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1.
Artigo em Inglês | MEDLINE | ID: mdl-32445174

RESUMO

Toripalimab is a monoclonal antibody targeting programmed cell death protein 1 (PD-1). It has recently been approved as an immune checkpoint inhibitor in second-line therapies in patients with unresectable or metastatic melanoma; however, it may be associated with various immune-related adverse events (irAEs). Here we report a case of toripalimab-induced dermatomyositis in a patient receiving treatment for metastatic melanoma. The symptoms were relieved by discontinuing toripalimab and administering once-daily intravenous methylprednisolone 1 mg/kg. We suggest that this case serves a warning to clinicians of the need to be aware of the possiblilty of toripalimab-induced dermatomyositis. Early recognition and treatment may prevent progression and improve prognosis of this irAE.

2.
Bioorg Chem ; 99: 103835, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32305695

RESUMO

A series ofN-acyl glucosamine-bearingtriterpenoidsaponins has been synthesized with cytotoxic activities evaluated against HL-60, PC-3, HCT-116, and CT-26 tumor cells. Saponins incorporated anoleanolic acid (OA) triterpenoidal core exhibited the highest cytotoxic activity. To study the influence of the lengths of acyl-carbon chain onN-position of glucosamine, cells were treated with28-propargylamides and then reacted with an azido-fluorogenic probe under CuAACclickreactions to visualize the intact distributions of these compounds by confocal microscopy and flow cytometry; it was found that cytotoxic-active compounds (30-32) located in the cytosol and inactivecompounds bearing longer carbon chains (33-35) were impenetrable across cell membranes.Our study demonstrated the defined lipophilic acyl-carbon chain length can precisely regulate thecytotoxic activityof saponins, which is useful for the future development of cytotoxic agents.Furthermore, using quantitative proteomics and immunolabeling,the mechanism ofcytotoxicity induced by the synthetic saponin after membrane penetration could be a result of activation of death receptor pathway and inhibition of PI3K/Akt/mTOR pathway.

3.
Nanoscale ; 12(16): 9186-9193, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32297890

RESUMO

Charged domain walls in ferroelectrics hold great promise for the design of novel electronic devices due to their enhanced local conductivity. In fact, charged domain walls show unique properties including the possibility of being created, moved and erased by an applied voltage. Here, we demonstrate that the charged domain walls are constituted by a core region where most of the screening charge is localized and such charge accumulation is responsible for their enhanced conductivity. In particular, the link between the local structural distortions and charge screening phenomena in 109° tail-to-tail domain walls of BiFeO3 is elucidated by a series of multiscale analysis performed by means of scanning probe techniques, including conductive atomic force microscopy (cAFM) and atomic resolution differential phase contrast scanning transmission electron microscopy (DPC-STEM). The results prove that an accumulation of oxygen vacancies occurs at the tail-to-tail domain walls as the leading charge screening process. This work constitutes a new insight in understanding the behavior of such complex systems and lays down the fundaments for their implementation into novel nanoelectronic devices.

4.
Life Sci ; 248: 117459, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32092332

RESUMO

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus that affects approximately half of patients with diabetes. Current treatment regimens cannot treat DPN effectively. Schwann cells (SCs) are very sensitive to glucose concentration and insulin, and closely associated with the occurrence and development of type 1 diabetic mellitus (T1DM) and DPN. Apoptosis of SCs is induced by hyperglycemia and is involved in the pathogenesis of DPN. This review considers the pathological processes of SCs apoptosis under high glucose, which include the following: oxidative stress, inflammatory reactions, endoplasmic reticulum stress, autophagy, nitrification and signaling pathways (PI3K/AKT, ERK, PERK/Nrf2, and Wnt/ß-catenin). The clarification of mechanisms underlying SCs apoptosis induced by high glucose will help us to understand and identify more effective strategies for the treatment of T1DM DPN.


