A76;&#x3092;&#x5F37;&#x8ABF;&#x8868;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;

&#x810A;&#x690E;&#x52D5;&#x7269;&#x306E;&#x795E;&#x7D4C;&#x7CFB;&#x306B;&#x304A;&#x3051;&#x308B;Notch&#xFF1A;&#x65B0;&#x3057;&#x3044;&#x30C8;&#x30EA;&#x30C3;&#x30AF;&#x3068;&#x8001;&#x72AC;

&#xB178;&#xCE58; &#xD1B5;&#xB85C; &#xCC99;&#xCD94; &#xC2E0;&#xACBD; &#xAC1C;&#xBC1C; &#xADDC;&#xC81C;&#xC5D0; &#xC54C;&#xB824;&#xC838; &#xADF8; &#xAC00;&#xC6B4;&#xB370; &#xB208;&#xC5D0; &#xB744;&#xB294;. &#xB178;&#xCE58; &#xC218;&#xC6A9; &#xCCB4; &#xD65C;&#xC131;&#xD654;, &#xC2E0;&#xC0DD;&#xC744; &#xC5B5;&#xC81C; &#xC218; &#xC2E0;&#xACBD; &#xC870;&#xC0C1; &#xBB38;&#xC790;&#xB97C; &#xC720;&#xC9C0; &#xD558; &#xACE0; &#xC77C;&#xBD80; &#xCEE8;&#xD14D;&#xC2A4;&#xD2B8;&#xC5D0;&#xC11C; &#xD64D;&#xBCF4; gliogenesis&#xC640; &#xB4DC;&#xB77C;&#xC774;&#xBE0C; &#xC774;&#xC9C4; &#xC6B4;&#xBA85; &#xC120;&#xD0DD;. &#xC774;&#xC804;&#xC5D0; &#xAC1C;&#xCD5C; &#xC5B4;&#xC124;&#xC158;&#xC744; &#xACBD;&#xD654;&#xC640; &#xB178;&#xCE58; &#xAE30;&#xB2A5; &#xC131;&#xCCB4; &#xC911; &#xACE0; &#xC131;&#xC778; &#xB450;&#xB1CC;&#xC758; &#xC6B0;&#xB9AC;&#xC758; &#xC774;&#xD574;&#xB97C; &#xD655;&#xC7A5; &#xBAA8;&#xB450;&#xB294; &#xCD5C;&#xADFC; &#xD765;&#xBBF8;&#xB85C;&#xC6B4; &#xC5F0;&#xAD6C;&#xC758; &#xBB3C;&#xACB0; &#xB4F1;&#xC7A5; &#xD588;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xC5F0;&#xAD6C;&#xB294; &#xD1B5;&#xB85C; &#xB808; &#xADE4; &#xB808;&#xC774; &#xD130;&#xC640; &#xC0C1;&#xD638; &#xC791;&#xC6A9; &#xBFD0;&#xB9CC; &#xC544;&#xB2C8;&#xB77C; &#xD1B5;&#xB85C; &#xC5ED;&#xD559;, &#xC720;&#xC804;&#xC790; &#xBC1C;&#xD604; &#xBC0F; &#xC140; &#xC2E0;&#xD638;&#xC5D0; &#xB300;&#xD574;&#xC11C; &#xC0B4;&#xD3B4;&#xBCF4;&#xC558;&#xB2E4;. &#xC5EC;&#xAE30;&#xC5D0; &#xD604;&#xC7AC; &#xBB38;&#xD559; &#xAC80;&#xD1A0; &#xCC99;&#xCD94; &#xB3D9;&#xBB3C;&#xC5D0; &#xC8FC;&#xB85C; &#xCD08;&#xC810;&#xC744; &#xB9DE;&#xCD94;&#xACE0;, &#xB2E8;&#xACC4;&#xC5D0;&#xC11C; &#xC2E0; &#xACBD;&#xACC4;&#xC5D0; &#xC2E0;&#xD638; &#xD558; &#xACE0; &#xD765;&#xBBF8;&#xC640; &#xC608;&#xAE30;&#xCE58; &#xC54A;&#xC740; &#xC120;&#xC9C4; &#xC0DD;&#xC131; &#xB2E4; &#xC218;&#xC758; &#xCD5C;&#xADFC; &#xC5F0;&#xAD6C;&#xB97C; &#xAC15;&#xC870; &#xD45C;&#xC2DC; &#xD569;&#xB2C8;&#xB2E4;.

&#xCC99;&#xCD94; &#xC2E0; &#xACBD;&#xACC4;&#xC5D0; &#xB178;&#xCE58;: &#xC0C8;&#xB85C;&#xC6B4; &#xD2B8;&#xB9AD;&#xACFC; &#xB299;&#xC740; &#xAC1C;.

