in-vivo-optogenetic-stimulation-of-the-rodent-central-nervous-system

<em>In vivo</em> Optogenetic Stimulation of the Rodent Central Nervous System

The ability to probe defined neural circuits in awake, freely-moving animals with cell-type specificity, spatial precision, and high temporal resolution ...

University of Pittsburgh Medical Center

The systemic autoimmune disease lupus erythematosus (SLE) is frequently accompanied by neuropsychiatric manifestations and brain lesions of unknown etiology. The MRL-lpr mice show behavioral dysfunction concurrent with progression of a lupus-like disease, thus providing a valuable model in understanding the pathogenesis of autoimmunity-induced CNS damage. Profound neurodegeneration in the limbic system of MRL-lpr mice is associated with cytotoxicity of their cerebrospinal fluid (CSF) to mature and immature neurons. We have recently shown that IgG-rich CSF fraction largely accounts for this effect. The present study examines IgG levels in serum and CSF, as well as the permeability of the blood-brain barrier in mice that differ in immune status, age, and brain morphology. In comparison to young MRL-lpr mice and age-matched congenic controls, a significant elevation of IgG and albumin levels were detected in the CSF of aged autoimmune MRL-lpr mice. Two-dimensional gel electrophoresis and MALDI-TOF MS confirmed elevation in IgG heavy and Ig light chain isoforms in the CSF. Increased permeability of the blood-brain barrier correlated with neurodegeneration (as revealed by Fluoro Jade B staining) in periventricular areas. Although the source and specificity of neuropathogenic antibodies remain to be determined, these results support the hypothesis that a breached blood-brain barrier and IgG molecules are involved in the etiology of CNS damage during SLE-like disease.

Elevated immunoglobulin levels in the cerebrospinal fluid from lupus-prone mice.

Brain atrophy, neurologic and psychiatric (NP) manifestations are common complications in the systemic autoimmune disease, lupus erythematosus (SLE). Here we show that the cerebrospinal fluid (CSF) from autoimmune MRL-lpr mice and a deceased NP-SLE patient reduce the viability of brain cells which proliferate in vitro. This detrimental effect was accompanied by periventricular neurodegeneration in the brains of autoimmune mice and profound in vivo neurotoxicity when their CSF was administered to the CNS of a rat. Multiple ionic responses with microfluorometry and protein peaks on electropherograms suggest more than one mechanism of cellular demise. Similar to the CSF from diseased MRL-lpr mice, the CSF from a deceased SLE patient with a history of psychosis, memory impairment, and seizures, reduced viability of the C17.2 neural stem cell line. Proposed mechanisms of cytotoxicity involve binding of intrathecally synthesized IgG autoantibodies to target(s) common to different mammalian species and neuronal populations. More importantly, these results indicate that the viability of proliferative neural cells can be compromised in systemic autoimmune disease. Antibody-mediated lesions of germinal layers may impair the regenerative capacity of the brain in NP-SLE and possibly, brain development and function in some forms of CNS disorders in which autoimmune phenomena have been documented.

Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease.

The elevated plus maze (EPM) is one of the most widely used and established tests to assess anxiety-related behaviours and has been validated for use in both mice and rats. Although relatively quick and simple to conduct, there always exists the potential for observer bias during data collection. The KinderScientific EPM system uses a series of apparatus-embedded photobeams to collect spatiotemporal measures such as the amount of time spent in each zone of the maze (centre, open and closed arms), and the frequency of arm entries. Risk assessment behaviours, such as head dips and protected stretches, are also measured which represents a unique feature of this system over other automated EPM systems. We compared observer derived spatiotemporal and risk assessment measurements with automated generated data to test the reliability and accuracy of the automated system. Data were manually collected using different zone entry/exit criteria (2 vs. 4 paws). Automated data were generated using both the default zone map provided with the system and a user-modified zone map. We show that the automated EPM provides accurate and reliable measurements of both spatiotemporal and risk assessment behaviours. In addition, we show that the default zone map overestimated visually observed arm entries while our modified zone map generated data comparable to manually generated data using a 4 paws open arm entry criteria which is most consistently used to define arm entry in the literature. The KinderScientific automated EPM system represents a reliable tool for collection of a wide range of anxiety-related behavioural measures.

Validation of an automated system for measuring anxiety-related behaviours in the elevated plus maze.

The role of antidepressants in the acute treatment of bipolar depression remains a contentious issue. A previous meta-analysis of randomized controlled trials (RCTs) concluded that antidepressants were effective and safe for bipolar depression. Several trials published since then suggest that antidepressants may not be as beneficial as previously concluded. The current systematic review and meta-analyses reexamine the efficacy and safety of antidepressant use for the acute treatment of bipolar depression.

Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis.

Polymorphisms in circadian genes such as CLOCK convey risk for bipolar disorder. While studies have begun to elucidate the molecular mechanism whereby disruption of Clock alters cellular function within mesolimbic brain regions, little remains known about how these changes alter gross neural circuit function and generate mania-like behaviors in Clock-Δ19 mice. Here we show that the phasic entrainment of nucleus accumbens (NAC) low-gamma (30-55 Hz) oscillations to delta (1-4 Hz) oscillations is negatively correlated with the extent to which wild-type (WT) mice explore a novel environment. Clock-Δ19 mice, which display hyperactivity in the novel environment, exhibit profound deficits in low-gamma and NAC single-neuron phase coupling. We also demonstrate that NAC neurons in Clock-Δ19 mice display complex changes in dendritic morphology and reduced GluR1 expression compared to those observed in WT littermates. Chronic lithium treatment ameliorated several of these neurophysiological deficits and suppressed exploratory drive in the mutants. These results demonstrate that disruptions of Clock gene function are sufficient to promote alterations in NAC microcircuits, and raise the hypothesis that dysfunctional NAC phase signaling may contribute to the mania-like behavioral manifestations that result from diminished circadian gene function.

Lithium ameliorates nucleus accumbens phase-signaling dysfunction in a genetic mouse model of mania.