Assuntos
Apoptose/efeitos dos fármacos , Neuropatias Diabéticas/genética , Glucose/farmacologia , Hiperglicemia/genética , Células de Schwann/efeitos dos fármacos , Animais , Apoptose/genética , Autofagia/efeitos dos fármacos , Autofagia/genética , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Hiperglicemia/complicações , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Insulina/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células de Schwann/metabolismo , Células de Schwann/patologia , Transdução de Sinais , beta Catenina/genética , beta Catenina/metabolismo
5.
Nat Commun ; 11(1): 902, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32060300

RESUMO

Electric fields can transform materials with respect to their structure and properties, enabling various applications ranging from batteries to spintronics. Recently electrolytic gating, which can generate large electric fields and voltage-driven ion transfer, has been identified as a powerful means to achieve electric-field-controlled phase transformations. The class of transition metal oxides provide many potential candidates that present a strong response under electrolytic gating. However, very few show a reversible structural transformation at room-temperature. Here, we report the realization of a digitally synthesized transition metal oxide that shows a reversible, electric-field-controlled transformation between distinct crystalline phases at room-temperature. In superlattices comprised of alternating one-unit-cell of SrIrO3 and La0.2Sr0.8MnO3, we find a reversible phase transformation with a 7% lattice change and dramatic modulation in chemical, electronic, magnetic and optical properties, mediated by the reversible transfer of oxygen and hydrogen ions. Strikingly, this phase transformation is absent in the constituent oxides, solid solutions and larger period superlattices. Our findings open up this class of materials for voltage-controlled functionality.

6.
Nat Commun ; 11(1): 184, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924767

RESUMO

Ionic substitution forms an essential pathway to manipulate the structural phase, carrier density and crystalline symmetry of materials via ion-electron-lattice coupling, leading to a rich spectrum of electronic states in strongly correlated systems. Using the ferromagnetic metal SrRuO3 as a model system, we demonstrate an efficient and reversible control of both structural and electronic phase transformations through the electric-field controlled proton evolution with ionic liquid gating. The insertion of protons results in a large structural expansion and increased carrier density, leading to an exotic ferromagnetic to paramagnetic phase transition. Importantly, we reveal a novel protonated compound of HSrRuO3 with paramagnetic metallic as ground state. We observe a topological Hall effect at the boundary of the phase transition due to the proton concentration gradient across the film-depth. We envision that electric-field controlled protonation opens up a pathway to explore novel electronic states and material functionalities in protonated material systems.

7.
Oxid Med Cell Longev ; 2020: 8172714, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998444

RESUMO

High-fat diet (HFD) often increases oxidative stress and enhances inflammatory status in the body. Toll-like receptor 4 (TLR4) is widely expressed in the pancreatic tissues and plays an important role in pancreatitis. This study is aimed at investigating the effect of HFD on acute pancreatitis (AP) and the role of TLR4-mediated necroptosis and inflammation in this disease. Weight-matched rats were allocated for an 8-week feeding on the standard chow diet (SCD) or HFD, and then, the AP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. Rats were sacrificed at an indicated time point after modeling. Additionally, inhibition of TLR4 signaling by TAK-242 in HFD rats with AP was conducted in vivo. The results showed that the levels of serum free fatty acid (FFA) in HFD rats were higher than those in SCD rats. Moreover, HFD rats were more vulnerable to AP injury than SCD rats, as indicated by more serious pathological damage and much higher pancreatic malondialdehyde (MDA) and lipid peroxidation (LPO) levels as well as lower pancreatic superoxide dismutase (SOD) activities and reduced glutathione (GSH) contents and more intense infiltration of MPO-positive neutrophils and CD68-positive macrophages. In addition, HFD markedly increased the expressions of TLR4 and necroptosis marker (RIP3) and aggravated the activation of NF-κB p65 and the expression of TNF-α in the pancreas of AP rats at indicated time points. However, TLR4 inhibition significantly attenuated the structural and functional damage of the pancreas induced by AP in HFD rats, as indicated by improvement of the above indexes. Taken together, these findings suggest that HFD exacerbated the extent and severity of AP via oxidative stress, inflammatory response, and necroptosis. Inhibition of TLR4 signaling by TAK-242 alleviated oxidative stress and decreased inflammatory reaction and necroptosis, exerting a protective effect during AP in HFD rats.

