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BACKGROUND: The healing process after a myocardial infarction (MI) in humans involves complex events that replace damaged tissue with a fibrotic scar. The affected cardiac tissue may lose its function permanently. In contrast, zebrafish display a remarkable capacity for scar-free heart regeneration. Previous studies have revealed that syndecan-4 (SDC4) regulates inflammatory response and fibroblast activity following cardiac injury in higher vertebrates. However, whether and how Sdc4 regulates heart regeneration in highly regenerative zebrafish remains unknown. METHODS AND RESULTS: This study showed that sdc4 expression was differentially regulated during zebrafish heart regeneration by transcriptional analysis. Specifically, sdc4 expression increased rapidly and transiently in the early regeneration phase upon ventricular cryoinjury. Moreover, the knockdown of sdc4 led to a significant reduction in extracellular matrix protein deposition, immune cell accumulation, and cell proliferation at the lesion site. The expression of tgfb1a and col1a1a, as well as the protein expression of Fibronectin, were all down-regulated under sdc4 knockdown. In addition, we verified that sdc4 expression was required for cardiac repair in zebrafish via in vivo electrocardiogram analysis. Loss of sdc4 expression caused an apparent pathological Q wave and ST elevation, which are signs of human MI patients. CONCLUSIONS: Our findings support that Sdc4 is required to mediate pleiotropic repair responses in the early stage of zebrafish heart regeneration.
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Coração , Regeneração , Sindecana-4 , Peixe-Zebra , Animais , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Sindecana-4/genética , Sindecana-4/metabolismo , Regeneração/genética , Coração/fisiologia , Coração/fisiopatologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Proliferação de Células/genética , Miocárdio/metabolismo , Miocárdio/patologia , Técnicas de Silenciamento de GenesRESUMO
In order to solve the problem of flexible sliding tactile composite sensing in the actual grasp of intelligent robot fingers, this paper proposes a research on a convex fiber grating tactile sliding sensor based on mechanical fingers. Based on the sensing principle of fiber Bragg grating, 3D printing technology was used to encapsulate the FBG sensor array with elastic 50 A resin, a double-layer "hemispherical cuboid" distributed sensing unit was designed, and the FBG slippery tactile sensor was actually pasted on the surface of the mechanical finger for static and dynamic experiments. The experimental results show that the slippery tactile sensor designed in this paper has a good linear relationship with temperature and strain. The temperature sensitivities of the polymer-packaged FBGs are KT1 = 13.04 pm/°C and KT2 = 12.91 pm/°C, and they have a pressure sensitivity of 40.4 pm/N and 31.2 pm/N, respectively. The FBG sliding tactile sensor not only realizes the identification of the sliding signal generation point and the end point but also completes the classification and identification of sandpaper, cardboard, and polypropylene plastic, and it has a high degree of fit with the robot finger, which has certain application value for the intelligent robot sliding tactile signal perception.
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Shape recognition plays a significant role in the field of robot perception. In view of the low efficiency and few types of shape recognition of the fiber tactile sensor applied to flexible skin, a convolutional-neural-network-based FBG tactile sensing array shape recognition method was proposed. Firstly, a sensing array was fabricated using flexible resin and 3D printing technology. Secondly, a shape recognition system based on the tactile sensing array was constructed to collect shape data. Finally, shape classification recognition was performed using convolutional neural network, random forest, support vector machine, and k-nearest neighbor. The results indicate that the tactile sensing array exhibits good sensitivity and perception capability. The shape recognition accuracy of convolutional neural network is 96.58%, which is 6.11%, 9.44%, and 12.01% higher than that of random forest, k-nearest neighbor, and support vector machine. Its F1 is 96.95%, which is 6.3%, 8.73%, and 11.94% higher than random forest, k-nearest neighbor, and support vector machine. The research of FBG shape sensing array based on convolutional neural network provides an experimental basis for shape perception of flexible tactile sensing.