La v&#xED;a de Notch es prominente entre los conocidos para regular el desarrollo neural en vertebrados. La activaci&#xF3;n del receptor Notch puede inhibir la neurog&#xE9;nesis, de mantener las caracter&#xED;sticas progenitoras neurales, y en algunos contextos promover gliog&#xE9;nesis y opciones de disco binarios destino. Recientemente, una ola de estudios ha surgido interesantes, que tiene tanto solidificado afirmaciones previamente realizadas y ampliado nuestra comprensi&#xF3;n de la funci&#xF3;n de Notch durante la neurog&#xE9;nesis y en el cerebro adulto. Estos estudios han examinado los reguladores de la v&#xED;a e interacciones, as&#xED; como la din&#xE1;mica de la v&#xED;a, con respecto a la expresi&#xF3;n de genes tanto y se&#xF1;alizaci&#xF3;n c&#xE9;lula-c&#xE9;lula. En este caso, centr&#xE1;ndose principalmente en los vertebrados, se revisa la literatura actual sobre la se&#xF1;alizaci&#xF3;n de Notch en el sistema nervioso, y poner de relieve numerosos estudios recientes que han generado avances interesantes e inesperados.

Muesca en el sistema nervioso de vertebrados: un perro viejo nuevos trucos

Abnormal neuronal activity in the subthalamic nucleus (STN) plays a crucial role in the pathophysiology of Parkinson's disease (PD). In this study we investigated changes in rat STN neuronal activity after 28days following the injection of 6-OHDA in the substantia nigra pars compacta (SNc). This drug provoked a lesion of SNc that induced a dopamine (DA) depletion assessed by changes in rotating capacity in response to apomorphine injection and by histological analysis. By means of extracellular recordings and waveshape spike sorting it was possible to analyze simultaneous spike trains and compute the crosscorrelations. Based on the analysis of the autocorrelograms we classified four types of firing patterns: regular (Poissonian-like), oscillatory (in the range 4-12Hz), bursty and cells characterized by a long refractoriness. The distribution of unit types in the control (n=61) and lesioned (n=83) groups was similar, as well as the firing rate. In 6-OHDA treated rats we observed a significant increase (from 26% to 48%) in the number of pairs with synchronous firing. These data suggest that the synchronous activity of STN cells, provoked by loss of DA cells in SNc, is likely to be among the most significant dysfunctions in the basal ganglia of Parkinsonian patients. We raise the hypothesis that in normal conditions, DA maintains a balance between funneling information via the hyperdirect cortico-subthalamic pathway and parallel processing through the parallel cortico-basal ganglia-subthalamic pathways, both of which are necessary for selected motor behaviors. This article is part of a Special Issue entitled 'Neural Coding'.

Dopamine deficiency increases synchronized activity in the rat subthalamic nucleus.

Expression of notch proteins in pyramidal neurons in vivo.

The reticular thalamic nucleus (RTN) of the mouse is characterized by an overwhelming majority of GABAergic neurons receiving afferences from both the thalamus and the cerebral cortex and sending projections mainly on thalamocortical neurons. The RTN neurons express high levels of the "slow Ca(2+) buffer" parvalbumin (PV) and are characterized by low-threshold Ca(2+) currents, I(T). We performed extracellular recordings in ketamine/xylazine anesthetized mice in the rostromedial portion of the RTN. In the RTN of wild-type and PV knockout (PVKO) mice we distinguished four types of neurons characterized on the basis of their firing pattern: irregular firing (type I), medium bursting (type II), long bursting (type III), and tonically firing (type IV). Compared with wild-type mice, we observed in the PVKOs the medium bursting (type II) more frequently than the long bursting type and longer interspike intervals within the burst without affecting the number of spikes. This suggests that PV may affect the firing properties of RTN neurons via a mechanism associated with the kinetics of burst discharges. Ca(v)3.2 channels, which mediate the I(T) currents, were more localized to the somatic plasma membrane of RTN neurons in PVKO mice, whereas Ca(v)3.3 expression was similar in both genotypes. The immunoelectron microscopy analysis showed that Ca(v)3.2 channels were localized at active axosomatic synapses, thus suggesting that the differential localization of Ca(v)3.2 in the PVKOs may affect bursting dynamics. Cross-correlation analysis of simultaneously recorded neurons from the same electrode tip showed that about one-third of the cell pairs tended to fire synchronously in both genotypes, independent of PV expression. In summary, PV deficiency does not affect the functional connectivity between RTN neurons but affects the distribution of Ca(v)3.2 channels and the dynamics of burst discharges of RTN cells, which in turn regulate the activity in the thalamocortical circuit.

The calcium-binding protein parvalbumin modulates the firing 1 properties of the reticular thalamic nucleus bursting neurons.

Notch signaling is an evolutionarily conserved pathway, which is fundamental for neuronal development and specification. In the last decade, increasing evidence has pointed out an important role of this pathway beyond embryonic development, indicating that Notch also displays a critical function in the mature brain of vertebrates and invertebrates. This pathway appears to be involved in neural progenitor regulation, neuronal connectivity, synaptic plasticity and learning/memory. In addition, Notch appears to be aberrantly regulated in neurodegenerative diseases, including Alzheimer's disease and ischemic injury. The molecular mechanisms by which Notch displays these functions in the mature brain are not fully understood, but are currently the subject of intense research. In this review, we will discuss old and novel Notch targets and molecular mediators that contribute to Notch function in the mature brain and will summarize recent findings that explore the two facets of Notch signaling in brain physiology and pathology.