&#x9502;&#x88AB;&#x5E7F;&#x6CDB;&#x7528;&#x4E8E;&#x60C5;&#x7EEA;&#x7A33;&#x5B9A;&#xFF0C;&#x7279;&#x522B;&#x662F;&#x6709;&#x6548;&#x6CBB;&#x7597;&#x53CC;&#x76F8;&#x8E81;&#x3002;&#x540C;&#x5176;&#x4ED6;&#x836F;&#x7269;&#x4E00;&#x6837;&#x7528;&#x4E8E;&#x7CBE;&#x795E;&#x79D1;&#x75BE;&#x75C5;&#x7684;&#x6CBB;&#x7597;&#xFF0C;&#x5B83;&#x6709;&#x5065;&#x5EB7;&#x7684;&#x4EBA;&#x7684;&#x60C5;&#x7EEA;&#x7684;&#x5F71;&#x54CD;&#x5C0F;&#x3002;&#x6211;&#x4EEC;&#x4EE5;&#x524D;&#x7684;&#x7814;&#x7A76;&#x53D1;&#x73B0;&#x4E0E;&#x65F6;&#x949F; (Clock&Delta;19) &#x57FA;&#x56E0;&#x7A81;&#x53D8;&#x5C0F;&#x9F20;&#x5B8C;&#x6574;&#x884C;&#x4E3A;&#x7684;&#x914D;&#x7F6E;&#x6587;&#x4EF6;&#x975E;&#x5E38;&#x7C7B;&#x4F3C;&#x4E8E;&#x4EBA;&#x7C7B;&#x7684;&#x72C2;&#x70ED;&#xFF0C;&#x53EF;&#x4EE5;&#x626D;&#x8F6C;&#x4E0E;&#x6162;&#x6027;&#x9502;&#x6CBB;&#x7597;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x57FA;&#x7840;&#x53CA;&#x5176;&#x6709;&#x9488;&#x5BF9;&#x6027;&#x7684;&#x6CBB;&#x7597;&#x6548;&#x679C;&#x7684;&#x8702;&#x7A9D;&#x548C;&#x751F;&#x7406;&#x7684;&#x5F71;&#x54CD;&#x4ECD;&#x7136;&#x672A;&#x77E5;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x627E;&#x5230; Clock&Delta;19 &#x5C0F;&#x9F20;&#x5728;&#x8179;&#x4FA7;&#x88AB;&#x76D6;&#x533A; &#xFF08;VTA&#xFF09; &#x4E2D;&#x7684;&#x591A;&#x5DF4;&#x80FA;&#x80FD;&#x6D3B;&#x6027;&#x589E;&#x52A0;&#x548C;&#x9502;&#x7684;&#x5F85;&#x9047;&#x6709;&#x9009;&#x62E9;&#x6027;&#x5730;&#x51CF;&#x5C11;&#x4E86;&#x5BF9;&#x91CE;&#x751F;&#x578B;&#x5C0F;&#x9F20;&#x6D3B;&#x52A8;&#x6CA1;&#x6709;&#x4EFB;&#x4F55;&#x5F71;&#x54CD;&#x7684;&#x57FA;&#x56E0;&#x7A81;&#x53D8;&#x5C0F;&#x9F20;&#x7684;&#x70E7;&#x6210;&#x7387;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x9502;&#x6CBB;&#x7597;&#x53EF;&#x964D;&#x4F4E;&#x6838;&#x4F0F; (NAc) &#x591A;&#x5DF4;&#x80FA;&#x6C34;&#x5E73;&#x6709;&#x9009;&#x62E9;&#x6027;&#x5730;&#x5728;&#x57FA;&#x56E0;&#x7A81;&#x53D8;&#x7684;&#x5C0F;&#x9F20;&#x3002;&#x65F6;&#x949F;&#x7A81;&#x53D8;&#x4F53;&#x4E2D;&#x7684;&#x591A;&#x7684;&#x5DF4;&#x80FA;&#x6D3B;&#x52A8;&#x662F;&#x4E0E;&#x591A;&#x5DF4;&#x80FA;&#x795E;&#x7ECF;&#x5143;&#xFF0C;&#x8FD9;&#x4E5F;&#x7531;&#x9502;&#x6CBB;&#x7597;&#x6551;&#x51FA;&#x7EC6;&#x80DE;&#x4F53;&#x79EF;&#x53D8;&#x5316;&#x76F8;&#x5173;&#x8054;&#x3002;&#x82E5;&#x8981;&#x786E;&#x5B9A;&#x591A;&#x5DF4;&#x80FA;&#x80FD;&#x6D3B;&#x6027;&#x548C;&#x8E81;&#x72C2;&#x6837;&#x884C;&#x4E3A;&#x4E2D;&#x7684;&#x591A;&#x5DF4;&#x80FA;&#x795E;&#x7ECF;&#x5143;&#x7684;&#x5F62;&#x6001;&#x5B66;&#x53D8;&#x5316;&#x7684;&#x4F5C;&#x7528;&#xFF0C;&#x6211;&#x4EEC;&#x53D7;&#x5230;&#x8D85;&#x91CF;&#x8868;&#x8FBE;&#x5185;&#x5FC3;&#x6574;&#x6D41;&#x94BE;&#x901A;&#x9053;&#x4E9A;&#x5355;&#x4F4D; (Kir2.1) &#x6709;&#x9009;&#x62E9;&#x6027;&#x5730;&#x5728; VTA Clock&Delta;19 &#x5C0F;&#x9F20;&#x548C;&#x91CE;&#x751F;&#x578B;&#x5C0F;&#x9F20;&#x4F7F;&#x7528;&#x75C5;&#x6BD2;&#x4ECB;&#x5BFC;&#x7684;&#x57FA;&#x56E0;&#x8F6C;&#x79FB;&#x7684;&#x64CD;&#x7EB5;&#x8FD9;&#x4E9B;&#x795E;&#x7ECF;&#x5143;&#x5174;&#x594B;&#x6027;&#x3002;&#x6B64;&#x901A;&#x9053;&#x5F15;&#x8FDB;&#x6A21;&#x4EFF;&#x9502;&#x6CBB;&#x7597; Clock&Delta;19 &#x5C0F;&#x9F20;&#x591A;&#x5DF4;&#x80FA;&#x795E;&#x7ECF;&#x5143;&#x7684;&#x70E7;&#x6210;&#x7387;&#x7684;&#x5F71;&#x54CD;&#xFF0C;&#x5BFC;&#x81F4;&#x591A;&#x5DF4;&#x80FA;&#x7EC6;&#x80DE;&#x4F53;&#x79EF;&#x7C7B;&#x4F3C;&#x53D8;&#x5316;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x70E7;&#x6210;&#x7387; Clock&Delta;19 &#x52A8;&#x7269;&#x4E2D;&#x7684;&#x591A;&#x5DF4;&#x80FA;&#x80FD;&#x51CF;&#x5C11;&#x5BFC;&#x81F4;&#x6B63;&#x5E38;&#x5316;&#x7684;&#x81EA;&#x53D1;&#x548C;&#x7126;&#x8651;&#x6709;&#x5173;&#x7684;&#x884C;&#x4E3A;&#xFF0C;&#x975E;&#x5E38;&#x7C7B;&#x4F3C;&#x4E8E;&#x9502;&#x6CBB;&#x7597; &#xFF1B;&#x7136;&#x800C;&#xFF0C;&#x5B83;&#x5E76;&#x4E0D;&#x8DB3;&#x4EE5;&#x626D;&#x8F6C;&#x4E0E;&#x6291;&#x90C1;&#x75C7;&#x76F8;&#x5173;&#x7684;&#x884C;&#x4E3A;&#x3002;&#x8FD9;&#x4E9B;&#x7ED3;&#x679C;&#x8868;&#x660E;&#x5F02;&#x5E38;&#x7684;&#x591A;&#x5DF4;&#x80FA;&#x7EC6;&#x80DE;&#x5C04;&#x51FB;&#x548C;&#x5173;&#x8054;&#x7684;&#x5F62;&#x6001;&#x5B66;&#x57FA;&#x7840;&#x4E2D;&#x4E24;&#x6781;&#x8E81;&#x72C2;&#x3001; &#x7126;&#x8651;&#x76F8;&#x5173;&#x884C;&#x4E3A;&#x7684;&#x6539;&#x53D8;&#x548C;&#x9502;&#x7684;&#x7597;&#x6548;&#x6765;&#x81EA;&#x8FD9;&#x4E9B;&#x5F02;&#x5E38;&#x8868;&#x578B;&#x7684;&#x9006;&#x8F6C;&#x3002;

