RESUMO
Galanin receptor1 (GalR1) transcript levels are elevated in the rat ventral periaqueductal gray (vPAG) after chronic mild stress (CMS) and are related to depression-like behavior. To explore the mechanisms underlying the elevated GalR1 expression, we carried out molecular biological experiments in vitro and in animal behavioral experiments in vivo. It was found that a restricted upstream region of the GalR1 gene, from -250 to -220, harbors an E-box and plays a negative role in the GalR1 promoter activity. The transcription factor Scratch2 bound to the E-box to down-regulate GalR1 promoter activity and lower expression levels of the GalR1 gene. The expression of Scratch2 was significantly decreased in the vPAG of CMS rats. Importantly, local knockdown of Scratch2 in the vPAG caused elevated expression of GalR1 in the same region, as well as depression-like behaviors. RNAscope analysis revealed that GalR1 mRNA is expressed together with Scratch2 in both GABA and glutamate neurons. Taking these data together, our study further supports the involvement of GalR1 in mood control and suggests a role for Scratch2 as a regulator of depression-like behavior by repressing the GalR1 gene in the vPAG.
Assuntos
Comportamento Animal , Depressão/patologia , Substância Cinzenta Periaquedutal/patologia , Receptor Tipo 1 de Galanina/metabolismo , Fatores de Transcrição/metabolismo , Animais , Elementos E-Box/genética , Neurônios GABAérgicos/metabolismo , Regulação da Expressão Gênica , Ácido Glutâmico/metabolismo , Células PC12 , Regiões Promotoras Genéticas/genética , Ligação Proteica , Ratos , Receptor Tipo 1 de Galanina/genética , Estresse Psicológico/complicações , Fatores de Transcrição/genética , Sítio de Iniciação de TranscriçãoRESUMO
Autonomous underwater vehicles (AUVs)-assisted mobile data collection in underwater wireless sensor networks (UWSNs) has received significant attention because of their mobility and flexibility. To satisfy the increasing demand of diverse application requirements for underwater data collection, such as time-sensitive data freshness, emergency event security as well as energy efficiency, in this paper, we propose a novel multi-modal AUV-assisted data collection scheme which integrates both acoustic and optical technologies and takes advantage of their complementary strengths in terms of communication distance and data rate. In this scheme, we consider the age of information (AoI) of the data packet, node transmission energy as well as energy consumption of the AUV movement, and we make a trade-off between them to retrieve data in a timely and reliable manner. To optimize these, we leverage a deep reinforcement learning (DRL) approach to find the optimal motion trajectory of AUV by selecting the suitable communication options. In addition to that, we also design an optimal angle steering algorithm for AUV navigation under different communication scenarios to reduce energy consumption further. We conduct extensive simulations to verify the effectiveness of the proposed scheme, and the results show that the proposed scheme can significantly reduce the weighted sum of AoI as well as energy consumption.
Assuntos
Algoritmos , Redes de Comunicação de Computadores , Tecnologia sem Fio , Comunicação , AcústicaRESUMO
Olfactory impairment is an initial non-motor symptom of Parkinson's disease that causes the deposition of aggregated α-synuclein (α-syn) in olfactory neurons. Transient receptor potential canonical (TRPC) channels are a diverse group of non-selective Ca2+ entry channels involved in the progression or pathogenesis of PD via Ca2+ homeostatic regulation. However, the relationship between TRPC and α-syn pathology in an olfactory system remains unclear. To address this issue, we assessed the olfactory function in α-syn transgenic mice. In contrast with control mice, the transgenic mice exhibited impaired olfaction, TRPC3 activation and apoptotic neuronal cell death in the olfactory system. Similar results were observed in primary cultures of olfactory neurons, that is TRPC3 activation, increasing intracellular Ca2+ concentration and apoptotic cell death in the α-syn-overexpressed neurons. These changes were significantly attenuated by TRPC3 knockdown. Therefore, our findings suggest that TRPC3 activation and calcium dyshomeostasis play a key role in α-syn-induced olfactory dysfunction in mice.