8.
Carbohydr Polym ; 229: 115496, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826425

RESUMO

Chondroitin sulfates (CS) account for more than 80% of the glycosaminoglycans of articular cartilage, which impart its physiological functions. We quantified the absolute concentration of the CS components of the full thickness cartilages from the knees of patients with terminal-phase osteoarthritis. Osteochondrol biopsies were removed from the medial femoral condyle and lateral femoral condyle of sixty female patients received total knee arthroplasty, aged from 58 to 83 years old. We found the total CS concentrations and chondroitin-4-sulfate disaccharide were significantly lowered in osteoarthritic samples. Microstructure analysis indicated while chondroitin-0-sulfate was equally distributed across different zones of the osteoarthritic cartilages, chondroitin-4-sulfate is significantly less in the deep zones. Down-regulation of sulfotransferases, the enzymes responsible for CS sulfation, in the lesion site of cartilage were observed. Our study suggested chondroitin-4-sulfate down-regulation can be a diagnostic marker for degraded osteoarthritis cartilage, with potential implications in cartilage regeneration.


Assuntos
Cartilagem Articular/metabolismo , Sulfatos de Condroitina/metabolismo , Osteoartrite/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cartilagem Articular/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite/patologia
9.
Medicine (Baltimore) ; 98(40): e17444, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577768

RESUMO

RATIONALE: Canaliculitis is a frequently overlooked and misdiagnosed disease. Concurrent corneal ulceration with canaliculitis is uncommon. We report such a case. PATIENT CONCERNS: An 87-year-old woman complained of swelling and pain of the right eye after acute angle closure glaucoma attack. Slit-lamp examination was compatible with the features of infectious keratitis, and the cultures from corneal scrapings grew Streptococcus anginosus later. Hourly topical vancomycin (25 mg/ml) was instilled, then the corneal ulceration improved initially but became stationary after 1-week treatment. DIAGNOSIS: Discharge from the upper punctum was noted subsequently and canalicular concretions were found through curettage. The cultures from canalicular discharge and concretions also revealed the presence of S. anginosus. Thus, infectious keratitis secondary to canaliculitis was diagnosed. INTERVENTIONS: Canaliculotomy was performed to remove the large concretion and vancomycin was injected locally. OUTCOMES: The corneal ulceration resolved after canaliculitis was appropriately treated. LESSONS: Canaliculitis could be a reservoir for organisms that may make compromised corneas liable to infections. Only the appropriate diagnosis and aggressive treatment of canaliculitis leads to the eradication of associated corneal infections.


Assuntos
Canaliculite/complicações , Úlcera da Córnea/microbiologia , Infecções Oculares Bacterianas/complicações , Infecções Estreptocócicas/complicações , Streptococcus anginosus , Idoso de 80 Anos ou mais , Canaliculite/diagnóstico , Canaliculite/terapia , Úlcera da Córnea/diagnóstico , Úlcera da Córnea/terapia , Infecções Oculares Bacterianas/diagnóstico , Infecções Oculares Bacterianas/terapia , Feminino , Humanos , Infecções Estreptocócicas/diagnóstico , Infecções Estreptocócicas/terapia
11.
Adv Sci (Weinh) ; 6(20): 1901432, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31637170

RESUMO

Ionic evolution-induced phase transformation can lead to wide ranges of novel material functionalities with promising applications. Here, using the gating voltage during ionic liquid gating as a tuning knob, the brownmillerite SrCoO2.5 is transformed into a series of protonated H x SrCoO2.5 phases with distinct hydrogen contents. The unexpected electron to charge-neutral doping crossover along with the increase of proton concentration from x = 1 to 2 suggests the formation of exotic charge neutral H-H dimers for higher proton concentration, which is directly visualized at the vacant tetrahedron by scanning transmission electron microscopy and then further supported by first principles calculations. Although the H-H dimers cause no change of the valency of Co2+ ions, they result in clear enhancement of electronic bandgap and suppression of magnetization through lattice expansion. These results not only reveal a hydrogen chemical state beyond anion and cation within the complex oxides, but also suggest an effective pathway to design functional materials through tunable ionic evolution.

