RESUMEN
Retinitis pigmentosa (RP) is the most common group of inherited retinal degenerative diseases, whose most debilitating phase is cone photoreceptor death. Perimetric and electroretinographic methods are the gold standards for diagnosing and monitoring RP and assessing cone function. However, these methods lack the spatial resolution and sensitivity to assess disease progression at the level of individual photoreceptor cells, where the disease originates and whose degradation causes vision loss. High-resolution retinal imaging methods permit visualization of human cone cells in vivo but have only recently achieved sufficient sensitivity to observe their function as manifested in the cone optoretinogram. By imaging with phase-sensitive adaptive optics optical coherence tomography, we identify a biomarker in the cone optoretinogram that characterizes individual cone dysfunction by stimulating cone cells with flashes of light and measuring nanometer-scale changes in their outer segments. We find that cone optoretinographic responses decrease with increasing RP severity and that even in areas where cone density appears normal, cones can respond differently than those in controls. Unexpectedly, in the most severely diseased patches examined, we find isolated cones that respond normally. Short-wavelength-sensitive cones are found to be more vulnerable to RP than medium- and long-wavelength-sensitive cones. We find that decreases in cone response and cone outer-segment length arise earlier in RP than changes in cone density but that decreases in response and length are not necessarily correlated within single cones.
Asunto(s)
Oftalmoscopía/métodos , Retina/metabolismo , Células Fotorreceptoras Retinianas Conos/metabolismo , Retinitis Pigmentosa/metabolismo , Electrorretinografía , Proteínas del Ojo/metabolismo , HumanosRESUMEN
Human color vision is achieved by mixing neural signals from cone photoreceptors sensitive to different wavelengths of light. The spatial arrangement and proportion of these spectral types in the retina set fundamental limits on color perception, and abnormal or missing types are responsible for color vision loss. Imaging provides the most direct and quantitative means to study these photoreceptor properties at the cellular scale in the living human retina, but remains challenging. Current methods rely on retinal densitometry to distinguish cone types, a prohibitively slow process. Here, we show that photostimulation-induced optical phase changes occur in cone cells and carry substantial information about spectral type, enabling cones to be differentiated with unprecedented accuracy and efficiency. Moreover, these phase dynamics arise from physiological activity occurring on dramatically different timescales (from milliseconds to seconds) inside the cone outer segment, thus exposing the phototransduction cascade and subsequent downstream effects. We captured these dynamics in cones of subjects with normal color vision and a deuteranope, and at different macular locations by: (i) marrying adaptive optics to phase-sensitive optical coherence tomography to avoid optical blurring of the eye, (ii) acquiring images at high speed that samples phase dynamics at up to 3 KHz, and (iii) localizing phase changes to the cone outer segment, where photoactivation occurs. Our method should have broad appeal for color vision applications in which the underlying neural processing of photoreceptors is sought and for investigations of retinal diseases that affect cone function.
Asunto(s)
Visión de Colores/fisiología , Estimulación Luminosa/métodos , Células Fotorreceptoras Retinianas Conos/clasificación , Células Fotorreceptoras Retinianas Conos/fisiología , Adulto , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Retina/diagnóstico por imagen , Retina/fisiología , Tomografía de Coherencia Óptica , Adulto JovenRESUMEN
Background Recent studies showing gadolinium deposition in multiple organs have raised concerns about the safety of gadolinium-based contrast agents (GBCAs). Purpose To explore whether gadolinium deposition in brain structures will cause any motor or behavioral alterations. Materials and Methods This study was performed from July 2019 to December 2020. Groups of 17 female BALB/c mice were each repeatedly injected with phosphate-buffered saline (control group, group A), a macrocyclic GBCA (group B), or a linear GBCA (group C) for 8 weeks (5 mmol per kilogram of bodyweight per week for GBCAs). Brain MRI studies were performed every other week to observe the signal intensity change caused by the gadolinium deposition. After the injection period, rotarod performance test, open field test, elevated plus-maze test, light-dark anxiety test, locomotor activity assessment test, passive avoidance memory test, Y-maze test, and forced swimming test were performed to assess the locomotor abilities, anxiety level, and memory. Among-group differences were compared by using one-way or two-way factorial analysis of variance with Tukey post hoc testing or Dunnett post hoc testing. Results Gadolinium deposition in the bilateral deep cerebellar nuclei was confirmed with MRI only in mice injected with a linear GBCA. At 8 weeks, contrast ratio of group C (0.11; 95% CI: 0.10, 0.12) was higher than that of group A (-2.1 × 10-3; 95% CI: -0.011, 7.5 × 10-3; P < .001) and group B (2.7 × 10-4; 95% CI: -8.2 × 10-3, 8.7 × 10-3; P < .001). Behavioral analyses showed that locomotor abilities, anxiety level, and long-term or short-term memory were not different in mice injected with linear or macrocyclic GBCAs. Conclusion No motor or behavioral alterations were observed in mice with brain gadolinium deposition. Also, the findings support the safety of macrocyclic gadolinium-based contrast agents. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Chen in this issue.
Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Medios de Contraste/farmacología , Gadolinio/farmacología , Actividad Motora/efectos de los fármacos , Animales , Encéfalo/diagnóstico por imagen , Modelos Animales de Enfermedad , Femenino , Imagen por Resonancia Magnética/métodos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos BALB CRESUMEN
Ganglion cells (GCs) are fundamental to retinal neural circuitry, processing photoreceptor signals for transmission to the brain via their axons. However, much remains unknown about their role in vision and their vulnerability to disease leading to blindness. A major bottleneck has been our inability to observe GCs and their degeneration in the living human eye. Despite two decades of development of optical technologies to image cells in the living human retina, GCs remain elusive due to their high optical translucency. Failure of conventional imaging-using predominately singly scattered light-to reveal GCs has led to a focus on multiply-scattered, fluorescence, two-photon, and phase imaging techniques to enhance GC contrast. Here, we show that singly scattered light actually carries substantial information that reveals GC somas, axons, and other retinal neurons and permits their quantitative analysis. We perform morphometry on GC layer somas, including projection of GCs onto photoreceptors and identification of the primary GC subtypes, even beneath nerve fibers. We obtained singly scattered images by: (i) marrying adaptive optics to optical coherence tomography to avoid optical blurring of the eye; (ii) performing 3D subcellular image registration to avoid motion blur; and (iii) using organelle motility inside somas as an intrinsic contrast agent. Moreover, through-focus imaging offers the potential to spatially map individual GCs to underlying amacrine, bipolar, horizontal, photoreceptor, and retinal pigment epithelium cells, thus exposing the anatomical substrate for neural processing of visual information. This imaging modality is also a tool for improving clinical diagnosis and assessing treatment of retinal disease.
Asunto(s)
Células Amacrinas/ultraestructura , Óptica y Fotónica/métodos , Células Bipolares de la Retina/ultraestructura , Células Fotorreceptoras Retinianas Conos/ultraestructura , Células Ganglionares de la Retina/ultraestructura , Células Horizontales de la Retina/ultraestructura , Tomografía de Coherencia Óptica/métodos , Adulto , Células Amacrinas/fisiología , Recuento de Células , Voluntarios Sanos , Humanos , Persona de Mediana Edad , Fibras Nerviosas/fisiología , Fibras Nerviosas/ultraestructura , Óptica y Fotónica/instrumentación , Células Bipolares de la Retina/fisiología , Células Fotorreceptoras Retinianas Conos/fisiología , Células Ganglionares de la Retina/fisiología , Células Horizontales de la Retina/fisiología , Tomografía de Coherencia Óptica/instrumentación , Visión Ocular/fisiologíaRESUMEN
A quantitative signal amplitude estimator for optical coherence tomography (OCT) is presented. It is based on a statistical model of OCT signal and noise, using a Bayesian maximum a posteriori (MAP) estimation framework. Multiple OCT images are used for estimation, similar to the widely utilized intensity averaging method. The estimator is less biased especially at low-intensity regions, where intensity averaging approaches the noise power and hence is biased. The estimator is applied to posterior ocular OCT images and provides high-contrast visualization of pathologies. In addition, histogram analysis objectively shows the superior performance of the estimator compared with intensity averaging.