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Aiming at the problems of lateral force interference and non-uniform strain of robot fingers in the process of pressure tactile sensing, a flexible tactile sensor with a square hole structure based on fiber Bragg grating (FBG) is proposed in this paper. Firstly, the optimal embedding depth of the FBG in the sensor matrix model was determined by finite element simulation. Secondly, according to the size of the finger knuckle and the simulation analysis based on the pressure tactile sensor element for the robot finger, the square hole structure was designed, and the overall dimensions of the sensing element and size of the square hole were determined. Thirdly, the FBG was embedded in the polydimethylsiloxane (PDMS) elastic matrix to make a sensor model, and the tactile sensor was fabricated. Finally, the FBG pressure tactile sensing system platform was built by using optical fiber sensing technology, and the experiment of the FBG tactile sensor was completed through the sensing system platform. Experimental results show that the tactile sensor designed in this paper has good repeatability and creep resistance. The sensitivity is 8.85 pm/N, and the resolution is 0.2 N. The loading sensitivity based on the robot finger is 27.3 pm/N, the goodness of fit is 0.996, and the average value of interference in the sensing process is 7.63%, which is lower than the solid structure sensor. These results verify that the sensor can effectively reduce the lateral force interference and solve the problem of non-uniform strain and has high fit with fingers, which has a certain application value for the research of robot pressure tactile intelligent perception.
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We introduce adiabaticity engineering in coupled waveguide devices to achieve shortcuts to adiabaticity in multi-wavelength systems. By engineering the adiabaticity distribution using a single control parameter, we obtain large operating bandwidth in a compact device. Multi-wavelength adiabaticity engineering is applied to the design of silicon polarization splitter-rotators. The total length of the designed polarization splitter-rotator is 141 µm, and simulations show that the device exhibits extinction ratios above 28 dB and 16 dB for the TE0 and TM0 modes, respectively, with a bandwidth of 300 nm (from 1.4 µm to 1.7 µm). The fabrication tolerance of the designed device is also simulated.
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This publisher's note contains corrections to [Opt. Express30, 20213 (2022)10.1364/OE.457921].
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Flexible, stretchable, and bendable electronics and optoelectronics have a great potential for wide applications in smart life. An environmentally friendly, cost effective and wide-angle emission laser is indispensable for the emerging technology. In this work, circumvent the challenge issue, cavity-free and stretchable white light lasers based on all carbon materials have been demonstrated by integration of fluorescent carbon quantum dots (CQDs) and crumpled graphene. The typical emission spectrum of the cavity-free laser based on all-carbon materials has a CIE chromaticity coordinate of (0.30, 0.38) exhibiting an intriguing broadband white-light emission. The unprecedented and non-toxic stretchable and white light cavity-free lasers based on all-carbon materials can serve as next-generation optoelectronic devices for a wide range application covering solid-state lighting and future wearable technologies.
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In this study, a twisted nematic mode polymer-stabilized liquid crystal (TN mode PSLC) integrated with a crossed polarizer was used to create a transparent waveguide display. When a voltage was applied, the PSLC scattered the waveguide light with a high polarization selectivity such that no substantial loss of the outgoing light intensity was observed after integrating the polarizer. However, with a crossed polarizer, in the ON state, the background light was not only scattered but also absorbed by the analyzer. Using this device configuration, with a 12 µm cell gap and 7% monomer concentration, we successfully realized a normally transparent waveguide display. The contrast ratio of the waveguide outgoing light was 26 and that of the undesired background reached 90. This device can display images due to waveguide edge-lit light scattering and simultaneously block the background information to improve the image quality.
