RESUMEN
Depression is the leading cause of disability and produces enormous health and economic burdens. Current treatment approaches for depression are largely ineffective and leave more than 50% of patients symptomatic, mainly because of non-selective and broad action of antidepressants. Thus, there is an urgent need to design and develop novel therapeutics to treat depression. Given the heterogeneity and complexity of the brain, identification of molecular mechanisms within specific cell-types responsible for producing depression-like behaviors will advance development of therapies. In the reward circuitry, the nucleus accumbens (NAc) is a key brain region of depression pathophysiology, possibly based on differential activity of D1- or D2- medium spiny neurons (MSNs). Here we report a circuit- and cell-type specific molecular target for depression, Shisa6, recently defined as an AMPAR component, which is increased only in D1-MSNs in the NAc of susceptible mice. Using the Ribotag approach, we dissected the transcriptional profile of D1- and D2-MSNs by RNA sequencing following a mouse model of depression, chronic social defeat stress (CSDS). Bioinformatic analyses identified cell-type specific genes that may contribute to the pathogenesis of depression, including Shisa6. We found selective optogenetic activation of the ventral tegmental area (VTA) to NAc circuit increases Shisa6 expression in D1-MSNs. Shisa6 is specifically located in excitatory synapses of D1-MSNs and increases excitability of neurons, which promotes anxiety- and depression-like behaviors in mice. Cell-type and circuit-specific action of Shisa6, which directly modulates excitatory synapses that convey aversive information, identifies the protein as a potential rapid-antidepressant target for aberrant circuit function in depression.
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Núcleo Accumbens , Receptores de Dopamina D1 , Animales , Depresión , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismoRESUMEN
UNLABELLED: Depression is a recurring and life-threatening illness that affects up to 120 million people worldwide. In the present study, we show that chronic social defeat stress, an ethologically validated model of depression in mice, increases SIRT1 levels in the nucleus accumbens (NAc), a key brain reward region. Increases in SIRT1, a well characterized class III histone deacetylase, after chronic social defeat suggest a role for this enzyme in mediating depression-like behaviors. When resveratrol, a pharmacological activator of SIRT1, was directly infused bilaterally into the NAc, we observed an increase in depression- and anxiety-like behaviors. Conversely, intra-NAc infusions of EX-527, a SIRT1 antagonist, reduced these behaviors; EX-527 also reduced acute stress responses in stress-naive mice. Next, we increased SIRT1 levels directly in NAc by use of viral-mediated gene transfer and observed an increase in depressive- and anxiety-like behaviors when mice were assessed in the open-field, elevated-plus-maze, and forced swim tests. Using a Cre-inducible viral vector system to overexpress SIRT1 selectively in dopamine D1 or D2 subpopulations of medium spiny neurons (MSNs) in the NAc, we found that SIRT1 promotes depressive-like behaviors only when overexpressed in D1 MSNs, with no effect seen in D2 MSNs. Conversely, selective ablation of SIRT1 in the NAc using viral-Cre in floxed Sirt1 mice resulted in decreased depression- and anxiety-like behaviors. Together, these results demonstrate that SIRT1 plays an essential role in the NAc in regulating mood-related behavioral abnormalities and identifies a novel signaling pathway for the development of innovative antidepressants to treat major depressive disorders. SIGNIFICANCE STATEMENT: In this study, we demonstrate a pivotal role for SIRT1 in anxiety- and depression-like behaviors in the nucleus accumbens (NAc), a key brain reward region. We show that stress stably induces SIRT1 expression in this brain region and that altering SIRT1 activity using a pharmacological or genetic approach regulates anxiety- and depression-like behaviors. These results suggest that SIRT1 plays an essential role in regulating mood-related behaviors and introduces a novel signaling pathway for the development of innovative antidepressants to treat depression and other stress-related disorders. A recent groundbreaking publication by the CONVERGE Consortium (2015) identified a reproducible association of the SIRT1 locus with major depression in humans. Therefore, our results are timely and have significant translational relevance.