&#x8179;&#x4FA7;&#x80CC;&#x76D6;&#x533A;&#x591A;&#x5DF4;&#x80FA;&#x795E;&#x7ECF;&#x5143;&#x653E;&#x7535;&#x7387;&#x548C;&#x7126;&#x8651;&#x6709;&#x5173;&#xFF0C;&#x662F;&#x626D;&#x8F6C;&#x5F62;&#x6001;&#x7684;&#x7279;&#x5B9A;&#x4F5C;&#x7528;&#xFF0C;&#x4F46; Clock&Delta;19 &#x5C0F;&#x9F20;&#x6A21;&#x578B;&#x7684;&#x8E81;&#x72C2;&#x4E0E;&#x6291;&#x90C1;&#x6709;&#x5173;&#x7684;&#x4E0D;&#x884C;&#x4E3A;&#x3002;

Lithium has been used extensively for mood stabilization, and it is particularly efficacious in the treatment of bipolar mania. Like other drugs used in the treatment of psychiatric diseases, it has little effect on the mood of healthy individuals. Our previous studies found that mice with a mutation in the Clock gene (ClockÎ”19) have a complete behavioral profile that is very similar to human mania, which can be reversed with chronic lithium treatment. However, the cellular and physiological effects that underlie its targeted therapeutic efficacy remain unknown. Here we find that ClockÎ”19 mice have an increase in dopaminergic activity in the ventral tegmental area (VTA), and that lithium treatment selectively reduces the firing rate in the mutant mice with no effect on activity in wild-type mice. Furthermore, lithium treatment reduces nucleus accumbens (NAc) dopamine levels selectively in the mutant mice. The increased dopaminergic activity in the Clock mutants is associated with cell volume changes in dopamine neurons, which are also rescued by lithium treatment. To determine the role of dopaminergic activity and morphological changes in dopamine neurons in manic-like behavior, we manipulated the excitability of these neurons by overexpressing an inwardly rectifying potassium channel subunit (Kir2.1) selectively in the VTA of ClockÎ”19 mice and wild-type mice using viral-mediated gene transfer. Introduction of this channel mimics the effects of lithium treatment on the firing rate of dopamine neurons in ClockÎ”19 mice and leads to a similar change in dopamine cell volume. Furthermore, reduction of dopaminergic firing rates in ClockÎ”19 animals results in a normalization of locomotor- and anxiety-related behavior that is very similar to lithium treatment; however, it is not sufficient to reverse depression-related behavior. These results suggest that abnormalities in dopamine cell firing and associated morphology underlie alterations in anxiety-related behavior in bipolar mania, and that the therapeutic effects of lithium come from a reversal of these abnormal phenotypes.

Specific role of VTA dopamine neuronal firing rates and morphology in the reversal of anxiety-related, but not depression-related behavior in the ClockÎ”19 mouse model of mania.

Au lithium a &eacute;t&eacute; largement utilis&eacute; pour la stabilisation de l&#39;humeur, et il est particuli&egrave;rement efficace dans le traitement de la manie bipolaire. Comme les autres m&eacute;dicaments utilis&eacute;s dans le traitement des maladies psychiatriques, il a peu d&#39;effet sur l&#39;humeur des individus en bonne sant&eacute;. Nos &eacute;tudes pr&eacute;c&eacute;dentes constat&eacute; que les souris pr&eacute;sentant une mutation dans le g&egrave;ne de l&#39;horloge (Clock&Delta;19) ont un profil comportemental complet qui est tr&egrave;s similaire &agrave; la manie humaine, qui peut &ecirc;tre renvers&eacute;e avec traitement chronique au lithium. Cependant, les effets cellulaires et physiologiques qui sous-tendent son efficacit&eacute; th&eacute;rapeutique cibl&eacute;e demeurent inconnus. Ici, nous trouvons que Clock&Delta;19 souris ont une augmentation de l&#39;activit&eacute; dopaminergique dans l&#39;aire tegmentale ventrale (VTA), et que le traitement au lithium s&eacute;lectivement r&eacute;duit le taux de d&eacute;charge dans les souris mutantes sans effet sur l&#39;activit&eacute; chez les souris de type sauvage. En outre, traitement au lithium r&eacute;duit les niveaux de dopamine noyau accumbens (NAc) s&eacute;lectivement chez les souris mutantes. L&#39;activit&eacute; dopaminergique accrue chez les mutants de l&#39;horloge est associ&eacute;e aux variations de volume des cellules dans des neurones de dopamine, qui sont &eacute;galement sauv&eacute;s par un traitement au lithium. Pour d&eacute;terminer le r&ocirc;le de l&#39;activit&eacute; dopaminergique et des changements morphologiques dans les neurones de dopamine dans le comportement de type maniaque, nous avons manipul&eacute; l&#39;excitabilit&eacute; de ces neurones en surexprimant une sous-unit&eacute; int&eacute;rieurement rectification du canal potassium (Kir2.1) s&eacute;lectivement dans l&#39;aire tegmentale ventrale du Clock&Delta;19 souris et souris de type sauvage &agrave; l&#39;aide de transfert de g&egrave;nes viraux. Introduction de ce canal imite les effets du traitement au lithium sur le taux de d&eacute;charge des neurones de dopamine chez les souris Clock&Delta;19 et conduit &agrave; un changement similaire dans le volume des cellules dopaminergiques. Par ailleurs, r&eacute;duction de dopaminergique taux chez les animaux Clock&Delta;19 de combustion entra&icirc;ne une normalisation du comportement locomoteur - et li&eacute;es &agrave; l&#39;anxi&eacute;t&eacute; qui est tr&egrave;s similaire &agrave; un traitement au lithium ; Cependant, il ne suffit pas d&#39;inverser les comportements li&eacute;s &agrave; la d&eacute;pression. Ces r&eacute;sultats sugg&egrave;rent que des anomalies dans le tir de cellule de dopamine et de la morphologie associ&eacute;e sous-tendent alt&eacute;rations de comportement li&eacute; &agrave; l&#39;anxi&eacute;t&eacute; dans la manie bipolaire, et que les effets th&eacute;rapeutiques du lithium proviennent d&#39;un renversement de ces ph&eacute;notypes anormales.

R&ocirc;le sp&eacute;cifique du taux de d&eacute;charge neuronale dopamine VTA et morphologie dans le renversement de li&eacute;es &agrave; l&#39;anxi&eacute;t&eacute;, mais non li&eacute;e &agrave; la d&eacute;pression comportement dans le mod&egrave;le de souris Clock&Delta;19 de la manie.