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Dietary restriction (DR; sometimes called calorie restriction) has profound beneficial effects on physiological, psychological, and behavioral outcomes in animals and in humans. We have explored the molecular mechanism of DR-induced memory enhancement and demonstrate that dietary tryptophan-a precursor amino acid for serotonin biosynthesis in the brain-and serotonin receptor 5-hydroxytryptamine receptor 6 (HTR6) are crucial in mediating this process. We show that HTR6 inactivation diminishes DR-induced neurological alterations, including reduced dendritic complexity, increased spine density, and enhanced long-term potentiation (LTP) in hippocampal neurons. Moreover, we find that HTR6-mediated mechanistic target of rapamycin complex 1 (mTORC1) signaling is involved in DR-induced memory improvement. Our results suggest that the HTR6-mediated mTORC1 pathway may function as a nutrient sensor in hippocampal neurons to couple memory performance to dietary intake.
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Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Memória/fisiologia , Receptores de Serotonina/metabolismo , Ácido 3-Hidroxibutírico/sangue , Animais , Western Blotting , Corticosterona/sangue , Eletrofisiologia , Teste de Tolerância a Glucose , Hipocampo/citologia , Hipocampo/metabolismo , Potenciação de Longa Duração/fisiologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Neurônios/metabolismo , RNA Mensageiro/metabolismo , Receptores de Serotonina/genética , Serotonina/sangue , Transdução de Sinais/genética , Transdução de Sinais/fisiologiaRESUMO
Aiming at the problem of flexible sliding tactile sensing for the actual grasp of intelligent robot fingers, a double-layer sliding tactile sensor based on fiber Bragg grating (FBG) for robot fingers is proposed in this paper. Firstly, the optimal embedding depth range of FBG in the elastic matrix of polydimethylsiloxane (PDMS) was determined through finite element analysis and static detection experiments of finger tactile sensing. Secondly, the sensor structure is optimized and designed through the simulation and dynamic experiments of sliding sensing to determine the final array structure. Thirdly, the sensing array is actually pasted on the surface of the robot finger and the sensing characteristics testing platform is built to test and analyze the basic performance of the sliding tactile sensor. Then, the sensor array is actually attached to the finger surface of the robot and the sensing characteristics testing platform is built to experiment and analyze the basic performance of the sliding tactile sensor. Finally, a sliding tactile sensing experiment of robot finger grasping is conducted. The experimental results show that the sliding tactile sensor designed in this paper has good repeatability and creep resistance, with sensitivities of 12.4 pm/N, 11.6 pm/N, and 14.5 pm/N, respectively, and the overall deviation is controlled within 5 pm. Meanwhile, it can effectively sense the signals of the robot fingers during static contact and sliding. The sensor has a high degree of fit with the robot finger structure, and has certain application value for the perception of sliding tactile signals in the object grasping of intelligent robot objects.
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Robótica , Percepção do Tato , Tato , Dedos , Força da MãoRESUMO
Against the backdrop of "Internet+" and Made in China 2025, Chinese medicinal processing equipment embraces various opportunities and develops to an unprecedented level. In the 20 years of the new century, the processing equipment has gradually developed in the direction of high efficiency, energy saving, environmental protection, integration, and automation, and this field has tended to highlight the establishment and application of the linkage production line for the processing of Chinese medicinal decoction pieces. Integrating automation control technology, online detection technique, and the internet of things technology, the online detection system of Chinese medicinal processing equipment and the computer information management system of Chinese medicinal proces-sing are the mainstream development trends of Chinese medicinal processing equipment. Standard Chinese medicine processing equipment is the prerequisite for the standardization of processing parameters. A standard system for processing equipment and processing parameters is the key to the modernization of Chinese medicinal decoction pieces. This paper summarized the research and application of Chinese medicinal processing equipment in the 20 years of the 21 st century and predicted the development trend, which is expected to serve as a reference for the technological innovation and development of the processing equipment.