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Depresión/metabolismo , Regulación de la Expresión Génica/fisiología , Núcleo Accumbens/fisiología , Sirtuina 1/metabolismo , Animales , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Carbazoles/farmacología , Carbazoles/uso terapéutico , Depresión/tratamiento farmacológico , Depresión/etiología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Sistemas de Liberación de Medicamentos , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Preferencias Alimentarias/efectos de los fármacos , Preferencias Alimentarias/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Núcleo Accumbens/citología , Núcleo Accumbens/efectos de los fármacos , Receptores de Dopamina D1 , Receptores de Dopamina D2 , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/genética , Estrés Psicológico/complicaciones , Estrés Psicológico/metabolismo , Natación/psicologíaRESUMEN
Recently, polymer-coated magnetite (Fe3 O4 ) nanoparticles (NPs) are extensively studied for applications in therapeutics or diagnostics using photothermal effect. Therefore, it is essential to understand the interactions between Fe3 O4 NPs and polymers when optical stimuli are applied. Herein, the photonic reactions of Fe3 O4 NPs and polymer composites upon application of a 780 nm multiphoton laser are analyzed. The photonic reactions produce unique results including fluorescence from conformationally changed polymer and low-temperature phase transformation of Fe3 O4 NPs. Typically, π-conjugated chains are formed, inducing fluorescence through a series of main and side-chain cleavage reactions of polymers with the aliphatic chain. In addition, fluorescence is detected in the cellular system by photonic reactions between Fe3 O4 NPs and biomolecules. After multiphoton laser irradiation, light emission is detected near the intracellular Fe3 O4 NPs, and a stronger intensity is observed in large-sized NPs.
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Rayos Láser , Nanopartículas de Magnetita/química , Fotones , Polímeros/química , Temperatura , Línea Celular , Humanos , Conformación Molecular , Polimetil Metacrilato/química , Espectrometría de Fluorescencia , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
Acute and prolonged exposure to drugs of abuse induces changes in gene expression, synaptic function, and neural plasticity in brain regions involved in reward. Numerous genes are involved in this process, and persistent changes in gene expression coincide with epigenetic histone modifications and DNA methylation. Histone modifications are attractive regulatory mechanisms, which can encode complex environmental signals in the genome of postmitotic cells, like neurons. Recently, it has been demonstrated that specific histone modifications are involved in addiction-related gene regulatory mechanisms, by a diverse set of histone-modifying enzymes and readers. These histone modifiers and readers may prove to be valuable pharmacological targets for effective treatments for drug addiction.
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Epigénesis Genética/genética , Código de Histonas/efectos de los fármacos , Drogas Ilícitas/farmacología , Trastornos Relacionados con Sustancias/genética , Acetilación , Encéfalo/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Código de Histonas/genética , Código de Histonas/fisiología , Humanos , Drogas Ilícitas/toxicidad , Metilación , Proteínas del Tejido Nervioso/metabolismo , Fosforilación , Poli Adenosina Difosfato Ribosa/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , RecompensaRESUMEN
The Aharonov-Bohm effect in ring structures in the presence of electronic correlation and disorder is an open issue. We report novel oscillations of a strongly correlated exciton pair, similar to a Wigner molecule, in a single nanoquantum ring, where the emission energy changes abruptly at the transition magnetic field with a fractional oscillation period compared to that of the exciton, a so-called fractional optical Aharonov-Bohm oscillation. We have also observed modulated optical Aharonov-Bohm oscillations of an electron-hole pair and an anticrossing of the photoluminescence spectrum at the transition magnetic field, which are associated with disorder effects such as localization, built-in electric field, and impurities.