Asunto(s)
Procesamiento de Imagen Asistido por Computador/métodos , Relación Señal-Ruido , Tomografía de Coherencia Óptica , Teorema de BayesRESUMEN
Type 1 inositol 1,4,5-trisphosphate receptors (IP3 R-1) are among the important calcium channels regulating intracellular Ca(2+) concentration in the central nervous system. In a previous study, we showed that drugs of abuse, such as cocaine, methamphetamine, and ethanol, induced IP3 R-1 upregulation via the calcium signal transduction pathway in psychological dependence. Although nicotine, a major component in tobacco smoke, participates in psychological and/or physical dependence, it has not yet been clarified how nicotine alters IP3 R-1 expression. The present study, therefore, seeks to clarify the mechanism bgy which nicotine modifies IP3 R-1 expression by using mouse cerebral cortical neurons in primary culture. Nicotine induced dose- and time-dependent upregulation of IP3 R-1 protein following its mRNA increase, and the latter was significantly suppressed by a nonselective nicotinic acetylcholine receptors (nAChR) antagonist, mecamylamine. Both cFos and phosphorylated-cJun (p-cJun) were immediately increased in the nucleus, together with an increase of calmodulin kinase (CaMK) IV but not CaMKII expression after nicotine exposure. A nonselective inhibitor of CaMKs, KN-93, and a calcium chelating regent, BAPTA-AM, completely suppressed the expression of cFos and p-cJun in the nucleus as well as the nicotine-induced IP3 R-1 upregulation. These results indicate that nAChR activation by nicotine upregulates IP3 R-1 via increase of activator protein-1, which is a cFos and cJun dimmer, in the nucleus, with activation of Ca(2+) signaling transduction processes.
Asunto(s)
Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Neuronas/metabolismo , Receptores Nicotínicos/metabolismo , Regulación hacia Arriba/fisiología , Animales , Bencilaminas/farmacología , Calcio/metabolismo , Proteína Quinasa Tipo 4 Dependiente de Calcio Calmodulina/genética , Células Cultivadas , Corteza Cerebral/citología , Quelantes/farmacología , Ácido Egtácico/análogos & derivados , Ácido Egtácico/farmacología , Receptores de Inositol 1,4,5-Trifosfato/genética , Ratones , Neuronas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-jun/metabolismo , ARN Mensajero/metabolismo , Receptores Nicotínicos/genética , Sulfonamidas/farmacología , Factores de Tiempo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
We propose a method to measure the in-plane and out-of-plane displacements of tissue using the correlation coefficients of optical coherence tomography (OCT) signals. The displacements are determined by the local correlation coefficients between digitally shifted reference OCT images and a target image. The method achieves sub-micron displacement measurement with an accuracy better than 0.32 µm and repeatability better than 0.36 µm. The feasibility of the method was examined by measuring the displacement field of a laser irradiated porcine retina. This method successfully visualized the dynamic change of the displacement field during laser irradiation.
Asunto(s)
Procesamiento de Imagen Asistido por Computador/métodos , Tomografía de Coherencia Óptica/métodos , Animales , Ojo/citología , Fantasmas de Imagen , PorcinosRESUMEN
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are classified to a multigene family of channel proteins that mediate Ca2+ release from endoplasmic reticulum, and are one of regulators to modify intracellular Ca2+ concentration. Little is known about functional relationship between rewarding effects due to drugs of abuse and IP3Rs. This report reviews the roles and regulatory mechanisms of intracellular Ca2+ channels, especially type 1 IP3Rs (IP3Rs-1), in brain of animals with rewarding effects produced by drugs of abuse. Our recent studies have reported that the blockade of IP3Rs suppresses the development of rewarding effects on methamphetamine or cocaine, suggesting that functional up-regulation of IP3R-1 occurs during the development of rewarding effects. Moreover, the critical expression of IP3R-1 in the development of methamphetamine- and cocaine-induced rewarding effects are regulated by Ca2+ participating in signal transduction pathways via both dopamine D1 and D2 receptors. Taken together these results it is suggested that the changes in IP3R-1 play an essential role in the development of drug dependence.