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Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Automação , Controle de Qualidade , Padrões de ReferênciaRESUMO
This study aimed to forecast the main active components of Xiaoer Chiqiao Qingre Granules(XECQ) in the treatment of children with acute upper respiratory tract infection by UPLC-MS, network pharmacology, molecular docking and cell biology, and explore the mechanism of action, so as to provide certain reference for the research on its pharmacodynamics substances and mechanism of action. The main chemical components of XECQ were comprehensively analyzed by UPLC-Q-TOF-MS combined with UNIFI platform. According to the MS1 and MS2 data of XECQ, comparison and identification were carried out in combination with reference substances and reference articles. On this basis, the chemical components of XECQ were targeted and enriched by network pharmacology, to screen the main pharmacodynamic substances of XECQ in the treatment of acute upper respiratory tract infection in children and discuss the mechanism of action. In addition, the binding degree of core targets and main active components was verified by molecular docking. The results revealed that 202 compounds were identified from XECQ, among which 22 were the main active components, including obovatol, dihydroartemisinin, and longikaurin A. Enrichment analysis of the key target pathways showed that XECQ played its role in the treatment of children with acute upper respiratory tract infection mainly by regulating PI3K/Akt signaling pathway and MAPK signaling pathway. In the experimental verification by Western Blot(WB), it was found that XECQ significantly inhibited the expression of PI3K and Akt, which was consistent with the prediction results of network pharmacology. In conclusion, the potential pharmacodynamic substances of XECQ were obovatol, dihydroartemisinin, longikaurin A and other 19 active components. It treated children with acute upper respiratory tract infection by regulating the PI3K/Akt signaling pathway.
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Artemisininas , Medicamentos de Ervas Chinesas , Infecções Respiratórias , Criança , Humanos , Cromatografia Líquida , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt , Espectrometria de Massas em Tandem , Infecções Respiratórias/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologiaRESUMO
BACKGROUND: Methamphetamine (METH) is one of the most widely abused illicit substances worldwide; unfortunately, its addiction mechanism remains unclear. Based on accumulating evidence, changes in gene expression and chromatin modifications might be related to the persistent effects of METH on the brain. In the present study, we took advantage of METH-induced behavioral sensitization as an animal model that reflects some aspects of drug addiction and examined the changes in gene expression and histone acetylation in the prefrontal cortex (PFC) of adult rats. METHODS: We conducted mRNA microarray and chromatin immunoprecipitation (ChIP) coupled to DNA microarray (ChIP-chip) analyses to screen and identify changes in transcript levels and histone acetylation patterns. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, were performed to analyze the differentially expressed genes. We then further identified alterations in ANP32A (acidic leucine-rich nuclear phosphoprotein-32A) and POU3F2 (POU domain, class 3, transcription factor 2) using qPCR and ChIP-PCR assays. RESULTS: In the rat model of METH-induced behavioral sensitization, METH challenge caused 275 differentially expressed genes and a number of hyperacetylated genes (821 genes with H3 acetylation and 10 genes with H4 acetylation). Based on mRNA microarray and GO and KEGG enrichment analyses, 24 genes may be involved in METH-induced behavioral sensitization, and 7 genes were confirmed using qPCR. We further examined the alterations in the levels of the ANP32A and POU3F2 transcripts and histone acetylation at different periods of METH-induced behavioral sensitization. H4 hyperacetylation contributed to the increased levels of ANP32A mRNA and H3/H4 hyperacetylation contributed to the increased levels of POU3F2 mRNA induced by METH challenge-induced behavioral sensitization, but not by acute METH exposure. CONCLUSIONS: The present results revealed alterations in transcription and histone acetylation in the rat PFC by METH exposure and provided evidence that modifications of histone acetylation contributed to the alterations in gene expression caused by METH-induced behavioral sensitization.