RESUMEN
Previous studies have shown that chronic cocaine administration induces SIRT1, a Class III histone deacetylase, in the nucleus accumbens (NAc), a key brain reward region, and that such induction influences the gene regulation and place conditioning effects of cocaine. To determine the mechanisms by which SIRT1 mediates cocaine-induced plasticity in NAc, we used chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq), 1 d after 7 daily cocaine (20 mg/kg) or saline injections, to map SIRT1 binding genome-wide in mouse NAc. Our unbiased results revealed two modes of SIRT1 action. First, despite its induction in NAc, chronic cocaine causes depletion of SIRT1 from most affected gene promoters in concert with enrichment of H4K16ac (itself a deacetylation target of SIRT1), which is associated with increased expression of these genes. Second, we deduced the forkhead transcription factor (FOXO) family to be a downstream mechanism through which SIRT1 regulates cocaine action. We proceeded to demonstrate that SIRT1 induction causes the deacetylation and activation of FOXO3a in NAc, which leads to the induction of several known FOXO3a gene targets in other systems. Finally, we directly establish a role for FOXO3a in promoting cocaine-elicited behavioral responses by use of viral-mediated gene transfer: we show that overexpressing FOXO3a in NAc enhances cocaine place conditioning. The discovery of these two actions of SIRT1 in NAc in the context of behavioral adaptations to cocaine represents an important step forward in advancing our understanding of the molecular adaptations underlying cocaine action.
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Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Factores de Transcripción Forkhead/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Sirtuina 1/metabolismo , Análisis de Varianza , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Inmunoprecipitación de Cromatina , Condicionamiento Operante/efectos de los fármacos , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/genética , Regulación de la Expresión Génica/efectos de los fármacos , Técnicas de Transferencia de Gen , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Sirtuina 1/genética , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/metabolismoRESUMEN
Pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH) is essential for pituitary gonadotrope function. Although the importance of pulsatile GnRH secretion has been recognized for several decades, the mechanisms underlying GnRH pulse generation in hypothalamic neural networks remain elusive. Here, we demonstrate the ultradian rhythm of GnRH gene transcription in single GnRH neurons using cultured hypothalamic slices prepared from transgenic mice expressing a GnRH promoter-driven destabilized luciferase reporter. Although GnRH promoter activity in each GnRH neuron exhibited an ultradian pattern of oscillations with a period of â¼10 h, GnRH neuronal cultures exhibited partially synchronized bursts of GnRH transcriptional activity at â¼2-h intervals. Surprisingly, pulsatile administration of kisspeptin, a potent GnRH secretagogue, evoked dramatic synchronous activation of GnRH gene transcription with robust stimulation of pulsatile GnRH secretion. We also addressed the issue of hierarchical interaction between the circadian and ultradian rhythms by using Bmal1-deficient mice with defective circadian clocks. The circadian molecular oscillator barely affected basal ultradian oscillation of GnRH transcription but was heavily involved in kisspeptin-evoked responses of GnRH neurons. In conclusion, we have clearly shown synchronous bursts of GnRH gene transcription in the hypothalamic GnRH neuronal population in association with episodic neurohormone secretion, thereby providing insight into GnRH pulse generation.
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Regulación de la Expresión Génica/fisiología , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/metabolismo , Kisspeptinas/farmacología , Red Nerviosa/metabolismo , Transcripción Genética/fisiología , Factores de Transcripción ARNTL/deficiencia , Ciclos de Actividad/fisiología , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Kisspeptinas/administración & dosificación , Luciferasas , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Flujo Pulsátil , Transcripción Genética/efectos de los fármacosRESUMEN
Disruption of circadian rhythm is a major cause of breast cancer in humans. Cryptochrome (CRY), a circadian transcription factor, is a risk factor for initiation of breast cancer, and it is differentially expressed between normal and breast cancer tissues. Here, we evaluated the anti-proliferative and pro-apoptotic activity of KS15, a recently discovered small-molecule inhibitor of CRY, in human breast cancer cells. First, we investigated whether KS15 treatment could promote E-box-mediated transcription by inhibiting the activity of CRY in MCF-7 human breast cancer cells. Protein and mRNA levels of regulators of cell cycle and apoptosis, as well as core clock genes, were differentially modulated in response to KS15. Next, we investigated whether KS15 could inhibit proliferation and increase sensitivity to anti-tumor drugs in MCF-7 cells. We found that KS15 decreased the speed of cell growth and increased the chemosensitivity of MCF-7 cells to doxorubicin and tamoxifen, but had no effect on MCF-10A cells. These findings suggested that pharmacological inhibition of CRY by KS15 exerts an anti-proliferative effect and increases sensitivity to anti-tumor drugs in a specific type of breast cancer.