Assuntos
Transtornos do Olfato , Canais de Cátion TRPC , alfa-Sinucleína , Animais , Cálcio/metabolismo , Camundongos , Camundongos Transgênicos , Transtornos do Olfato/genética , Fosforilação , Canais de Cátion TRPC/genética , Canais de Cátion TRPC/metabolismo , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
The neuropeptide galanin coexists in rat brain with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus (LC), and it has been suggested to be involved in depression. We studied rats exposed to chronic mild stress (CMS), a rodent model of depression. As expected, these rats showed several endophenotypes relevant to depression-like behavior compared with controls. All these endophenotypes were normalized after administration of a selective serotonin reuptake inhibitor. The transcripts for galanin and two of its receptors, galanin receptor 1 (GALR1) and GALR2, were analyzed with quantitative real-time PCR using laser capture microdissection in the following brain regions: the hippocampal formation, LC, and ventral periaqueductal gray (vPAG). Only Galr1 mRNA levels were significantly increased, and only in the latter region. After knocking down Galr1 in the vPAG with an siRNA technique, all parameters of the depressive behavioral phenotype were similar to controls. Thus, the depression-like behavior in rats exposed to CMS is likely related to an elevated expression of Galr1 in the vPAG, suggesting that a GALR1 antagonist could have antidepressant effects.
Assuntos
Depressão/etiologia , Substância Cinzenta Periaquedutal/fisiologia , Receptor Tipo 1 de Galanina/fisiologia , Animais , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Locus Cerúleo/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Galanina/antagonistas & inibidores , Serotonina/fisiologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
Localization is a critical issue for Underwater Acoustic Sensor Networks (UASNs). Existing localization algorithms mainly focus on localizing unknown nodes (location-unaware) by measuring their distances to beacon nodes (location-aware), whereas ignoring additional challenges posed by harsh underwater environments. Especially, underwater nodes move constantly with ocean currents and measurement noises vary with distances. In this paper, we consider a special drifting-restricted UASN and propose a novel beacon-free algorithm, called MAP-PSO. It consists of two steps: MAP estimation and PSO localization. In MAP estimation, we analyze nodes' mobility patterns, which provide the priori knowledge for localization, and characterize distance measurements under the assumption of additive and multiplicative noises, which serve as the likelihood information for localization. Then the priori and likelihood information are fused to derive the localization objective function. In PSO localization, a swarm of particles are used to search the best location solution from local and global views simultaneously. Moreover, we eliminate the localization ambiguity using a novel reference selection mechanism and improve the convergence speed using a bound constraint mechanism. In the simulations, we evaluate the performance of the proposed algorithm under different settings and determine the optimal values for tunable parameters. The results show that our algorithm outperforms the benchmark method with high localization accuracy and low energy consumption.
RESUMO
Localization is one of the critical services in Underwater Acoustic Sensor Networks (UASNs). Due to harsh underwater environments, the nodes often move with currents continuously. Consequently, the acoustic signals usually propagate with varying speeds in non-straight lines and the noise levels change frequently with the motion of the nodes. These limitations pose huge challenges for localization in UASNs. In this paper, we propose a novel localization method based on a variational filtering technique, in which the spatial correlation and temporal dependency information are utilized to improve localization performance. In the method, a state evolution model is employed to characterize the mobility pattern of the nodes and capture the uncertainty of the location transition. Then, a measurement model is used to reflect the relation between the measurements and the locations considering the dynamics of the acoustic speed and range noise. After that, a variational filtering scheme is adopted to determine the nodes’ locations, which consists of two phases: variational prediction and update. In the former phase, the coarse estimation of each node’ location is computed based on its previous location; in the latter phase, the coarse location is optimized by incorporating the measurements from the reference nodes as precisely as possible. At last, an iterative localization scheme is applied, in which a node labels itself as a reference node if the confidence of its location estimation is higher than the predefined threshold. We conducted extensive simulations under different parameter settings, and the results indicate that the proposed method has better localization accuracy compared to a typical SLMP algorithm while maintaining relatively high localization coverage. Moreover, spatialâ»temporal variational filtering (STVF) is more robust to the change of the parameter settings compared to SLMP.
RESUMO
α-Synuclein accumulation and transmission are vital to the pathogenesis of Parkinson's disease, although the mechanisms underlying misfolded α-synuclein accumulation and propagation have not been conclusively determined. The expression of low-density lipoprotein receptor-related protein 1, which is abundantly expressed in neurons and considered to be a multifunctional endocytic receptor, is elevated in the neurons of patients with Parkinson's disease. However, whether there is a direct link between low-density lipoprotein receptor- related protein 1 and α-synuclein aggregation and propagation in Parkinson's disease remains unclear. Here, we established animal models of Parkinson's disease by inoculating monkeys and mice with α-synuclein pre-formed fibrils and observed elevated low-density lipoprotein receptor-related protein 1 levels in the striatum and substantia nigra, accompanied by dopaminergic neuron loss and increased α-synuclein levels. However, low-density lipoprotein receptor-related protein 1 knockdown efficiently rescued dopaminergic neurodegeneration and inhibited the increase in α-synuclein levels in the nigrostriatal system. In HEK293A cells overexpressing α-synuclein fragments, low-density lipoprotein receptor-related protein 1 levels were upregulated only when the N-terminus of α-synuclein was present, whereas an α-synuclein fragment lacking the N-terminus did not lead to low-density lipoprotein receptor-related protein 1 upregulation. Furthermore, the N-terminus of α-synuclein was found to be rich in lysine residues, and blocking lysine residues in PC12 cells treated with α-synuclein pre-formed fibrils effectively reduced the elevated low-density lipoprotein receptor-related protein 1 and α-synuclein levels. These findings indicate that low-density lipoprotein receptor-related protein 1 regulates pathological transmission of α-synuclein from the striatum to the substantia nigra in the nigrostriatal system via lysine residues in the α-synuclein N-terminus.