Lithium wurde ausgiebig f&uuml;r Stimmung Stabilisierung verwendet, und es ist besonders wirksam bei der Behandlung der bipolaren Manie. Wie andere Medikamente zur Behandlung von psychiatrischen Erkrankungen eingesetzt hat kaum Auswirkungen auf die Stimmung von gesunden Personen. Unsere fr&uuml;heren Studien festgestellt, dass M&auml;use mit Mutationen im Clock-gen (Clock&Delta;19) eine vollst&auml;ndige Verhaltensprofil, die sehr &auml;hnlich wie menschliche Manie, die mit chronischen Lithium-Behandlung r&uuml;ckg&auml;ngig gemacht werden k&ouml;nnen. Die zellul&auml;ren und physiologischen Wirkungen, die seine gezielte therapeutische Wirksamkeit zugrunde liegen bleiben jedoch unbekannt. Hier finden wir, dass Clock&Delta;19 M&auml;use eine Erh&ouml;hung der dopaminergen Aktivit&auml;t in der ventralen Haubengebiet (VTA haben) und, dass Lithium-Behandlung selektiv die Feuerrate der Mutanten M&auml;usen mit keinen Einfluss auf die Aktivit&auml;t in den Wildtyp M&auml;usen reduziert. Dar&uuml;ber hinaus reduziert Lithium-Behandlung Nucleus Accumbens (NAc) Dopaminspiegel selektiv in die Mutante M&auml;use. Die erh&ouml;hte dopaminerge Aktivit&auml;t in die Clock-Mutanten ist mit Zelle Volumens&auml;nderungen an Dopamin-Neuronen, die auch durch Lithium-Behandlung gerettet werden. Um die Rolle der dopaminergen Aktivit&auml;t und morphologische Ver&auml;nderungen im Dopamin-Neuronen im manisch-&auml;hnliches Verhalten bestimmen, haben wir die Reizbarkeit von dieser Neuronen von &uuml;berexprimierenden ein einw&auml;rtsgleichrichtenden Kalium Kanal Untereinheit (Kir2.1) selektiv in den VTA Clock&Delta;19 M&auml;use und Wildtyp M&auml;usen mit viral-vermittelte Gentransfer manipuliert. Einf&uuml;hrung dieses Kanals ahmt die Wirkung von Lithium-Behandlung auf die Feuerrate der Dopamin-Neuronen im Clock&Delta;19 M&auml;use und f&uuml;hrt zu einer &auml;hnlichen Dopamin Zelle Volumenver&auml;nderung. Dar&uuml;ber hinaus f&uuml;hrt zu Verringerung der dopaminergen feuern Preise bei Clock&Delta;19 Tieren eine Normalisierung der Bewegungsapparat und Angst-bezogenes Verhalten, die Lithium-Behandlung sehr &auml;hnlich ist; Es reicht jedoch nicht, Depression bezogenes Verhalten umzukehren. Diese Ergebnisse legen nahe, dass Anomalien Dopamin Zelle ausl&ouml;sen und damit verbundenen Morphologie Ver&auml;nderungen Angst bezogenes Verhalten in bipolaren Manie zugrunde liegen, und dass eine Umkehrung der diese abnormalen Ph&auml;notypen die therapeutische Wirkung von Lithium herkommen.

Besondere Rolle der VTA Dopamin neuronale feuern Preise und Morphologie in der Aufl&ouml;sung von Angst-bezogene, aber nicht depressionsbedingten Verhalten im Mausmodell der Manie Clock&Delta;19.

Litio &egrave; stato usato estesamente per la stabilizzazione dell&#39;umore, ed &egrave; particolarmente efficacia nel trattamento della mania bipolare. Come altri farmaci utilizzati nel trattamento delle malattie psichiatriche, ha poco effetto sull&#39;umore di individui sani. I nostri studi precedenti trovano che topi con una mutazione nel gene dell&#39;orologio (Clock&Delta;19) hanno un profilo completo del comportamento che &egrave; molto simile alla mania umana, che pu&ograve; essere invertito con trattamento cronico litio. Tuttavia, gli effetti fisiologici e cellulari che sottendono la sua efficacia terapeutica mirata rimangono sconosciuti. Qui troviamo che Clock&Delta;19 topi hanno un aumento in attivit&agrave; dopaminergica nell&#39;area tegmentale ventrale (VTA), e che il trattamento con litio riduce in modo selettivo il tasso di infornamento in topi mutanti con nessun effetto sull&#39;attivit&agrave; nei topi wild-type. Inoltre, trattamento del litio riduce i livelli di dopamina Nucleo accumbens (NAc) selettivamente in topi mutanti. L&#39;attivit&agrave; dopaminergica aumentata i mutanti orologio &egrave; associato con le variazioni di volume delle cellule in neuroni della dopamina, che sono anche salvati dal trattamento del litio. Per determinare il ruolo dell&#39;attivit&agrave; dopaminergica e cambiamenti morfologici nei neuroni della dopamina nel comportamento maniacale, abbiamo modificato l&#39;eccitabilit&agrave; di questi neuroni con sovraesprimono relativa un&#39;interiormente rettifica secondaria della scanalatura del potassio (sono) selettivamente nella VTA di Clock&Delta;19 topi e topi wild-type mediante trasferimento di geni virali-mediata. Introduzione di questo canale imita gli effetti del trattamento del litio sul tasso di infornamento dei neuroni della dopamina nei topi Clock&Delta;19 e conduce ad un simile cambiamento nel volume delle cellule della dopamina. Inoltre, riduzione di dopaminergico sparando tariffe in Clock&Delta;19 animali si traduce in una normalizzazione del comportamento motorio ansia-correlati e che &egrave; molto simile al trattamento del litio; Tuttavia, non &egrave; sufficiente ad invertire il comportamento relativo alla depressione. Questi risultati suggeriscono che anomalie nell&#39;infornamento delle cellule della dopamina e morfologia associato alla base di alterazioni nel comportamento correlato all&#39;ansia nella mania bipolare, e che gli effetti terapeutici del litio provengono da un&#39;inversione di questi fenotipi anormali.

Ruolo specifico di tassi di infornamento di un neurone della dopamina VTA e morfologia nell&#39;inversione di ansia-correlati, ma non correlati a depressione comportamento nel modello del mouse Clock&Delta;19 di mania.