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Antineoplásicos/farmacología , Criptocromos/antagonistas & inhibidores , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Bibliotecas de Moléculas Pequeñas/farmacología , Apoptosis/efectos de los fármacos , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ritmo Circadiano/genética , Criptocromos/genética , Criptocromos/metabolismo , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Células MCF-7 , Especificidad de Órganos , Transducción de Señal , Tamoxifeno/farmacologíaRESUMEN
Pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH) is indispensable for controlling proper pituitary gonadotrope functions; however, the mechanism underlying GnRH pulse generation remains largely unknown. It is important to understand the cellular oscillator in individual GnRH neurons and temporal synchronization among GnRH neurons. In this brief review, we summarize our recent findings on episodic GnRH gene transcription at the single GnRH neuron level and in synchronized multicellular burst in relation to the temporal pattern of GnRH secretion. We also detail the effects of kisspeptin on ultradian rhythmic GnRH gene transcription and secretion. We extend our discussion to the hierarchical interaction between circadian and ultradian rhythms. Taken together, the current review elucidates the genomic control of GnRH pulse generation in hypothalamic neurons.
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Hormona Liberadora de Gonadotropina/genética , Hormona Liberadora de Gonadotropina/metabolismo , Kisspeptinas/metabolismo , Neuronas/metabolismo , Área Preóptica/metabolismo , Transcripción Genética , Animales , Ritmo Circadiano , Luciferasas , Ratones , Ratones Transgénicos , Regiones Promotoras GenéticasRESUMEN
Semiconducting carbon nanotubes (CNTs) provide an exceptional platform for studying one-dimensional excitons (bound electron-hole pairs), but the role of defects and quenching centers in controlling emission remains controversial. Here we show that, by wrapping the CNT in a polymer sheath and cooling to 4.2 K, ultranarrow photoluminescence (PL) emission line widths below 80 µeV can be seen from individual solution processed CNTs. Hyperspectral imaging of the tubes identifies local emission sites and shows that some previously dark quenching segments can be brightened by the application of high magnetic fields, and their effect on exciton transport and dynamics can be studied. Using focused high intensity laser irradiation, we introduce a single defect into an individual nanotube which reduces its quantum efficiency by the creation of a shallow bound exciton state with enhanced electron-hole exchange interaction. The emission intensity of the nanotube is then reactivated by the application of the high magnetic field.
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Inorganic nanoparticles (NPs) have been widely recognized for their stability and biocompatibility, leading to their widespread use in biomedical applications. Our study introduces a novel approach that harnesses inorganic magnetic nanoparticles (MNPs) to stimulate apical-basal polarity and induce epithelial traits in cancer cells, targeting the hybrid epithelial/mesenchymal (E/M) state often linked to metastasis. We employed mesocrystalline iron oxide MNPs to apply an external magnetic field, disrupting normal cell polarity and simulating an artificial cellular environment. These led to noticeable changes in the cell shape and function, signaling a shift toward the hybrid E/M state. Our research suggests that apical-basal stimulation in cells through MNPs can effectively modulate key cellular markers associated with both epithelial and mesenchymal states without compromising the structural properties typical of mesenchymal cells. These insights advance our understanding of how cells respond to physical cues and pave the way for novel cancer treatment strategies. We anticipate that further research and validation will be instrumental in exploring the full potential of these findings in clinical applications, ensuring their safety and efficacy.