Asunto(s)
Canales de Calcio/metabolismo , Calcio/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/fisiología , Familia de Multigenes/fisiología , Trastornos Relacionados con Sustancias/genética , Animales , Cocaína , Retículo Endoplásmico/metabolismo , Humanos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Metanfetamina , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/fisiología , Transducción de Señal/genética , Transducción de Señal/fisiología , Trastornos Relacionados con Sustancias/metabolismo , Regulación hacia ArribaRESUMEN
This study involved mice that received 4 days of ethanol (EtOH) vapor inhalation and then were assessed for type 1 inositol 1,4,5-trisphosphate receptor (IP3 Rs-1) expression and the development of EtOH-induced place preference at various time points in withdrawal. IP3 R-1 protein was found to be significantly increased in the nucleus accumbens (NAcc) of mice immediately after 4-day EtOH vapor inhalation, while it significantly reduced to the control level during the next 3 days of withdrawal from EtOH inhalation. EtOH (2 g/kg, i.p.)-induced place preference after 3 days of withdrawal from EtOH vapor inhalation increased dose dependently for 4 days, which was significantly inhibited by 2-aminophenoxyethane-borate, an antagonist for IP3 Rs. EtOH conditioning significantly increased, compared to alcohol-naïve control mice, both IP3 R-1 protein and the release of dopamine in the NAcc of mice after 3 days of withdrawal from EtOH vapor inhaled for 4 days, and this increase of IP3 R-1 protein was completely abolished by intracerebroventricular injection of FK506, an inhibitor for calcineurin. These results indicate that the sensitization of EtOH-induced place preference is due to up-regulated IP3 R-1 via calcineurin-mediated pathway after enhanced release of dopamine in the NAcc on EtOH administration during EtOH conditioning. We revealed signal transduction pathways that may promote sensitization of ethanol (EtOH)-induced place preference. EtOH facilitated the release of dopamine (DA) in the Nucleus accumbens (NAcc), enhancing calcineurin function via dopamine D1-like and D2-like receptor activation, which in turn resulted in increased NFATc4 expression. Increase in NFATc4 may further facilitate transcription factor binding to IP3 R-1 promoter domain to stimulate IP3 R-1 synthesis. Such increased IP3 R-1 elevates intracellular Ca(2+) concentration via facilitated mobilization of Ca(2+) from the intracellular Ca(2+) stores to the cytosol.
Asunto(s)
Calcio/metabolismo , Etanol/farmacología , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Núcleo Accumbens/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Dopamina/metabolismo , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/metabolismo , Transducción de Señal/efectos de los fármacos , Activación Transcripcional/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The present study investigated the effect of ryanodine receptors (RyRs) in the development and expression of morphine-induced conditioned place preference (CPP). Type 2 RyRs (RyRs-2) in the nucleus accumbens (NAcc) significantly increased in morphine-conditioned mice, whereas type 1, 2, and 3 RyRs in the frontal cortex and ventral tegmental area showed no changes. Intracerebroventricular pretreatment with dantrolene, a RyRs antagonist, during the conditioning phase of CPP, dose-dependently inhibited morphine-induced CPP. The expression of morphine-induced CPP was abolished by dantrolene administration before the post-conditioning test. These findings suggest that RyRs-2 in the NAcc participate in the development and expression of morphine-induced CPP.