Notch signaling in the brain: in good and bad times.

Asthma: a clinical condition for brain health.

The function of the nuclear receptor Rev-erbα (Nr1d1) in the brain is, apart from its role in the circadian clock mechanism, unknown. Therefore, we compared gene expression profiles in the brain between wild-type and Rev-erbα knock-out (KO) animals. We identified fatty acid binding protein 7 (Fabp7, Blbp) as a direct target of repression by REV-ERBα. Loss of Rev-erbα manifested in memory and mood related behavioral phenotypes and led to overexpression of Fabp7 in various brain areas including the subgranular zone (SGZ) of the hippocampus, where neuronal progenitor cells (NPCs) can initiate adult neurogenesis. We found increased proliferation of hippocampal neurons and loss of its diurnal pattern in Rev-erbα KO mice. In vitro, proliferation and migration of glioblastoma cells were affected by manipulating either Fabp7 expression or REV-ERBα activity. These results suggest an important role of Rev-erbα and Fabp7 in adult neurogenesis, which may open new avenues for treatment of gliomas as well as neurological diseases such as depression and Alzheimer.

The nuclear receptor REV-ERBα regulates Fabp7 and modulates adult hippocampal neurogenesis.

Several laboratories have developed genetic methods to monitor Notch activity in developing and adult mice. These approaches have been useful in identifying Notch signaling with high temporal and spatial resolution. This research has contributed substantially to our understanding of the role of Notch in cell specification and cellular physiology. Here, we present two protocols to monitor Notch activity in the mouse brain: (1) by intraventricular electroporation and (2) by intracranial viral injections of Notch reporter constructs. These methods allow monitoring of Notch signaling in specific brain regions from development to adulthood. In addition, using the appropriate modifications, the Notch reporter systems can also be used to monitor Notch activity in other organs of the mouse such as retina, skin, skeletal muscle, and cancer cells.

Monitoring Notch activity in the mouse.

Notch signalling plays an important role in synaptic plasticity, learning and memory functions in both Drosophila and rodents. In this paper, we report that this feature is not restricted to hippocampal networks but also involves the olfactory bulb (OB). Odour discrimination and olfactory learning in rodents are essential for survival. Notch1 expression is enriched in mitral cells of the mouse OB. These principal neurons are responsive to specific input odorants and relay the signal to the olfactory cortex. Olfactory stimulation activates a subset of mitral cells, which show an increase in Notch activity. In Notch1cKOKln mice, the loss of Notch1 in mitral cells affects the magnitude of the neuronal response to olfactory stimuli. In addition, Notch1cKOKln mice display reduced olfactory aversion to propionic acid as compared to wildtype controls. This indicates, for the first time, that Notch1 is involved in olfactory processing and may contribute to olfactory behaviour.

Notch1 activity in the olfactory bulb is odour-dependent and contributes to olfactory behaviour.

Memory is a temporally evolving molecular and structural process, which involves changes from local synapses to complex neural networks. There is increasing evidence for an involvement of developmental pathways in regulating synaptic communication in the adult nervous system. Notch signaling has been implicated in memory formation in a variety of species. Nevertheless, the mechanism of Notch underlying memory consolidation remains poorly understood. In this commentary, besides offering an overview of the advances in the field of Notch in memory, we highlight some of the weaknesses of the studies and attempt to cast light on the apparent discrepancies on the role of Notch in memory. We believe that future studies, employing high-throughput technologies and targeted Notch loss and gain of function animal models, will reveal the mechanisms of Notch dependent plasticity and resolve whether this signaling pathway is implicated in the cognitive deficit associated with dementia. © 2015 Wiley Periodicals, Inc.

Notch in memories: Points to remember.

Memory is a temporally evolving molecular and structural process, which involves changes from local synapses to complex neural networks. There is increasing evidence for an involvement of developmental pathways in regulating synaptic communication in the adult nervous system. Notch signaling has been implicated in memory formation in a variety of species. Nevertheless, the mechanism of Notch in memory consolidation remains poorly understood. In this commentary, besides offering an overview of the advances in the field of Notch in memory, we highlight some of the weaknesses of the studies and attempt to cast light on some of the apparent discrepancies on the role of Notch in memory. We believe that future studies, employing high-throughput technologies and targeted Notch loss and gain of function animal models, will reveal the mechanisms of Notch-dependent plasticity and resolve whether this signaling pathway is implicated in the cognitive deficit associated with dementia. © 2015 Wiley Periodicals, Inc.

Lavinia Alberi

Unit of Anatomy,
Department of Medicine,
Unit of Anatomy, Department of Medicine

University of Fribourg

Simple and Computer-assisted Olfactory Testing for Mice

Lavinia Alberi

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Unit of Anatomy,Department of Medicine,Unit of Anatomy, Department of Medicine

University of Fribourg

Simple and Computer-assisted Olfactory Testing for Mice

Unit of Anatomy,
Department of Medicine,
Unit of Anatomy, Department of Medicine