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Polaridad Celular , Neoplasias , Transición Epitelial-Mesenquimal , Células Epiteliales/metabolismo , Fenotipo , Integrinas/metabolismo , Neoplasias/metabolismoRESUMEN
BACKGROUND: Major depression and anxiety disorders are significant causes of disability and socioeconomic burden. Despite the prevalence and considerable impact of these affective disorders, their pathophysiology remains elusive. Thus, there is an urgent need to develop novel therapeutics for these conditions. We evaluated the role of SIRT1 in regulating dysfunctional processes of reward by using chronic social defeat stress to induce depression- and anxiety-like behaviors. Chronic social defeat stress induces physiological and behavioral changes that recapitulate depression-like symptomatology and alters gene expression programs in the nucleus accumbens, but cell type-specific changes in this critical structure remain largely unknown. METHODS: We examined transcriptional profiles of D1-expressing medium spiny neurons (MSNs) lacking deacetylase activity of SIRT1 by RNA sequencing in a cell type-specific manner using the RiboTag line of mice. We analyzed differentially expressed genes using gene ontology tools including SynGO and EnrichR and further demonstrated functional changes in D1-MSN-specific SIRT1 knockout (KO) mice using electrophysiological and behavioral measurements. RESULTS: RNA sequencing revealed altered transcriptional profiles of D1-MSNs lacking functional SIRT1 and showed specific changes in synaptic genes including glutamatergic and GABAergic (gamma-aminobutyric acidergic) receptors in D1-MSNs. These molecular changes may be associated with decreased excitatory and increased inhibitory neural activity in Sirt1 KO D1-MSNs, accompanied by morphological changes. Moreover, the D1-MSN-specific Sirt1 KO mice exhibited proresilient changes in anxiety- and depression-like behaviors. CONCLUSIONS: SIRT1 coordinates excitatory and inhibitory synaptic genes to regulate the GABAergic output tone of D1-MSNs. These findings reveal a novel signaling pathway that has potential for the development of innovative treatments for affective disorders.
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Depresión , Ratones Noqueados , Núcleo Accumbens , Sirtuina 1 , Animales , Núcleo Accumbens/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Ratones , Masculino , Depresión/genética , Depresión/metabolismo , Ratones Endogámicos C57BL , Estrés Psicológico/metabolismo , Estrés Psicológico/genética , Ansiedad/genética , Ansiedad/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Derrota Social , Regulación de la Expresión Génica/genética , Conducta Animal/fisiología , Neuronas/metabolismo , Modelos Animales de EnfermedadRESUMEN
Glucocorticoid (GC) is an adrenal steroid with diverse physiological effects. It undergoes a robust daily oscillation, which has been thought to be driven by the master circadian clock in the suprachiasmatic nucleus of the hypothalamus via the hypothalamus-pituitary-adrenal axis. However, we show that the adrenal gland has its own clock and that the peripheral clockwork is tightly linked to steroidogenesis by the steroidogenic acute regulatory protein. Examination of mice with adrenal-specific knockdown of the canonical clock protein BMAL1 reveals that the adrenal clock machinery is required for circadian GC production. Furthermore, behavioral rhythmicity is drastically affected in these animals, together with altered expression of Period1, but not Period2, in several peripheral organs. We conclude that the adrenal peripheral clock plays an essential role in harmonizing the mammalian circadian timing system by generating a robust circadian GC rhythm.