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Estimulantes do Sistema Nervoso Central/farmacologia , Expressão Gênica/efeitos dos fármacos , Histonas/metabolismo , Metanfetamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Acetilação/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Transtornos Relacionados ao Uso de Substâncias/metabolismoRESUMO
Variable thickness composite laminates (VTCL) are susceptible to impact during use and may result in irreparable internal damage. In order to locate the internal impact damage of complex composite structures and monitor the impact signals of VTCL at the same time, a low velocity impact (LVI) monitoring system based on an optical fiber sensing network was constructed. Fiber Bragg grating (FBG) sensors are suitable for monitoring strain characteristics. By arranging FBG sensors on the laminate, we studied the spectrum analysis and localization of the impact signal collected by a FBG demodulator at constant temperature. The prior knowledge of variable thickness composite structures is difficult to obtain, and the multi-sensor dynamic monitoring is complex and difficult to realize. In order to locate the LVI of composite structures without prior knowledge, based on empirical mode decomposition (EMD), we proposed an impact localization method with zero-mean normalized cross-correlation (ZNCC) and thickness correction. The experimental results of LVI localization verification show that the ZNCC algorithm can effectively remove the temperature cross-sensitivity and impact energy influencing factors, and the thickness correction can reduce the interference of variable thickness characteristics on localization performance. The maximum localization error is 24.41 mm and the average error is 15.67 mm, which meets engineering application requirements. The method of variable-thickness normalization significantly improves impact localization performance for VTCL.
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Morphine is a potent opioid analgesic used to alleviate moderate or severe pain, but the development of drug tolerance and dependence limits its use in pain management. Our previous studies showed that the candidate protein for I1 imidazoline receptor, imidazoline receptor antisera-selected (IRAS)/Nischarin, interacts with µ opioid receptor (MOR) and modulates its trafficking. However, there is no report of the effect of IRAS on morphine tolerance and physical dependence. In the present study, we found that IRAS knockout (KO) mice showed exacerbated analgesic tolerance and physical dependence compared to wild-type (WT) mice by chronic morphine treatment. Chronic morphine treatment down-regulated the expression of MOR in spinal cord of IRAS KO mice, while had no significant effect on MOR expression in WT mice. We observed the compensatory increase of cAMP accumulation in spinal cord after morphine tolerance, and this change was more significant in KO mice than WT mice. Furthermore, KO mice showed more elevation in the phosphorylation of AMPA receptor GluR1-S845 than WT mice, while the total expression of GluR1 remained unchanged after morphine dependence. Altogether, these data suggest that IRAS may play an important role in the development of morphine tolerance and physical dependence in vivo through modulating MOR expression, as well as AMPA GluR1-S845 phosphorylation, which might be one of the mechanisms underlying the development of opiate addiction.
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Analgésicos Opioides/farmacologia , Tolerância a Medicamentos , Receptores de Imidazolinas/metabolismo , Dependência de Morfina/metabolismo , Morfina/farmacologia , Animais , AMP Cíclico/metabolismo , Receptores de Imidazolinas/genética , Camundongos , Camundongos Knockout , Dependência de Morfina/genéticaRESUMO
MoS2 quantum dots (QDs)-based white-light-emitting diodes (QD-WLEDs) are designed, fabricated, and demonstrated. The highly luminescent, histidine-doped MoS2 QDs synthesized by microwave induced fragmentation of 2D MoS2 nanoflakes possess a wide distribution of available electronic states as inferred from the pronounced excitation-wavelength-dependent emission properties. Notably, the histidine-doped MoS2 QDs show a very strong emission intensity, which exceeds seven times of magnitude larger than that of pristine MoS2 QDs. The strongly enhanced emission is mainly attributed to nitrogen acceptor bound excitons and passivation of defects by histidine-doping, which can enhance the radiative recombination drastically. The enabled electroluminescence (EL) spectra of the QD-WLEDs with the main peak around 500 nm are found to be consistent with the photoluminescence spectra of the histidine-doped MoS2 QDs. The enhanced intensity of EL spectra with the current increase shows the stability of histidine-doped MoS2 based QD-WLEDs. The typical EL spectrum of the novel QD-WLEDs has a Commission Internationale de l'Eclairage chromaticity coordinate of (0.30, 0.36) exhibiting an intrinsic broadband white-light emission. The unprecedented and low-toxicity QD-WLEDs based on a single light-emitting material can serve as an excellent alternative for using transition metal dichalcogenides QDs as next generation optoelectronic devices.