12.
Adv Mater ; 31(49): e1903679, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31639262

RESUMO

Resistive switching (RS) memory has stayed at the forefront of next-generation nonvolatile memory technologies. Recently, a novel class of transition metal oxides (TMOs), which exhibit reversible topotactic phase transformation between insulating brownmillerite (BM) phase and conducting perovskite (PV) phase, has emerged as promising candidate materials for RS memories. Nevertheless, the microscopic mechanism of RS in these TMOs is still unclear. Furthermore, RS devices with simultaneously high density and superior memory performance are yet to be reported. Here, using SrFeOx as a model system, it is directly observed that PV SrFeO3 nanofilaments are formed and extend almost through the BM SrFeO2.5 matrix in the ON state and are ruptured in the OFF state, unambiguously revealing a filamentary RS mechanism. The nanofilaments are ≈10 nm in diameter, enabling to downscale Au/SrFeOx /SrRuO3 RS devices to the 100 nm range for the first time. These nanodevices exhibit good performance including ON/OFF ratio as high as ≈104 , retention time over 105 s, and endurance up to 107 cycles. This study significantly advances the understanding of the RS mechanism in TMOs exhibiting topotactic phase transformation, and it also demonstrates the potential of these materials for use in high-density RS memories.

13.
Science ; 365(6453): 578-582, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31395780

RESUMO

Dielectric capacitors with ultrahigh power densities are fundamental energy storage components in electrical and electronic systems. However, a long-standing challenge is improving their energy densities. We report dielectrics with ultrahigh energy densities designed with polymorphic nanodomains. Guided by phase-field simulations, we conceived and synthesized lead-free BiFeO3-BaTiO3-SrTiO3 solid-solution films to realize the coexistence of rhombohedral and tetragonal nanodomains embedded in a cubic matrix. We obtained minimized hysteresis while maintaining high polarization and achieved a high energy density of 112 joules per cubic centimeter with a high energy efficiency of ~80%. This approach should be generalizable for designing high-performance dielectrics and other functional materials that benefit from nanoscale domain structure manipulation.

15.
Appl Opt ; 58(13): 3418-3425, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31044837

RESUMO

A multidimensional vector quantization-based fast statistical-estimation (VQ-FSE) algorithm is proposed to enhance data compression performance in digitalized radio over fiber (D-RoF) systems. The original samples with Gaussian distribution are first transformed into these with uniform distribution via companding transformation. After the companding transformation operation, the signal vector is constructed by grouping multiple samples in a certain way so that there is little correlation among them. The constructed signal vector may follow approximately multidimensional uniform distribution, and then multidimensional uniform quantization can be easily carried out, where the complex optimized process in nonuniform quantization is not required. For the proposed two-dimensional (2D) VQ-FSE algorithm, the proposed scheme is numerically verified in a 20 km D-RoF system with 2 Gbit/s RF wireless signal. Compared with the scalar-quantization-based FSE algorithm, its compression ratio is significantly enhanced. In comparison to the 2D k-means-clustering-based VQ algorithm, the proposed scheme shares a similar compression ratio and offers lower computational complexity. Therefore, the proposed algorithm has the ability to provide better compression and lower complexity for the digitized D-RoF system when the original sample follows Gaussian distribution.

16.
Horm Metab Res ; 51(4): 220-229, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31022738

RESUMO

High blood pressure is related with increased cerebrovascular accident. High visfatin / NAMPT(nicotinamide phosphoribosyltransferase) plasma levels may promote vascular inflammation and atherosclerotic plaque destabilization and have been evaluated as a marker for identifying stages of essential hypertension. However, its role in the pathogenesis of hypertension and cerebrovascular accident (CVA) is still uncertain. In order to review and meta-analyze observational studies investigating visfatin concentration and the risk for hypertension or CVA, a systematic search of PubMed, ovid EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) until December 07, 2016 was performed. After data extraction and quality assessment, a meta-analysis was performed using RevMan 5.3 and STATA 14.0. A total of 1693 adults from 8 studies for hypertension (974 with hypertension) and 1696 adults from 7 CVA studies (957 with CVA) were enrolled in the current meta-analysis. Cochran's Q-statistic and I2 test were applied to estimate the heterogeneity of the studies. The fixed-effects were used to compute the weighted mean difference in visfatin levels. Plasma visfatin concentration was much higher in hypertension and CVA patients than in healthy individuals. These evidences suggested the association of hypertension and CVA with higher plasma visfatin level.