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Glándulas Suprarrenales/metabolismo , Ritmo Circadiano/fisiología , Glucocorticoides/biosíntesis , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Factores de Transcripción ARNTL , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Conducta Animal/fisiología , Proteínas de Ciclo Celular/biosíntesis , Proteínas de Ciclo Celular/genética , Línea Celular , Proteínas del Ojo/biosíntesis , Proteínas del Ojo/genética , Técnicas de Silenciamiento del Gen , Glucocorticoides/genética , Masculino , Ratones , Ratones Transgénicos , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , Proteínas Circadianas Period , Núcleo Supraquiasmático/metabolismo , Factores de Transcripción/biosíntesis , Factores de Transcripción/genéticaRESUMEN
Multicistronic elements, such as the internal ribosome entry site (IRES) and 2A-like cleavage sequence, serve crucial roles in the eukaryotic ectopic expression of exogenous genes. For utilization of multicistronic elements, the cleavage efficiency and order of elements in multicistronic vectors have been investigated; however, the dynamics of multicistronic element-mediated expression remains unclear. Here, we investigated the dynamics of encephalomyocarditis virus (EMCV) IRES- and porcine teschovirus-1 2A (p2A)-mediated expression. By utilizing real-time fluorescent imaging at a minute-level resolution, we monitored the expression of fluorescent reporters bridged by either EMCV IRES or p2A in two independent cultured cell lines, HEK293 and Neuro2a. We observed significant correlations for the two fluorescent reporters in both multicistronic elements, with a higher correlation coefficient for p2A in HEK293 but similar coefficients for IRES-mediated expression and p2A-mediated expression in Neuro2a. We further analyzed the causal relationship of multicistronic elements by convergent cross mapping (CCM). CCM revealed that in all four conditions examined, the expression of the preceding gene causally affected the dynamics of the subsequent gene. As with the cross correlation, the predictive skill of p2A was higher than that of IRES in HEK293, while the predictive skills of the two multicistronic elements were indistinguishable in Neuro2a. To summarize, we report a significant temporal correlation in both EMCV IRES- and p2A-mediated expression based on the simple bicistronic vector and real-time fluorescent monitoring. The current system also provides a valuable platform to examine the dynamic aspects of expression mediated by diverse multicistronic elements under various physiological conditions.
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Virus de la Encefalomiocarditis/genética , Sitios Internos de Entrada al Ribosoma/genética , Teschovirus/genética , Animales , Virus de la Encefalomiocarditis/metabolismo , Regulación Viral de la Expresión Génica , Vectores Genéticos , Proteínas Fluorescentes Verdes , Células HEK293 , Humanos , Proteínas Luminiscentes , Ratones , Modelos Moleculares , Teschovirus/metabolismo , Proteína Fluorescente RojaRESUMEN
A major mechanism contributing to synaptic plasticity involves alterations in the number of AMPA receptors (AMPARs) expressed at synapses. Hippocampal CA1 synapses, where this process has been most extensively studied, are highly heterogeneous with respect to their probability of neurotransmitter release, P(r). It is unknown whether there is any relationship between the extent of plasticity-related AMPAR trafficking and the initial P(r) of a synapse. To address this question, we induced metabotropic glutamate receptor (mGluR) dependent long-term depression (mGluR-LTD) and assessed AMPAR trafficking and P(r) at individual synapses, using SEP-GluA2 and FM4-64, respectively. We found that either pharmacological or synaptic activation of mGluR1 reduced synaptic SEP-GluA2 in a manner that depends upon P(r); this process involved an activity-dependent reduction in surface mGluR1 that selectively protects high-P(r) synapses from synaptic weakening. Consequently, the extent of postsynaptic plasticity can be pre-tuned by presynaptic activity.
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Membrana Celular/metabolismo , Neurotransmisores/metabolismo , Receptores AMPA/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Espinas Dendríticas/efectos de los fármacos , Espinas Dendríticas/metabolismo , Endocitosis/efectos de los fármacos , Glutamatos/metabolismo , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Masculino , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/farmacología , Probabilidad , Transporte de Proteínas/efectos de los fármacos , Ratas Sprague-Dawley , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Ritmo Teta/efectos de los fármacosRESUMEN
Both the introduction of antibiotics and improvements in oral hygiene have made deep neck infections occur less frequently today than in the past. Nevertheless, the complications from these infections are often life-threatening. The purpose of this article was to review the clinical findings of deep neck infections and identify the predisposing factors of these complications. The present study reviewed 158 cases of deep neck infections between the years of 1995 to 2004, 23 of which had life-threatening complications. Cases were excluded if they had peritonsillar abscesses, superficial infections, infections related to external neck wounds, or head and neck tumors. The authors used multiple linear regression and the logistic regression analysis in order to determine the clinical parameters that are associated with longer hospitalizations and complicated deep neck infections, respectively. The multiple linear regression showed that patients with a large number of involved spaces, diabetes mellitus, and complications required longer hospitalizations (p < 0.05). The logistic regression showed that patients with more than two involved spaces were more likely to have complicated deep neck infections (p < 0.05). Patients with odontogenic causes had negative correlation (p < 0.05). We recommend that high-risk groups, such as diabetic patients and/or patients with more than two involved spaces, should be more closely monitored throughout their hospitalization.