Asunto(s)
Conducta Animal , Condicionamiento Psicológico , Morfina , Núcleo Accumbens/metabolismo , Trastornos Relacionados con Opioides/metabolismo , Trastornos Relacionados con Opioides/psicología , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Bloqueadores de los Canales de Calcio/administración & dosificación , Condicionamiento Psicológico/efectos de los fármacos , Dantroleno/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inyecciones Intraventriculares , Masculino , Ratones , Núcleo Accumbens/efectos de los fármacos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Canal Liberador de Calcio Receptor de Rianodina/efectos de los fármacos , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Ca2+ influx into neuron through L-type voltage-gated Ca2+ channels (VDCCs) plays an important role in psychostimulant-induced behaviroal and neuronal plasticity. On the other hand, Ca2+ release from ryanodine receptors in the endoplasmic reticulum is one mechanism altering the intracellular Ca2+ concentration. Little is known about functional relationship between psychological dependence due to drugs of abuse and L-type VDCCs or ryanodine receptors. In this paper, we review the roles and regulatory mechanisms of intracellular Ca2+ channels, especially L-type VDCCs and ryanodine receptors in brain of animals with drug dependence. Our recent study have reported that blockade of L-type VDCCs inhibits the development of rewarding effects on drugs of abuse (methamphetamine, cocaine and morphine), suggesting that up-regulation of L-type VDCCs (alpha 1C and alpha 1D subunits) occurs during the development of psychological dependence. Moreover, the critical expression of type-1 and -2 ryanodine receptors in the development of methamphetamine- and cocaine-induced rewarding effects are regulated by dopamine D1 receptors. These results suggest that changes in intracellular Ca2+ dynamics play an essential role in the development of drug dependence.
Asunto(s)
Señalización del Calcio/fisiología , Calcio/metabolismo , Calcio/fisiología , Neuronas/metabolismo , Trastornos Relacionados con Sustancias/etiología , Trastornos Relacionados con Sustancias/metabolismo , Animales , Canales de Calcio Tipo L/metabolismo , Cocaína , Humanos , Metanfetamina , Ratones , Morfina , Ratas , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Regulación hacia ArribaRESUMEN
Clinicians are unable to detect glaucoma until substantial loss or dysfunction of retinal ganglion cells occurs. To this end, novel measures are needed. We have developed an optical imaging solution based on adaptive optics optical coherence tomography (AO-OCT) to discern key clinical features of glaucoma and other neurodegenerative diseases at the cellular scale in the living eye. Here, we test the feasibility of measuring AO-OCT-based reflectance, retardance, optic axis orientation, and angiogram at specifically targeted locations in the living human retina and optic nerve head. Multifunctional imaging, combined with focus stacking and global image registration algorithms, allows us to visualize cellular details of retinal nerve fiber bundles, ganglion cell layer somas, glial septa, superior vascular complex capillaries, and connective tissues. These are key histologic features of neurodegenerative diseases, including glaucoma, that are now measurable in vivo with excellent repeatability and reproducibility. Incorporating this noninvasive cellular-scale imaging with objective measurements will significantly enhance existing clinical assessments, which is pivotal in facilitating the early detection of eye disease and understanding the mechanisms of neurodegeneration.
RESUMEN
The gut microbiota is associated with memory; however, the relationship between dysbiosis-induced memory deficits and hippocampal glutamatergic neurons remains unclear. In our study, a mouse dysbiosis model showed impaired memory-related behavior in the passive avoidance test; decreased expression levels of glutaminase, excitatory amino acid transporter (EAAT)1, EAAT2, vesicular glutamate transporter 2, synaptophysin, brain-derived neurotrophic factor, doublecortin, neuronal nuclear protein, glial fibrillary acidic protein, and S100ß; and decreased phosphorylation of N-methyl-D-aspartate receptor subunit 1, calmodulin-dependent protein kinase II, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1, and cAMP response element-binding protein in the hippocampus. This suggests that dysbiosis-induced memory dysfunction is associated with the hippocampal glutamatergic nervous system.