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Orexins (also called hypocretins) are implicated in reward and addiction, but little is known about their role(s) in the association between hippocampal synaptic plasticity and drug preference. Previously, we found that exogenous orexin via OX1 and OX2 receptors can impair low frequency stimulation-induced depotentiation, i.e. restoring potentiation of excitatory synaptic transmission (re-potentiation) in mouse hippocampal slices. Here, we found this re-potentiation in hippocampal slices from mice that had acquired conditioned place preference (CPP) to cocaine. Both 10 and 20 mg/kg of cocaine induced similar magnitudes of CPP in mice and re-potentiation in their hippocampal slices, but differed in their susceptibility to TCS1102, a dual (OX1 and OX2 ) orexin receptor antagonist. TCS1102 significantly attenuated CPP and hippocampal re-potentiation induced by cocaine at 10 mg/kg but not at 20 mg/kg. Nonetheless, SCH23390, an antagonist of dopamine D1-like receptors (D1-likeRs), inhibited the effects induced by both doses of cocaine. SKF38393, a D1-likeR-selective agonist, also induced hippocampal re-potentiation in vitro. Interestingly, this effect was attenuated by TCS1102. Conversely, SCH23390 prevented orexin A-induced hippocampal re-potentiation. These results suggest that endogenous orexins are released in mice during cocaine-CPP acquisition, which sustains potentiated hippocampal transmission via OX1 /OX2 receptors and may contribute to the addiction memory of cocaine. This effect of endogenous orexins, however, may be substituted by dopamine that may dominate hippocampal re-potentiation and CPP via D1-likeRs when the reinforcing effect of cocaine is high.
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Região CA1 Hipocampal/metabolismo , Cocaína/administração & dosagem , Condicionamento Clássico/fisiologia , Inibidores da Captação de Dopamina/administração & dosagem , Plasticidade Neuronal , Receptores de Orexina/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Benzazepinas/farmacologia , Benzimidazóis/farmacologia , Benzoxazóis , Região CA1 Hipocampal/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Camundongos , Naftiridinas , Antagonistas dos Receptores de Orexina/farmacologia , Orexinas/farmacologia , Pirrolidinas/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Transmissão Sináptica , Ureia/análogos & derivadosRESUMO
The precise contributions of ventral tegmental area (VTA) dopaminergic (DAergic) neurons to reward-related behaviors are a longstanding hot topic of debate. Whether the activity of VTA DAergic neurons directly modulates rewarding behaviors remains uncertain. In the present study, we investigated the fundamental role of VTA DAergic neurons in reward-related movement and reinforcement by employing dopamine transporter (DAT)-Cre transgenic mice expressing hM3Dq, hM4Di or channelrhodopsin 2 (ChR2) in VTA DAergic neurons through Cre-inducible adeno-associated viral vector transfection. On the one hand, locomotion was tested in an open field to examine motor activity when VTA DAergic neurons were stimulated or inhibited by injection of the hM3Dq or hM4Di ligand clozapine-N-oxide (CNO), respectively. CNO injection to selectively activate or inhibit VTA DAergic neurons significantly increased or decreased locomotor activity, respectively, compared with vehicle injection, indicating that VTA DAergic neuron stimulation is directly involved in the regulation of motor activity. On the other hand, we used the optical intracranial self-stimulation (oICSS) model to investigate the causal link between reinforcement and VTA DAergic neurons. Active poking behavior but not inactive poking behavior was significantly escalated in a frequency- and pulse duration-dependent manner. In addition, microdialysis revealed that the concentration of dopamine (DA) in the nucleus accumbens (NAc) was enhanced by selective optogenetic activation of VTA DAergic neurons. Furthermore, systemic administration of a DA D1 receptor antagonist significantly decreased oICSS reinforcement. Our research profoundly demonstrates a direct regulatory role of VTA DAergic neurons in movement and reinforcement and provides meaningful guidance for the development of novel treatment strategies for neuropsychiatric diseases related to the malfunction of the reward system.