&#x6C17;&#x5206;&#x5B89;&#x5B9A;&#x306B;&#x30EA;&#x30C1;&#x30A6;&#x30E0;&#x304C;&#x5E83;&#x304F;&#x4F7F;&#x7528;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3001;&#x305D;&#x308C;&#x306F;&#x7279;&#x306B;&#x30D0;&#x30A4;&#x30DD;&#x30FC;&#x30E9; &#x30DE;&#x30CB;&#x30A2;&#x306E;&#x6CBB;&#x7642;&#x306B;&#x52B9;&#x679C;&#x7684;&#x3067;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x7CBE;&#x795E;&#x75BE;&#x60A3;&#x306E;&#x6CBB;&#x7642;&#x306B;&#x4F7F;&#x7528;&#x3055;&#x308C;&#x3066;&#x3001;&#x4ED6;&#x306E;&#x85AC;&#x306E;&#x3088;&#x3046;&#x306A;&#x305D;&#x308C;&#x5065;&#x5168;&#x306A;&#x500B;&#x4EBA;&#x306E;&#x6C17;&#x5206;&#x306B;&#x306F;&#x307B;&#x3068;&#x3093;&#x3069;&#x52B9;&#x679C;&#x304C;&#x3042;&#x308A;&#x307E;&#x305B;&#x3093;&#x3002;&#x672C;&#x7814;&#x7A76;&#x306F;&#x3001;&#x6642;&#x8A08;&#x907A;&#x4F1D;&#x5B50; (Clock&Delta;19) &#x306E;&#x7A81;&#x7136;&#x5909;&#x7570;&#x3092;&#x6301;&#x3064;&#x30DE;&#x30A6;&#x30B9;&#x6162;&#x6027;&#x30EA;&#x30C1;&#x30A6;&#x30E0;&#x6CBB;&#x7642;&#x3092;&#x53CD;&#x8EE2;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x4EBA;&#x9593;&#x306E;&#x30DE;&#x30CB;&#x30A2;&#x306B;&#x975E;&#x5E38;&#x306B;&#x3088;&#x304F;&#x4F3C;&#x305F;&#x5B8C;&#x5168;&#x306A;&#x884C;&#x52D5;&#x30D7;&#x30ED;&#x30D5;&#x30A3;&#x30FC;&#x30EB;&#x898B;&#x3064;&#x3051;&#x305F;&#x3002;&#x305F;&#x3060;&#x3057;&#x3001;&#x305D;&#x306E;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x3092;&#x7D5E;&#x3063;&#x305F;&#x6CBB;&#x7642;&#x52B9;&#x679C;&#x306E;&#x6839;&#x5E95;&#x306B;&#x3042;&#x308B;&#x7D30;&#x80DE;&#x30FB;&#x751F;&#x7406;&#x5B66;&#x7684;&#x52B9;&#x679C;&#x306F;&#x4E0D;&#x660E;&#x306E;&#x307E;&#x307E;&#x3002;&#x3053;&#x3053; Clock&Delta;19 &#x30DE;&#x30A6;&#x30B9;&#x306F;&#x8179;&#x5074;&#x88AB;&#x84CB;&#x91CE; (VTA) &#x306B;&#x304A;&#x3051;&#x308B;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x6D3B;&#x52D5;&#x306E;&#x5897;&#x52A0;&#x304C;&#x3042;&#x308B;&#x3057;&#x3001;&#x305D;&#x306E;&#x30EA;&#x30C1;&#x30A6;&#x30E0;&#x6CBB;&#x7642;&#x3092;&#x9078;&#x629E;&#x7684;&#x306B;&#x91CE;&#x751F;&#x578B;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x6D3B;&#x52D5;&#x306B;&#x5F71;&#x97FF;&#x3092;&#x4E0E;&#x3048;&#x306A;&#x3044;&#x7A81;&#x7136;&#x5909;&#x7570;&#x4F53;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x767A;&#x706B;&#x7387;&#x4F4E;&#x6E1B;&#x3092;&#x898B;&#x3064;&#x3051;&#x307E;&#x3059;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;&#x30EA;&#x30C1;&#x30A6;&#x30E0;&#x6CBB;&#x7642;&#x5909;&#x7570;&#x30DE;&#x30A6;&#x30B9;&#x3067;&#x9078;&#x629E;&#x7684;&#x306B;&#x6838;&#x5074;&#x5750; &#xFF08;NAc&#xFF09; &#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x306E;&#x30EC;&#x30D9;&#x30EB;&#x3092;&#x4F4E;&#x6E1B;&#x3057;&#x307E;&#x3059;&#x3002;&#x6642;&#x8A08;&#x5909;&#x7570;&#x4F53;&#x306E;&#x5897;&#x52A0;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x6D3B;&#x52D5;&#x306B;&#x3088;&#x308B;&#x30EA;&#x30C1;&#x30A6;&#x30E0;&#x6CBB;&#x7642;&#x306E;&#x6551;&#x51FA;&#x307E;&#x305F;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x7523;&#x751F;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x7D30;&#x80DE;&#x4F53;&#x7A4D;&#x306B;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x6D3B;&#x52D5;&#x3068;&#x8E81;&#x306E;&#x3088;&#x3046;&#x306A;&#x52D5;&#x4F5C;&#x3067;&#x306E;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x7523;&#x751F;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306E;&#x5F62;&#x614B;&#x5909;&#x5316;&#x306E;&#x5F79;&#x5272;&#x3092;&#x6C7A;&#x5B9A;&#x3059;&#x308B;&#x306B;&#x306F;&#x3001;&#x6211;&#x3005; Clock&Delta;19 VTA &#x30DE;&#x30A6;&#x30B9;&#x304A;&#x3088;&#x3073;&#x91CE;&#x751F;&#x578B;&#x30DE;&#x30A6;&#x30B9;&#x306E;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x5A92;&#x4ECB;&#x6027;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x8EE2;&#x9001;&#x3092;&#x4F7F;&#x7528;&#x3057;&#x3066;&#x9078;&#x629E;&#x7684;&#x306B;&#x306F;&#x3001;&#x5185;&#x5411;&#x304D;&#x6574;&#x6D41;&#x6027;&#x30AB;&#x30EA;&#x30A6;&#x30E0; &#x30C1;&#x30E3;&#x30CD;&#x30EB; &#x30B5;&#x30D6;&#x30E6;&#x30CB;&#x30C3;&#x30C8; (Kir2.1) &#x3092;&#x904E;&#x5270;&#x306B;&#x3088;&#x3063;&#x3066;&#x3053;&#x308C;&#x3089;&#x306E;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306E;&#x8208;&#x596E;&#x6027;&#x3092;&#x64CD;&#x4F5C;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x3053;&#x306E;&#x30C1;&#x30E3;&#x30CD;&#x30EB;&#x306E;&#x5C0E;&#x5165;&#x306F;&#x3001;&#x30EA;&#x30C1;&#x30A6;&#x30E0;&#x6CBB;&#x7642; Clock&Delta;19 &#x30DE;&#x30A6;&#x30B9;&#x306B;&#x304A;&#x3051;&#x308B;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x7523;&#x751F;&#x30CB;&#x30E5;&#x30FC;&#x30ED;&#x30F3;&#x306E;&#x767A;&#x706B;&#x7387;&#x306E;&#x52B9;&#x679C;&#x3092;&#x6A21;&#x5023;&#x3057;&#x3001;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x7D30;&#x80DE;&#x4F53;&#x7A4D;&#x306E;&#x540C;&#x3058;&#x3088;&#x3046;&#x306A;&#x5909;&#x66F4;&#x306B; &#x3002;&#x3055;&#x3089;&#x306B;&#x3001;&#x767A;&#x706B;&#x7387; Clock&Delta;19 &#x52D5;&#x7269;&#x306B;&#x304A;&#x3051;&#x308B;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x306E;&#x524A;&#x6E1B;&#x30EA;&#x30C1;&#x30A6;&#x30E0;&#x6CBB;&#x7642;&#x306B;&#x975E;&#x5E38;&#x306B;&#x4F3C;&#x3066;&#x3044;&#x308B;&#x6B69;&#x884C;&#x3068;&#x4E0D;&#x5B89;&#x95A2;&#x9023;&#x884C;&#x52D5;&#x306E;&#x6B63;&#x898F;&#x5316;&#x306E;&#x7D50;&#x679C;;&#x3057;&#x304B;&#x3057;&#x3001;&#x3046;&#x3064;&#x75C5;&#x306B;&#x95A2;&#x9023;&#x3059;&#x308B;&#x52D5;&#x4F5C;&#x3092;&#x9006;&#x306B;&#x3059;&#x308B;&#x306E;&#x306B;&#x5341;&#x5206;&#x3067;&#x306F;&#x306A;&#x3044;&#x3067;&#x3059;&#x3002;&#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x7D30;&#x80DE;&#x306E;&#x767A;&#x706B;&#x3068;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x305F;&#x5F62;&#x614B;&#x7570;&#x5E38;&#x30D0;&#x30A4;&#x30DD;&#x30FC;&#x30E9; &#x30DE;&#x30CB;&#x30A2;&#x306B;&#x304A;&#x3051;&#x308B;&#x4E0D;&#x5B89;&#x95A2;&#x9023;&#x884C;&#x52D5;&#x306E;&#x5909;&#x5316;&#x306E;&#x6839;&#x5E95;&#x306B;&#x3042;&#x308B;&#x3053;&#x3068;&#x3068;&#x3001;&#x30EA;&#x30C1;&#x30A6;&#x30E0;&#x306E;&#x6CBB;&#x7642;&#x52B9;&#x679C;&#x3053;&#x308C;&#x3089;&#x306E;&#x7570;&#x5E38;&#x306A;&#x8868;&#x73FE;&#x578B;&#x306E;&#x9006;&#x8EE2;&#x304B;&#x3089;&#x6765;&#x308B;&#x3053;&#x3068;&#x304C;&#x793A;&#x5506;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;