Asunto(s)
Antibacterianos , Disbiosis , Ratones , Animales , Disbiosis/metabolismo , Hipocampo/metabolismo , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transportador 1 de Aminoácidos Excitadores/metabolismoRESUMEN
Patients with inflammatory bowel disease, including ulcerative colitis (UC) and Crohn's disease, have a high incidence of psychiatric disorders, including depression and anxiety. However, the underlying pathogenic mechanism remains unknown. Dextran sulfate sodium (DSS)-treated mice, a model of UC, exhibit depressive-like behavior and reduced adenosine monophosphate-activated protein kinase (AMPK) activity, which regulates various physiological functions in the brain and gut. However, comprehensive studies on UC pathophysiology with co-occurring depression focused on brain-gut AMPK activity are lacking. Therefore, we aimed to investigate whether resveratrol (RES), an AMPK activator, prevented DSS-induced UC-like symptoms and depressive-like behavior. DSS treatment induced UC-like pathology and depressive-like behavior, as assessed via the tail suspension test. Moreover, western blotting and immunohistochemical studies revealed that DSS increased p-p70S6 kinase (Thr389), p62, tumor necrosis factor-α, interleukin (IL)-1ß, IL-18, NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, cleaved Gasdermin-D (GSDMD), and cleaved caspase-3 expression levels in the rectum and hippocampus, and increased CD40, iNOS, and Kelch-like ECH-associated protein 1 expression levels, and the number of Iba1-positive cells in the hippocampus, and decreased p-AMPK and LC3II/I expression levels, and the number of NF-E2-related factor 2 (Nrf2)-positive cells, and reduced neurogenesis in the hippocampus. These changes were reversed by the RES administration. RES also enhanced PGC1α and SOD1 expression in the hippocampus of DSS-treated male mice. Moreover, NLRP3 staining was observed in the neurons and microglia, and cleaved GSDMD staining in neurons in the hippocampus of DSS-treated mice. Notably, RES prevented UC-like pathology and depressive-like behavior and enhancement of autophagy, decreased rectal and hippocampal inflammatory cytokines and inflammasome, and induced the Nrf2-PGC1α-SOD1 pathway in the hippocampus, resulting in neurogenesis in the hippocampal dentate gyrus. Our findings suggest that brain-gut AMPK activation may be an important therapeutic strategy in patients with UC and depression.
Asunto(s)
Colitis Ulcerosa , Colitis , Enterocolitis , Humanos , Masculino , Ratones , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Superóxido Dismutasa-1/metabolismo , Encéfalo/metabolismo , Inflamasomas/metabolismo , Enterocolitis/patología , Hipocampo/metabolismo , Ratones Endogámicos C57BL , Colitis/inducido químicamente , Colitis/patología , Modelos Animales de EnfermedadRESUMEN
Ulcerative colitis (UC) is a refractory inflammatory bowel disease, which is known to cause psychiatric disorders such as anxiety and depression at a high rate in addition to peripheral inflammatory symptoms. However, the pathogenesis of these psychiatric disorders remains mostly unknown. While prior research revealed that the Enterococcus faecalis 2001 (EF-2001) suppressed UC-like symptoms and accompanying depressive-like behaviors, observed in a UC model using dextran sulfate sodium (DSS), whether it has an anxiolytic effect remains unclear. Therefore, we examined whether EF-2001 attenuates DSS-induced anxiety-like behaviors. Treatment with 2% DSS for seven days induced UC-like symptoms and anxiety-like behavior through the hole-board test, increased serum lipopolysaccharide (LPS) and corticosterone concentration, and p-glucocorticoid receptor (GR) in the prefrontal cortex (PFC), and decreased N-methyl-D-aspartate receptor subunit (NR) 2A and NR2B expression levels in the PFC. Interestingly, these changes were reversed by EF-2001 administration. Further, EF-2001 administration enhanced CAMKII/CREB/BDNF-Drebrin pathways in the PFC of DSS-treated mice, and labeling of p-GR, p-CAMKII, and p-CREB showed colocalization with neurons. EF-2001 attenuated anxiety-like behavior by reducing serum LPS and corticosterone levels linked to the improvement of UC symptoms and by facilitating the CAMKII/CREB/BDNF-Drebrin pathways in the PFC. Our findings suggest a close relationship between UC and anxiety.