Assuntos
Citocinas/sangue , Hipertensão/sangue , Hipertensão/enzimologia , Nicotinamida Fosforribosiltransferase/sangue , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/enzimologia , Humanos , Viés de Publicação , Relatório de Pesquisa
17.
Front Psychol ; 10: 722, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31019479

RESUMO

Stress reduction through contact with nature is well established, but far less is known about the contribution of contact parameters - duration, frequency, and nature quality. This study describes the relationship between duration of a nature experience (NE), and changes in two physiological biomarkers of stress - salivary cortisol and alpha-amylase. It is the first study to employ long-term, repeated-measure assessment and the first evaluation wherein study participants are free to choose the time of day, duration, and the place of a NE in response to personal preference and changing daily schedules. During an 8-week study period, 36 urban dwellers were asked to have a NE, defined as spending time in an outdoor place that brings a sense of contact with nature, at least three times a week for a duration of 10 min or more. Their goal was compliance within the context of unpredictable opportunity for taking a nature pill. Participants provided saliva samples before and after a NE at four points over the study period. Before-NE samples established the diurnal trajectory of each stress indicator and these were in line with published outcomes of more closely controlled experiments. For salivary cortisol, an NE produced a 21.3%/hour drop beyond that of the hormone's 11.7% diurnal drop. The efficiency of a nature pill per time expended was greatest between 20 and 30 min, after which benefits continued to accrue, but at a reduced rate. For salivary alpha-amylase, there was a 28.1%/h drop after adjusting for its diurnal rise of 3.5%/h, but only for participants that were least active sitting or sitting with some walking. Activity type did not influence cortisol response. The methods for this adaptive management study of nature-based restoration break new ground in addressing some complexities of measuring an effective nature dose in the context of normal daily life, while bypassing the limitations of a clinical pharmacology dose-response study. The results provide a validated starting point for healthcare practitioners prescribing a nature pill to those in their care. This line of inquiry is timely in light of expanding urbanization and rising healthcare costs.

18.
Circ Res ; 124(9): 1350-1359, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30836825

RESUMO

RATIONALE: ßARs (ß-adrenergic receptors) are prototypical GPCRs (G protein-coupled receptors) that play a pivotal role in sympathetic regulation. In heart cells, ß1AR signaling mediates a global response, including both l-type Ca2+ channels in the sarcolemma/T tubules and RyRs (ryanodine receptors) in the SR (sarcoplasmic reticulum). In contrast, ß2AR mediates local signaling with little effect on the function of SR proteins. OBJECTIVE: To investigate the signaling relationship between ß1ARs and ß2ARs. METHOD AND RESULTS: Using whole-cell patch-clamp analyses combined with confocal Ca2+ imaging, we found that the activation of compartmentalized ß2AR signaling was able to convert the ß1AR signaling from global to local mode, preventing ß1ARs from phosphorylating RyRs that were only nanometers away from sarcolemma/T tubules. This offside compartmentalization was eliminated by selective inhibition of ß2AR, GRK2 (GPCR kinase-2), ßarr1 (ß-arrestin-1), and phosphodiesterase-4. A knockin rat model harboring mutations of the last 3 serine residues of the ß1AR C terminus, a component of the putative ßarr1 binding site and GRK2 phosphorylation site, eliminated the offside compartmentalization conferred by ß2AR activation. CONCLUSIONS: ß2AR stimulation compartmentalizes ß1AR signaling into nanoscale local domains in a phosphodiesterase-4-dependent manner by targeting the C terminus of ß1ARs. This finding reveals a fundamental negative feed-forward mechanism that serves to avoid the cytotoxicity of circulating catecholamine and to sharpen the transient ß1AR response of sympathetic excitation.