RESUMO
Previous studies have shown that α-synuclein (α-Syn) aggregates derived from the brains of patients with Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit different phosphorylation, cytotoxicity, and seeding activity. However, the mechanism underlying the differences remains poorly understood. Here, recombinant human α-Syn was incubated in the plasma of patients with PD and MSA, and the oligomers formed in the plasma (PD-O-α-Syn and MSA-O-α-Syn) were purified and analyzed for their phosphorylation, cytotoxicity and seeding activity. In vitro assays revealed that both PD-O-α-Syn and MSA-O-α-Syn were phosphorylated at serine 129. However, the phosphorylation degree of MSA-O-α-Syn was significantly higher than that of PD-O-α-Syn. In addition, MSA-O-α-Syn exhibited stronger cytotoxicity and seeding activity compared with PD-O-α-Syn. In vivo experiments showed that mice receiving intrastriatal inoculation of MSA-O-α-Syn developed more severe motor dysfunction and dopaminergic degeneration than mice receiving intrastriatal inoculation of PD-O-α-Syn. Compared with the mice inoculated with PD-O-α-Syn, the mice inoculated with MSA-O-α-Syn accumulated more phosphorylated and oligomerized α-Syn in the striatum and brain regions (substantia nigra, hippocampus and prefrontal cortex) away from the inoculated site. The results obtained suggest that α-Syn oligomers formed in PD and MSA plasma are different in phosphorylation, cytotoxicity, and seeding activity.
Assuntos
Atrofia de Múltiplos Sistemas , Doença de Parkinson , alfa-Sinucleína , alfa-Sinucleína/metabolismo , Atrofia de Múltiplos Sistemas/patologia , Atrofia de Múltiplos Sistemas/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/sangue , Humanos , Animais , Fosforilação , Masculino , Camundongos , Pessoa de Meia-Idade , Feminino , Idoso , Camundongos Endogâmicos C57BLRESUMO
AIMS: The etiology of Parkinson's disease (PD) is complex and the mechanism is unclear. It has become a top priority to find common factors that induce and affect PD pathology. We explored the key role of hypoxia in promoting the pathological propagation of α-synuclein (α-syn) and the progression of PD. METHODS: We performed PD modeling by conducting intracranial stereotaxic surgery in the unilateral striatum of mice. We then measured protein aggregation in vitro. The rotarod and pole tests were employed next to measure the damage of the phenotype. Pathological deposition and autophagy were also observed by immunofluorescence staining and protein levels measured by western blotting. RESULTS: We demonstrated that short-term hypoxia activated phosphorylated (p)-α-syn in mice. We confirmed that p-α-syn was more readily formed aggregates than α-syn in vitro. Furthermore, we found that hypoxia promoted the activation and propagation of endogenous α-syn, contributing to the earlier degeneration of dopaminergic neurons in the substantia nigra and the deposition of p-α-syn in our animal model. Finally, autophagy inhibition contributed to the above pathologies. CONCLUSION: Hypoxia was shown to accelerate the pathological progression and damage phenotype in PD model mice. The results provided a promising research target for determining common interventions for PD in the future.