Asunto(s)
Ansiolíticos , Sulfato de Dextran , Modelos Animales de Enfermedad , Enterococcus faecalis , Animales , Ratones , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Sulfato de Dextran/toxicidad , Masculino , Ansiedad/tratamiento farmacológico , Lipopolisacáridos , Corticosterona/sangre , Corteza Prefrontal/metabolismo , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colitis Ulcerosa/microbiología , Ratones Endogámicos C57BLRESUMEN
Impaired olfactory function may be associated with the development of psychiatric disorders such as depression and anxiety; however, knowledge on the mechanisms underlying psychiatric disorders is incomplete. A reversible model of olfactory dysfunction, zinc sulfate (ZnSO4) nasal-treated mice, exhibit depression-like behavior accompanying olfactory dysfunction. Therefore, we investigated olfactory function and depression-like behaviors in ZnSO4-treated mice using the buried food finding test and tail suspension test, respectively; investigated the changes in the hippocampal microglial activity and neurogenesis in the dentate gyrus by immunohistochemistry; and evaluated the inflammation and microglial polarity related-proteins in the hippocampus using western blot study. On day 14 after treatment, ZnSO4-treated mice showed depression-like behavior in the tail suspension test and recovery of the olfactory function in the buried food finding test. In the hippocampus of ZnSO4-treated mice, expression levels of ionized calcium-binding adapter molecule 1 (Iba1), cluster of differentiation 40, inducible nitric oxide synthase, interleukin (IL)-1ß, IL-6, tumor necrosis factor-α, cleaved caspase-3, as well as the number of Iba1-positive cells and cell body size increased, and arginase-1 expression and neurogenesis decreased. Except for the increased IL-6, these changes were prevented by a microglia activation inhibitor, minocycline. The findings suggest that neuroinflammation due to polarization of M1-type hippocampal microglia is involved in depression accompanied with olfactory dysfunction.
Asunto(s)
Depresión , Trastornos del Olfato , Humanos , Ratones , Animales , Depresión/metabolismo , Microglía/metabolismo , Interleucina-6/metabolismo , Hipocampo/metabolismoRESUMEN
An advanced version of Jones matrix optical coherence tomography (JMT) is demonstrated for Doppler and polarization sensitive imaging of the posterior eye. JMT is capable of providing localized flow tomography by Doppler detection and investigating the birefringence property of tissue through a three-dimensional (3-D) Jones matrix measurement. Owing to an incident polarization multiplexing scheme based on passive optical components, this system is stable, safe in a clinical environment, and cost effective. Since the properties of this version of JMT provide intrinsic compensation for system imperfection, the system is easy to calibrate. Compared with the previous version of JMT, this advanced JMT achieves a sufficiently long depth measurement range for clinical cases of posterior eye disease. Furthermore, a fine spectral shift compensation method based on the cross-correlation of calibration signals was devised for stabilizing the phase of OCT, which enables a high sensitivity Doppler OCT measurement. In addition, a new theory of JMT which integrates the Jones matrix measurement, Doppler measurement, and scattering measurement is presented. This theory enables a sensitivity-enhanced scattering OCT and high-sensitivity Doppler OCT. These new features enable the application of this system to clinical cases. A healthy subject and a geographic atrophy patient were measured in vivo, and simultaneous imaging of choroidal vasculature and birefringence structures are demonstrated.
Asunto(s)
Efecto Doppler , Tomografía de Coherencia Óptica/métodos , Anciano , Análisis de Fourier , Fondo de Ojo , Atrofia Geográfica/patología , Humanos , Mácula Lútea/patología , Masculino , Disco Óptico/patologíaRESUMEN
Although Type 1 inositol 1,4,5-trisphosphate receptors (IP(3) Rs-1) are one of the major calcium channels to regulate intracellular Ca(2+) concentration, there have been few available data how their expression is modified by long-term exposure to ethanol. The present study attempted to clarify mechanisms of modification of IP(3) R-1 expression during long-term ethanol exposure by γ-aminobutyric acid (GABA)A receptors using mouse cerebral cortical neurons. Long-term exposure to ethanol induced IP(3) R-1 protein upregulation following increased expression of its mRNA. Pretreatment with muscimol, a selective GABA(A) receptor agonist, significantly suppressed the ethanol-induced upregulation of IP(3) R-1 protein and its mRNA, which was significantly abolished by bicuculline, a selective GABA(A) receptor antagonist. These results indicate that GABA(A) receptors negatively regulate the ethanol-induced upregulation of IP(3) R-1 protein expression via the suppression of gene transcription.