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Neurônios Dopaminérgicos/metabolismo , Atividade Motora/fisiologia , Área Tegmentar Ventral/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Clozapina/análogos & derivados , Clozapina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Optogenética , Recompensa , Autoestimulação , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
Increasing evidence indicates that excessive drug consumption is sufficient for the transition from recreational and controlled drug use to uncontrolled use and addiction. However, the underlying mechanisms are debated. Some neurobehavioral and neuroimaging evidence indicates that dorsolateral striatum (dlStr)-dependent habit learning plays a key role in excessive drug intake and the transition to addiction, but little is known about the molecular events. The present study investigated whether dlStr miR-134, an important regulator of synaptic transmission and plasticity, is involved in excessive methamphetamine intake. We established excessive and uncontrolled methamphetamine self-administration model in rats by permitting animals extended access to drug (6 h/session/d, LgA group), whereas animals that were limited to access to drug (2 h/session/d, ShA group) exhibited low and controlled self-administration. miR-134 expression in dlStr was significantly increased and its target LIMK1 expression was decreased in the LgA group, but not in the ShA group, compared with the saline control group. However, passive methamphetamine exposure did not alter miR-134 and LIMK1 levels in dlStr. We also found that down-regulation of miR-134 in dlStr through local microinjection of a lentivirus carrying miR-134 sponge (LV-miR-134-Sil) significantly reduced methamphetamine infusions and excessive consumption in LgA group, rather than ShA group. These results indicated that dlStr miR-134, perhaps via its target LIMK1, contributed to excessive and uncontrolled methamphetamine intake, supporting the hypothesis that stimulus-response habit formation is an important mechanism underlying the transition from controlled drug use to uncontrolled drug use and addiction.
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Comportamento Aditivo/metabolismo , Estimulantes do Sistema Nervoso Central/administração & dosagem , Corpo Estriado/metabolismo , Metanfetamina/administração & dosagem , MicroRNAs/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , MicroRNAs/genética , Ratos , Ratos Sprague-Dawley , AutoadministraçãoRESUMO
BACKGROUND: Long-term potentiation (LTP) is well recognized as a cellular-correlated synaptic plasticity of learning and memory. However, its reversal forms of synaptic plasticity, depotentiation, is less studied and its association with behaviors is also far from clear. Previously, we have shown that nanomolar orexin A can prevent the depotentiation induced by low frequency stimulation (LFS) following theta burst stimulation-induced LTP, namely inducing re-potentiation, at hippocampal CA1 synapses in vitro. Here, we explored the functional correlate of this orexin-mediated hippocampal re-potentiation. METHODS AND RESULTS: We found that intraperitoneal (i.p.) injection process-paired contextual exposures during the conditioned place preference (CPP) task in mice resulted in re-potentiation at CA1 synapses of hippocampal slices, regardless of whether the CPP behavior is expressed or not. Simply exposing the mouse in the CPP apparatus, or giving the mouse consecutive i.p. injections of saline in its home cage or a novel cage did not lead to hippocampal re-potentiation. Besides, this CPP training process-induced hippocampal re-potentiation was prevented when mice were pretreated with TCS1102, a dual orexin receptor antagonist. These results suggest that the expression of hippocampal re-potentiation is orexin-dependent and requires the association of differential spatial contexts and i.p. injections in the CPP apparatus. CONCLUSIONS: Together, we reveal an unprecedentedly orexin-mediated modulation on hippocampal depotentiation by the training process in the CPP paradigm.