19.
Zhongguo Zhong Yao Za Zhi ; 44(1): 175-180, 2019 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-30868829

RESUMO

To observe the clinical curative effect of Qingying Tang in the treatment of psoriatic blood-heat syndrome and explore its intrinsic mechanism.In this study,we collected 72 patients with blood-heat syndrome psoriasis admitted to our dermatology clinic from January 2016 to December 2017 and divided into control group and observation group according to the random number table method,36 cases in each group.The patients in control group were given with Acitretin Capsules orally,10 mg/time,twice a day.The patients in observation group were given with Qingying Tang orally,150 mL/time,twice a day.The treatment period was 12 weeks in both groups.The traditional Chinese medicine(TCM) syndrome scores before and after treatment,psoriasis area and severity index(PASI) score,dermatology life quality index(DLQI) score,and the clinical efficacy of the two groups were compared between the two groups;flow cytometry was used to detect peripheral blood Th17 cell percentages before and after treatment in both groups;serum interleukin(IL)-17,IL-23,IL-22,and IL-21 levels in both groups before and after treatment were measured by ELISA;the expression levels of STAT3 and RORγt before and after treatment in patients were measured by using skin lesion immunohistochemical method.The results showed that the TCM symptoms were improved significantly in both groups(P<0.05),and the effect in observation group was significantly better than that in the control group(P<0.05).PASI and DLQI scores were decreased significantly after treatment in both groups(P<0.05),and the scores in observation group were significantly lower than those in the control group(P<0.05).The curative effect of the observation group was significantly higher than that of the control group(P<0.05).After treatment,the percentage of Th17 cells,as well as IL-17,IL-23,IL-22 and IL-21 levels in peripheral blood were significantly decreased in both groups(P<0.05),and the levels in observation group were significantly lower than those in the control group(P<0.05).The expression levels of STAT3 and RORγt in both groups were significantly lower than those before treatment(P<0.01),and the levels in observation group were significantly lower than those in the control group(P<0.05).All of the results indicted that Qingying Tang can effectively improve the skin lesions and TCM syndrome in patients with psoriasis and blood-heat syndrome,and improve patient health quality,which may be related to regulation of peripheral blood IL-23/Th17.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Interleucina-23/imunologia , Psoríase/tratamento farmacológico , Células Th17/imunologia , Administração Oral , Humanos , Resultado do Tratamento
20.
Curr Biol ; 29(4): 637-644.e3, 2019 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-30713103

RESUMO

Sleep is regulated by homeostatic process and circadian clock. Light indirectly modulates sleep by entraining the circadian clock to the solar day. Light can also influence sleep independent of photo-entrainment [1]. An acute light exposure could induce sleep, and an acute dark pulse could increase wakefulness in nocturnal animals [1, 2]. The photoreceptors and cell types in the retina that mediate light and dark effects on sleep are well characterized [1-4]. A few studies have explored the brain region involved in acute light induction of sleep. Fos expression and nonspecific lesions suggest that the superior colliculus (SC) may play a role in acute light induction of sleep [2, 5]. In contrast, the brain area and neural circuits mediating acute dark induction of wakefulness are unknown. Here, we demonstrated that retina ganglion cells (RGCs) had direct innervations on the GABAergic neurons in the mouse SC, and the activities of these cells were inhibited by an acute dark pulse, but not influenced by a light pulse. Moreover, ablating SC GABAergic neurons abolished the acute dark induction of wakefulness, but not light induction of sleep. Based on optogenetic and electrophysiological experiments, we found that SC GABAergic neurons formed monosynaptic functional connections with dopaminergic neurons in the ventral tegmental area (VTA). Selective lesions of VTA dopaminergic cells totally abolished acute dark induction of wakefulness without affecting the light induction of sleep. Collectively, our findings uncover a fundamental role for a retinal-SC GABAergic-VTA dopaminergic circuit in acute dark induction of wakefulness and indicate that the dark and light signals affect sleep-wake behaviors through distinct pathways.

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