&#x7279;&#x5B9A;&#x306E;&#x5F79;&#x5272;&#x306E; VTA &#x30C9;&#x30FC;&#x30D1;&#x30DF;&#x30F3;&#x795E;&#x7D4C;&#x7D30;&#x80DE;&#x306E;&#x767A;&#x706B;&#x7387;&#x304A;&#x3088;&#x3073;&#x5F62;&#x614B;&#x306E;&#x4E0D;&#x5B89;&#x306B;&#x95A2;&#x9023;&#x3059;&#x308B;&#x306E;&#x9006;&#x8EE2;&#x304C;&#x306A;&#x3044;&#x3046;&#x3064;&#x75C5;&#x306B;&#x95A2;&#x3059;&#x308B;&#x884C;&#x52D5;&#x30DE;&#x30CB;&#x30A2;&#x306E; Clock&Delta;19 &#x30DE;&#x30A6;&#x30B9; &#x30E2;&#x30C7;&#x30EB;&#x3002;

&#xB9AC;&#xD2AC; &#xC815;&#xCDE8; &#xC548;&#xC815;&#xD654;&#xC5D0; &#xB300; &#xD55C; &#xAD11;&#xBC94;&#xC704; &#xD558; &#xAC8C; &#xC0AC;&#xC6A9; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4; &#xADF8;&#xB9AC;&#xACE0; &#xD2B9;&#xD788; &#xBC14;&#xC774; &#xD3F4;&#xB77C; &#xB9E4;&#xB2C8;&#xC544;&#xC758; &#xCE58;&#xB8CC;&#xC5D0; &#xD6A8;&#xB2A5;. &#xC815;&#xC2E0; &#xC9C8;&#xD658;&#xC758; &#xCE58;&#xB8CC;&#xC5D0; &#xC0AC;&#xC6A9; &#xB418;&#xB294; &#xB2E4;&#xB978; &#xC57D;&#xBB3C; &#xCC98;&#xB7FC; &#xAC74;&#xAC15; &#xD55C; &#xAC1C;&#xC778;&#xC758; &#xAE30;&#xBD84;&#xC5D0;&#xB294; &#xD6A8;&#xACFC;&#xAC00; &#xAC70;&#xC758; &#xC788;&#xB2E4;. &#xC6B0;&#xB9AC;&#xC758; &#xC774;&#xC804; &#xC5F0;&#xAD6C; &#xC950; (Clock&Delta;19) &#xC2DC;&#xACC4; &#xC720;&#xC804;&#xC790;&#xC5D0; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774;&#xC640; &#xC778;&#xAC04;&#xC758; &#xB9E4;&#xB2C8;&#xC544; &#xB9CC;&#xC131; &#xB9AC;&#xD2AC; &#xCE58;&#xB8CC;&#xB97C; &#xB418;&#xB3CC;&#xB9B4; &#xC218; &#xC788;&#xB294; &#xB9E4;&#xC6B0; &#xBE44;&#xC2B7;&#xD55C; &#xC644;&#xC804; &#xD55C; &#xD589;&#xB3D9; &#xD504;&#xB85C; &#xD30C;&#xC77C; &#xBC1C;&#xACAC;. &#xADF8;&#xB7EC;&#xB098;, &#xD0C0;&#xAC9F;&#xB41C; &#xCE58;&#xB8CC; &#xD6A8;&#xB2A5;&#xC758; &#xAE30;&#xBC18;&#xC774; &#xB418;&#xB294; &#xC140;&#xB8F0;&#xB7EC;&#xC640; &#xC0DD;&#xB9AC; &#xC801; &#xD6A8;&#xACFC; &#xC54C; &#xC218; &#xC5C6;&#xB294; &#xB0A8;&#xC544; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC5EC;&#xAE30; &#xC6B0;&#xB9AC;&#xAC00; &#xCC3E;&#xC744; Clock&Delta;19 &#xB9C8;&#xC6B0;&#xC2A4; dopaminergic &#xD65C;&#xB3D9; &#xBCF5; &#xBD80; tegmental &#xC601;&#xC5ED; (VTA)&#xC5D0; &#xC788;&#xB294; &#xC99D;&#xAC00; &#xBC0F; &#xB9AC;&#xD2AC; &#xCE58;&#xB8CC;&#xB97C; &#xC120;&#xD0DD;&#xC801;&#xC73C;&#xB85C; &#xC57C;&#xC0DD;-&#xD0C0;&#xC785; &#xB9C8;&#xC6B0;&#xC2A4;&#xC758; &#xD65C;&#xB3D9;&#xC5D0; &#xC601;&#xD5A5;&#xC744; &#xC8FC;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4;&#xC640; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xC0DD;&#xC950;&#xC5D0; &#xBC1C;&#xC0AC; &#xC18D;&#xB3C4;&#xAC00; &#xC904;&#xC5B4;&#xB4ED;&#xB2C8;&#xB2E4;. &#xB610;&#xD55C;, &#xB9AC;&#xD2AC; &#xCE58;&#xB8CC; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xC0DD;&#xC950;&#xC5D0;&#xC11C; &#xC120;&#xD0DD;&#xC801;&#xC73C;&#xB85C; &#xD575; accumbens (NAc) &#xB3C4;&#xD30C;&#xBBFC; &#xC218;&#xC900;&#xC744; &#xAC10;&#xC18C; &#xC2DC;&#xD0A8;&#xB2E4;. &#xC2DC;&#xACC4; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774; &#xC788;&#xB294; &#xC99D;&#xAC00; dopaminergic &#xD65C;&#xB3D9; &#xC140; &#xBCFC;&#xB968; &#xBCC0;&#xD654; &#xB610;&#xD55C; &#xB9AC;&#xD2AC; &#xCE58;&#xB8CC;&#xC5D0; &#xC758;&#xD574; &#xAD6C;&#xCD9C; &#xB418;&#xC5B4; &#xB3C4;&#xD30C;&#xBBFC; &#xB274;&#xB7F0;&#xC5D0; &#xC5F0;&#xACB0; &#xB429;&#xB2C8;&#xB2E4;. &#xC870; &#xBCD1;-&#xAC19;&#xC740; &#xB3D9;&#xC791;&#xC5D0;&#xC11C; &#xB3C4;&#xD30C;&#xBBFC; &#xC2E0;&#xACBD; &#xC138;&#xD3EC;&#xC758; &#xD615;&#xD0DC;&#xD559; &#xBCC0;&#xD654; dopaminergic &#xD65C;&#xB3D9;&#xC758; &#xC5ED;&#xD560; &#xD655;&#xC778; &#xD558;&#xB824;&#xBA74; &#xC6B0;&#xB9AC; &#xC18C;&#xB294; &#xB0B4;&#xC2EC; &#xC815;&#xB958; &#xCE7C;&#xB968; &#xCC44;&#xB110; &#xB2E8;&#xC704; (Kir2.1) Clock&Delta;19 VTA &#xB9C8;&#xC6B0;&#xC2A4; &#xBC0F; &#xC911;&#xC7AC; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xC131; &#xC720;&#xC804;&#xC790; &#xC804;&#xC1A1;&#xC744; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xC57C;&#xC0DD;-&#xD0C0;&#xC785; &#xB9C8;&#xC6B0;&#xC2A4;&#xC5D0; &#xC120;&#xD0DD;&#xC801;&#xC73C;&#xB85C; overexpressing&#xC5D0; &#xC758;&#xD574; &#xC774;&#xB7EC;&#xD55C; &#xC2E0;&#xACBD; &#xC138;&#xD3EC;&#xC758; &#xD765;&#xBD84; &#xC870;&#xC791;. &#xC774; &#xCC44;&#xB110;&#xC758; &#xB3C4;&#xC785; Clock&Delta;19 &#xB9C8;&#xC6B0;&#xC2A4;&#xC5D0;&#xC11C; &#xB3C4;&#xD30C;&#xBBFC; &#xB274;&#xB7F0;&#xC758; &#xBC1C;&#xC0AC; &#xC18D;&#xB3C4;&#xC5D0; &#xB9AC;&#xD2AC; &#xCE58;&#xB8CC;&#xC758; &#xD6A8;&#xACFC; &#xBAA8;&#xBC29; &#xD558; &#xACE0; &#xB3C4;&#xD30C;&#xBBFC; &#xC138;&#xD3EC; &#xBCFC;&#xB968;&#xC5D0;&#xC11C; &#xC720;&#xC0AC;&#xD55C; &#xBCC0;&#xD654;&#xB97C;&#xC774; &#xB048;&#xB2E4;. &#xB610;&#xD55C;, dopaminergic &#xC694;&#xAE08; Clock&Delta;19 &#xB3D9;&#xBB3C;&#xC5D0;&#xC11C; &#xBC1C;&#xC0DD;&#xC758; &#xAC10;&#xC18C; &#xACB0;&#xACFC; &#xB9AC;&#xD2AC; &#xCE58;&#xB8CC;; &#xB9E4;&#xC6B0; &#xC720;&#xC0AC;&#xD55C; &#xC6B4;&#xC804; &#xBC0F; &#xBD88;&#xC548; &#xAD00;&#xB828; &#xD589;&#xB3D9;&#xC758; &#xC815;&#xADDC;&#xD654; &#xADF8;&#xB7EC;&#xB098;, &#xC6B0;&#xC6B8;&#xC99D; &#xAD00;&#xB828; &#xB3D9;&#xC791;&#xC744; &#xBC18;&#xB300;&#xB85C; &#xD558;&#xB824;&#xBA74; &#xCDA9;&#xBD84; &#xD558;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xACB0;&#xACFC; &#xB3C4;&#xD30C;&#xBBFC; &#xC138;&#xD3EC; &#xBC1C;&#xC0AC;&#xC640; &#xAD00;&#xB828;&#xB41C; &#xD615;&#xD0DC;&#xC5D0; &#xC774;&#xC0C1;&#xC774; &#xBCC0;&#xACBD; &#xBC14;&#xC774; &#xD3F4;&#xB77C; &#xB9E4;&#xB2C8;&#xC544;&#xC5D0; &#xBD88;&#xC548; &#xAD00;&#xB828; &#xD589;&#xB3D9;&#xC5D0; &#xAE30;&#xBC18;&#xC774; &#xB418; &#xACE0; &#xB9AC;&#xD2AC;&#xC758; &#xCE58;&#xB8CC; &#xD6A8;&#xACFC; &#xC774;&#xB7EC;&#xD55C; &#xBE44;&#xC815;&#xC0C1;&#xC801;&#xC778; &#xACE0;&#xAE30;&#xC758; &#xBC18;&#xC804;&#xC5D0;&#xC11C; &#xC11C; &#xC81C;&#xC548; &#xD569;&#xB2C8;&#xB2E4;.

VTA &#xB3C4;&#xD30C;&#xBBFC; &#xC2E0;&#xACBD; &#xBC1C;&#xC0AC; &#xC18D;&#xB3C4; &#xBD88;&#xC548; &#xAD00;&#xB828;&#xC758; &#xBC18;&#xC804;&#xC5D0; &#xD615;&#xD0DC;&#xD559;&#xC758; &#xD2B9;&#xC815; &#xC5ED;&#xD560; &#xC774;&#xC9C0;&#xB9CC; &#xAD11;&#xC758; Clock&Delta;19 &#xB9C8;&#xC6B0;&#xC2A4; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xB3D9;&#xC791; &#xD558;&#xC9C0; &#xC6B0;&#xC6B8;&#xC99D; &#xAD00;&#xB828;.