Assuntos
Doença de Parkinson , alfa-Sinucleína , Camundongos , Animais , alfa-Sinucleína/metabolismo , Neurônios Dopaminérgicos/metabolismo , Doença de Parkinson/genética , Substância Negra , Corpo Estriado/metabolismoRESUMO
Mitochondrial dysfunction and oxidative stress are thought to play a dominant role in the pathogenesis of Parkinson's disease (PD). Mogroside V (MV), extracted from Siraitia grosvenorii, exhibits antioxidant-like activities. The aim of this study was to investigate the function of MV in neuroprotection in PD and to reveal its mechanism of action. To that end, we firstly set up mice models of PD with unilateral striatum injection of 0.25 mg/kg rotenone (Rot) and co-treated with 2.5 mg/kg, 5 mg/kg, and 10 mg/kg MV by gavage. Results showed that Rot-induced motor impairments and dopaminergic neuronal damage were reversed by treatment of 10 mg/kg MV. Then, we established cellular models of PD using Rot-treated SH-SY5Y cells, which were divided into six groups, including control, Rot, and co-enzyme Q10 (CQ10), as well as MV groups, MV25, MV50, and MV100 treated with 25 µM, 50 µM, and 100 µM MV doses, respectively. Results demonstrated that MV effectively attenuates Rot neurotoxicity through a ROS-related intrinsic mitochondrial pathway. MV reduced overproduction of reactive oxygen species (ROS), recovered the mitochondrial membrane potential (MMP), and increased the oxygen consumption rate and adenosine triphosphate (ATP) production in a dose-dependent manner. Hence, treatment with MV led to a reduction in the number of apoptotic cells, as reflected by Annexin-V/propidium iodide co-staining using flow cytometry and TdT-mediated dUTP Nick-End Labeling (TUNEL) assay. In addition, the Sirtuin3 (SIRT3) protein level and activity were decreased upon exposure to Rot both in substantia nigra (SN) of mice and SH-SY5Y cells. SIRT3 impairment hyperacetylated a key mitochondrial antioxidant enzyme, superoxide dismutase 2 (SOD2). MV alleviates SIRT3 and SOD2 molecular changes. However, after successfully inhibiting SIRT3 by its specific inhibitor 3-1H-1, 2, 3-triazol-4-yl pyridine (3TYP), MV was not able to reduce ROS levels, reverse abnormal MMP, or decrease apoptotic cells. Motor impairments and dopaminergic neuronal injury in the SN were alleviated with the oral administration of MV in Rot-treated PD mice, indicating a relationship between protection against defective motility and preservation of dopaminergic neurons. Therefore, we conclude that MV can alleviate Rot-induced neurotoxicity in a PD model, and that SIRT3 may be an important regulator in the protection of MV.
Assuntos
Fármacos Neuroprotetores , Síndromes Neurotóxicas , Doença de Parkinson , Sirtuína 3 , Humanos , Antioxidantes/metabolismo , Neurônios Dopaminérgicos/metabolismo , Mitocôndrias/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/patologia , Estresse Oxidativo , Doença de Parkinson/patologia , Espécies Reativas de Oxigênio/metabolismo , Rotenona/farmacologia , Sirtuína 3/metabolismo , TriterpenosRESUMO
Underwater acoustic sensor networks (UWA-SNs) are envisioned to perform monitoring tasks over the large portion of the world covered by oceans. Due to economics and the large area of the ocean, UWA-SNs are mainly sparsely deployed networks nowadays. The limited battery resources is a big challenge for the deployment of such long-term sensor networks. Unbalanced battery energy consumption will lead to early energy depletion of nodes, which partitions the whole networks and impairs the integrity of the monitoring datasets or even results in the collapse of the entire networks. On the contrary, balanced energy dissipation of nodes can prolong the lifetime of such networks. In this paper, we focus on the energy balance dissipation problem of two types of sparsely deployed UWA-SNs: underwater moored monitoring systems and sparsely deployed two-dimensional UWA-SNs. We first analyze the reasons of unbalanced energy consumption in such networks, then we propose two energy balanced strategies to maximize the lifetime of networks both in shallow and deep water. Finally, we evaluate our methods by simulations and the results show that the two strategies can achieve balanced energy consumption per node while at the same time prolong the networks lifetime.
RESUMO
ETS-1 is a transcription factor that is a member of the E26 transformation-specific (ETS) family. Galanin receptor 2 (GalR2), a subtype of receptors of the neuropeptide galanin, has been shown to have an antidepressant-like effect after activation in rodents. Our previous study has shown that overexpression of ETS-1 increases the expression of GalR2 in PC12 phaeochromocytoma cells. However, whether ETS-1 has an antidepressant-like effect is still unclear. In this study, we found that chronic mild stress (CMS) decreased the expression of both ETS-1 and GalR2 in the ventral hippocampus of rats. Meanwhile, we demonstrated that overexpression of ETS-1 increased the expression of GalR2 in primary hippocampal neurons. Importantly, we showed that overexpression of ETS-1 in the ventral hippocampus counteracted the depression-like behaviors of CMS rats. Furthermore, we found that overexpression of ETS-1 increased the level of downstream phosphorylated extracellular signal-regulated protein kinases 1 and 2 (p-ERK1/2) of GalR2 in the ventral hippocampus of CMS rats. Taken together, our findings suggest that ETS-1 has an antidepressant-like effect in rats, which might be mediated by increasing the level of GalR2 and its downstream p-ERK1/2 in the ventral hippocampus.