Asunto(s)
Etanol/farmacología , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de GABA-A/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Animales , Bicuculina/farmacología , Corteza Cerebral/metabolismo , Agonistas de Receptores de GABA-A/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Receptores de Inositol 1,4,5-Trifosfato/genética , Ratones , Muscimol/farmacología , Neuronas/metabolismo , ARN Mensajero/biosíntesis , Transcripción Genética/efectos de los fármacosRESUMEN
BACKGROUND: Ryanodine receptors (RyRs) amplifying activity-dependent calcium influx via calcium-induced calcium release play an important role in central nervous system functions including learning, memory, and drug abuse. In this study, we investigated the role and the regulatory mechanisms of RyR expression under continuous exposure of mice to ethanol (EtOH) vapor for 9 days. METHODS: The model of EtOH physical dependence was prepared as follows: 8-week-old male ddY mice were exposed to EtOH vapor for 9 days. Protein and mRNA of RyR-1, RyR-2, and RyR-3 in the frontal cortex and limbic forebrain were determined by Western blot and real-time RT-PCR analysis, respectively. RESULTS: Exposure of mice to EtOH vapor for 9 days induced significant withdrawal signs when estimated with withdrawal score, which was dose-dependently suppressed by intracerebroventricular administration of dantrolene, an RyR antagonist. Protein levels of RyR-1 and RyR-2 in the frontal cortex and limbic forebrain significantly increased during EtOH vapor exposure for 9 days with increased expression of their mRNA, whereas that of RyR-3 in these 2 brain regions showed no changes. Increased proteins and mRNA of RyR-1 and RyR-2 were completely abolished by SCH23390, a selective antagonist of dopamine D1 receptors (D1DRs), but not by sulpiride, a selective antagonist of D2DRs. CONCLUSIONS: RyRs play a critical role in the development of EtOH physical dependence and that the up-regulation of RyRs in the brain of mouse, showing EtOH physical dependence is regulated by D1DRs.
Asunto(s)
Alcoholismo/metabolismo , Encéfalo/metabolismo , Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Receptores de Dopamina D1/fisiología , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Animales , Benzazepinas/farmacología , Western Blotting , Dantroleno/farmacología , Modelos Animales de Enfermedad , Lóbulo Frontal/metabolismo , Masculino , Ratones , Prosencéfalo/metabolismo , Receptores de Dopamina D1/antagonistas & inhibidores , Receptores de Dopamina D1/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Canal Liberador de Calcio Receptor de Rianodina/efectos de los fármacos , Canal Liberador de Calcio Receptor de Rianodina/genéticaRESUMEN
Calcium is a ubiquitous intracellular signaling molecule required for initiating and regulating neuronal functions. Ca(2+) release from intracellular stores in the endoplasmic reticulum into intracellular spaces via intracellular Ca(2+)-releasing channels, inositol 1,4,5-trisphosphate receptors (IP3Rs) and ryanodine receptors (RyRs), is one mechanism altering the intracellular Ca(2+) concentration. Functional abnormalities in endoplasmic calcium channels can disturb cellular calcium homeostasis and, in turn, produce pathological conditions. Indeed, our recent studies have indicated the involvement of these upregulated calcium channels in development of the rewarding effect of a drug of abuse and the suppression of its rewarding effect by calcium-channel inhibitors, which suggests a possible functional relationship between intracellular dynamics and the development of the rewarding effects induced by an abused drug. Although previous reports showed that the most important regulators of both RyR and IP3R channel functions are changes in the intracellular Ca(2+) concentration and in phosphorylation of these channels by numerous kinases and calcium modulators, little information is available to clarify how the expression of intracellular calcium channels is regulated. In this review, we therefore introduce the roles and regulatory mechanisms of intracellular calcium channels in drug dependence, especially in the rewarding effect induced by the abused drug.