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Absceso/patología , Cuello/patología , Absceso/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Lactante , Tiempo de Internación/estadística & datos numéricos , Modelos Lineales , Modelos Logísticos , Masculino , Persona de Mediana Edad , Absceso Peritonsilar/complicaciones , Absceso Peritonsilar/patologíaRESUMEN
Dysfunction of one or more of the ocular motor nerves or extraocular muscle injury commonly results in diplopia. Diplopia during endoscopic sinus surgery is caused by surgical trauma or local anesthetics. Transient abducens nerve palsy rarely occurs after an intranasal sphenopalatine nerve block. We report three cases of transient abducens nerve palsy during endoscopic sinus surgery and possible explanations are proposed with a review of literature.
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Enfermedades del Nervio Abducens/etiología , Endoscopía , Complicaciones Posoperatorias/etiología , Sinusitis/cirugía , Adolescente , Anestesia Local , Enfermedad Crónica , Diplopía/etiología , Humanos , Lidocaína , Masculino , Persona de Mediana Edad , Bloqueo Nervioso , Remisión EspontáneaRESUMEN
A vast challenge within neuropsychiatric research has been the development of animal models that accurately reflect symptoms associated with affective disorders. An ethologically valid model that has been shown to be effective in studying depression is the chronic social defeat stress model. In this model, C57BL/6J mice are subjected to chronic social defeat stress induced by CD-1 aggressor mice for 10 consecutive days. Discussed here is a protocol describing the screening process of the CD-1 aggressor mice, the confrontations between the C57BL/6J and CD-1 aggressor mice, and analysis of social avoidance scores as an indication of depression-like behaviors.
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Mitochondrial division is critical for the maintenance and regulation of mitochondrial function, quality and distribution. This process is controlled by cytosolic actin-based constriction machinery and dynamin-related protein 1 (Drp1) on mitochondrial outer membrane (OMM). Although mitochondrial physiology, including oxidative phosphorylation, is also important for efficient mitochondrial division, morphological alterations of the mitochondrial inner-membrane (IMM) have not been clearly elucidated. Here we report spontaneous and repetitive constriction of mitochondrial inner compartment (CoMIC) associated with subsequent division in neurons. Although CoMIC is potentiated by inhibition of Drp1 and occurs at the potential division spots contacting the endoplasmic reticulum, it appears on IMM independently of OMM. Intra-mitochondrial influx of Ca2+ induces and potentiates CoMIC, and leads to K+-mediated mitochondrial bulging and depolarization. Synergistically, optic atrophy 1 (Opa1) also regulates CoMIC via controlling Mic60-mediated OMM-IMM tethering. Therefore, we propose that CoMIC is a priming event for efficient mitochondrial division.
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Mitocondrias/metabolismo , Dinámicas Mitocondriales , Animales , Calcio/metabolismo , Dinaminas/genética , Dinaminas/metabolismo , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Humanos , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/química , Mitocondrias/genética , Membranas Mitocondriales/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Neuronas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
RcsA is a positive activator of extracellular polysaccharide (EPS) synthesis in the Enterobacteriaceae. The rcsA gene of the soft rot pathogen Pantoea sp. strain PPE7 in Pleurotus eryngii was cloned by PCR amplification, and its role in EPS synthesis and virulence was investigated. The RcsA protein contains 3 highly conserved domains, and the C-terminal end of the open reading frame shared significant amino acid homology to the helix-turn-helix DNA binding motif of bacterial activator proteins. The inactivation of rcsA by insertional mutagenesis created mutants that had decreased production of EPS compared to the wild-type strain and abolished the virulence of Pantoea sp. strain PPE7 in P. eryngii. The Pantoea sp. strain PPE7 rcsA gene was shown to strongly affect the formation of the disease symptoms of a mushroom pathogen and to act as the virulence factor to cause soft rot disease in P. eryngii.