Litio se ha utilizado ampliamente para la estabilizaci&oacute;n del estado de &aacute;nimo, y es particularmente eficaz en el tratamiento de la man&iacute;a bipolar. Como otros f&aacute;rmacos utilizados en el tratamiento de enfermedades psiqui&aacute;tricas, tiene poco efecto sobre el estado de &aacute;nimo de los individuos sanos. Nuestros estudios anteriores encontraron que ratones con una mutaci&oacute;n en el gene del reloj (Clock&Delta;19) tienen un perfil completo de comportamiento que es muy similar a la man&iacute;a humana, que puede revertirse con tratamiento cr&oacute;nico de litio. Sin embargo, los efectos celulares y fisiol&oacute;gicos que subyacen a su eficacia terap&eacute;utica espec&iacute;fica siguen siendo desconocidos. Aqu&iacute; encontramos que los ratones Clock&Delta;19 tienen un aumento en la actividad dopamin&eacute;rgica en el &aacute;rea tegmental ventral (VTA), y ese tratamiento de litio selectivamente reduce la velocidad de disparo en los ratones mutantes con ning&uacute;n efecto sobre la actividad en ratones de tipo salvaje. Adem&aacute;s, el tratamiento de litio reduce los niveles de dopamina de n&uacute;cleo accumbens (NAc) selectivamente en los ratones mutantes. La actividad dopamin&eacute;rgica creciente en los mutantes de reloj est&aacute; asociada con cambios de volumen de la c&eacute;lula en las neuronas de la dopamina, que tambi&eacute;n son rescatados por tratamiento de litio. Para determinar el papel de la actividad dopamin&eacute;rgica y cambios morfol&oacute;gicos en las neuronas de dopamina en comportamiento man&iacute;aco, manipulamos la excitabilidad de las neuronas por overexpressing una subunidad interiormente rectificaci&oacute;n del canal del potasio (Kir2.1) selectivamente en la VTA de Clock&Delta;19 ratones y ratones de tipo salvaje mediante transferencia g&eacute;nica viral transmitida por. Introducci&oacute;n de este canal imita los efectos del tratamiento con litio en la tasa de disparo de las neuronas dopamin&eacute;rgicas en ratones Clock&Delta;19 y conduce a un cambio similar en el volumen de la c&eacute;lula de dopamina. Adem&aacute;s, reducci&oacute;n de dopamin&eacute;rgica las tarifas en Clock&Delta;19 animales de le&ntilde;a da lugar a una normalizaci&oacute;n de comportamiento relacionadas con la ansiedad y aparato locomotor que es muy similar al tratamiento de litio; sin embargo, no es suficiente revertir el comportamiento relacionados con la depresi&oacute;n. Estos resultados sugieren que anormalidades en dopamina celular le&ntilde;a y morfolog&iacute;a asociada subyacen alteraciones de comportamiento relacionadas con la ansiedad en la man&iacute;a bipolar, y que los efectos terap&eacute;uticos del litio provienen de una revocaci&oacute;n de estos fenotipos anormales.

Papel espec&iacute;fico de las tasas de disparo neuronal dopamina VTA y morfolog&iacute;a en la reversi&oacute;n de relacionadas con la ansiedad, pero no relacionados con la depresi&oacute;n comportamiento en el modelo murino de Clock&Delta;19 de la man&iacute;a.

Psychiatry's age of enlightenment: optogenetics and the discovery of novel targets for the treatment of psychiatric disorders.

The effective treatment of depression in people with bipolar disorder remains a clinical challenge. The role of antidepressant medication in treating bipolar depression has been controversial. While early studies and meta-analyses supported a role for antidepressant medication, more recent, high quality randomized controlled trials in bipolar depression have generally not demonstrated efficacy for antidepressant medications. Although the risk of affective switch and long-term de-stabilization remains a concern when using antidepressant medications in bipolar disorder, the magnitude of this risk has been difficult to ascertain with confidence. Maintenance use of antidepressant medication has generally not demonstrated a favorable risk-benefit ratio. Future studies should explore the patient characteristics and response patterns that predict a more favorable response profile to antidepressants amongst patients with bipolar disorder so that the medications can be rationally used in those who are most likely to benefit.

An update on antidepressant use in bipolar depression.

Circadian clocks are temporal interfaces that organize biological systems and behavior to dynamic external environments. Components of the molecular clock are expressed throughout the brain and are centrally poised to play an important role in brain function. This paper focuses on key issues concerning the relationship among circadian clocks, brain function, and development, and discusses three topic areas: (1) sleep and its relationship to the circadian system; (2) systems development and psychopathology (spanning the prenatal period through late life); and (3) circadian factors and their application to neuropsychiatric disorders. We also explore circadian genetics and psychopathology and the selective pressures on the evolution of clocks. Last, a lively debate is presented on whether circadian factors are central to mood disorders. Emerging from research on circadian rhythms is a model of the interaction among genes, sleep, and the environment that converges on the circadian clock to influence susceptibility to developing psychopathology. This model may lend insight into effective treatments for mood disorders and inform development of new interventions.

Circadian clocks, brain function, and development.

The ability to probe defined neural circuits with both the spatial and temporal resolution imparted by optogenetics has transformed the field of neuroscience. Although much attention has been paid to the advantages of manipulating neural activity at millisecond timescales in order to elicit time-locked neural responses, little consideration has been given to the manipulation of circuit activity at physiologically relevant times of day, across multiple days. Nearly all biological events are governed by the circadian clock and exhibit 24 h rhythms in activity. Indeed, neural circuit activity itself exhibits a daily rhythm with distinct temporal peaks in activity occurring at specific times of the day. Therefore, experimentally probing circuit function within and across physiologically relevant time windows (minutes to hours) in behaving animals is fundamental to understanding the function of any one particular circuit within the intact brain. Furthermore, understanding how circuit function changes with repeated manipulation is important for modeling the circuit-wide disruptions that occur with chronic disease states. Here, we review recent advances in optogenetic technology that allow for chronic, temporally specific, control of circuit activity and provide examples of chronic optogenetic paradigms that have been utilized in the search for the neural circuit basis of behaviors relevant to human neuropsychiatric disease.

Article	Year
Elevated immunoglobulin levels in the cerebrospinal fluid from lupus-prone mice. Journal of neuroimmunology\| PubMed ID: 15972238	2005
Proliferating brain cells are a target of neurotoxic CSF in systemic autoimmune disease. Journal of neuroimmunology\| PubMed ID: 16198428	2005
Validation of an automated system for measuring anxiety-related behaviours in the elevated plus maze. Journal of neuroscience methods\| PubMed ID: 20100514	2010
Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. The Journal of clinical psychiatry\| PubMed ID: 21034686	2011
Lithium ameliorates nucleus accumbens phase-signaling dysfunction in a genetic mouse model of mania. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 21123577	2010
Specific role of VTA dopamine neuronal firing rates and morphology in the reversal of anxiety-related, but not depression-related behavior in the ClockÎ”19 mouse model of mania. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\| PubMed ID: 21430648	2011
Psychiatry's age of enlightenment: optogenetics and the discovery of novel targets for the treatment of psychiatric disorders. Journal of psychiatry & neuroscience : JPN\| PubMed ID: 22182794	2012
An update on antidepressant use in bipolar depression. Current psychiatry reports\| PubMed ID: 23065437	2012
Circadian clocks, brain function, and development. Annals of the New York Academy of Sciences\| PubMed ID: 24329517	2013
Timing matters: using optogenetics to chronically manipulate neural circuitry and rhythms. Frontiers in behavioral neuroscience\| PubMed ID: 24592222	2014

Michelle M. Sidor

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