Assuntos
Depressão/metabolismo , Hipocampo/metabolismo , Proteína Proto-Oncogênica c-ets-1/metabolismo , Anedonia , Animais , Sistema de Sinalização das MAP Quinases , Masculino , Ratos , Ratos Sprague-Dawley , Receptor Tipo 2 de Galanina/metabolismo , Sacarose , NataçãoRESUMO
MicroRNAs (miRNAs) play an important role in multiple biological processes, and many miRNAs have been shown to regulate cell proliferation and apoptosis. In this study, we investigated the role of miR-15b-5p in cell proliferation and apoptosis in PC12 cells. We found that overexpression of miR-15b-5p could decrease cell proliferation and induce apoptosis and cytotoxic activities in PC12 cells. Bioinformatics analysis and luciferase activities assays showed that miR-15b-5p might target extracellular signal-regulated kinase 1 (ERK1) by binding to its 3'-untranslated region (3'-UTR). Moreover, we also found that overexpression of ERK1 could attenuate the effects of miR-15b-5p in PC12 cells. Finally, our results suggest that miR-15b-5p might inhibit cell proliferation and induce apoptosis in PC12 cells by targeting ERK1.
Assuntos
Neoplasias das Glândulas Suprarrenais/enzimologia , Apoptose , Proliferação de Células , MicroRNAs/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Feocromocitoma/enzimologia , Regiões 3' não Traduzidas , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Animais , Sítios de Ligação , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Células PC12 , Feocromocitoma/genética , Feocromocitoma/patologia , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
Galanin receptor 2 (GAL2R) is a G protein-coupled receptor for the neuropeptide galanin that regulates many important physiological functions and pathological processes. To investigate the molecular mechanism governing GAL2R gene transcription, the rat GAL2R promoter was isolated and analyzed. We found that the region from -320 to -300 of the GAL2R promoter contains two putative ETS-1 elements and plays an important role in regulating GAL2R promoter activity. We also showed that transcription factor ETS-1 bound to this region in vitro and in vivo. Overexpression of ETS-1 significantly increased GAL2R promoter activity and transcription of the GAL2R gene, whereas knockdown of ETS-1 produced the opposite effects. In addition, we showed that ETS-1 recruited co-activator p300 to the GAL2R promoter. These data indicate a role for ETS-1 in the control of the GAL2R gene expression and provide a basis for understanding the transcriptional regulation of the GAL2R gene.
Assuntos
Regulação da Expressão Gênica , Regiões Promotoras Genéticas , Proteína Proto-Oncogênica c-ets-1/metabolismo , Receptor Tipo 2 de Galanina/genética , Animais , Sequência de Bases , Proteína p300 Associada a E1A , Células PC12 , Ligação Proteica , Ratos , Receptor Tipo 2 de Galanina/metabolismo , Sítio de Iniciação de TranscriçãoRESUMO
Focal cortical dysplasia (FCD) is a common cause of pharmacologically-intractable epilepsy, however, the precise mechanisms underlying the epileptogenicity of FCD remains to be determined. Neuropeptide Y (NPY), an endogenous anticonvulsant in the central nervous system, plays an important role in the regulation of neuronal excitability. Increased expression of NPY and its receptors has been identified in the hippocampus of patients with mesial temporal lobe epilepsy, presumed to act as an endogenous anticonvulsant mechanism. Therefore, we investigated whether expression changes in NPY receptors occurs in patients with FCD. We specifically investigated the expression of seizure-related NPY receptor subtypes Y1, Y2, and Y5 in patients with FCD versus autopsy controls. We found that Y1R and Y2R were up-regulated at the mRNA and protein levels in the temporal and frontal lobes in FCD lesions. By contrast, there was no significant change in either receptor detected in parietal lesions. Notably, overexpression of Y5R was consistently observed in all FCD lesions. Our results demonstrate the altered expression of Y1R, Y2R and Y5R occurs in FCD lesions within the temporal, frontal and parietal lobe. Abnormal NPY receptor subtype expression may be associated with the onset and progression of epileptic activity and may act as a therapeutic candidate for the treatment of refractory epilepsy caused by FCD.