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Using small molecules that trap translation factors within translating ribosomes, Gurzeler et al.1 and Oltion et al.2 identify a new branch of the ribosome-associated quality-control (RQC) pathway. This mode of translation regulation expands the number of mechanistically distinct RQC pathways.
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Proteínas de Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Ribossomos/metabolismo , Biossíntese de Proteínas , Processamento de Proteína Pós-TraducionalRESUMO
Background: Superficial siderosis of the central nervous system (SSCNS) is a rare progressive neurological disorder resulting from chronic subarachnoid hemorrhage and subsequent subpial hemosiderin deposition. A prolonged cerebrospinal fluid (CSF) leak is a known cause of SSCNS. We present a novel case where progressive SSCNS resulted from a chronic CSF leak related to an anterior cervical corpectomy. Case Description: A 73-year-old man presented with gait ataxia and progressive hearing loss. Thirteen years before, he had undergone a combined anterior-posterior cervical decompression for symptomatic ossification of the posterior longitudinal ligament (OPLL). The presenting MR imaging showed extensive superficial siderosis and focal spinal cord herniation at the site of a ventral dural defect at the corpectomy site. A CT myelogram showed extensive CSF leakage into the corpectomy surgical site and a communicating pseudomeningocele in the anterior neck. Conclusion: This is the first reported case of progressive SSCNS as a long-term complication of an anterior cervical corpectomy for OPLL. Clinicians should be aware of SSCNS secondary to a chronic CSF leak in patients with a prior corpectomy.
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The advent of animal husbandry and hunting increased human exposure to zoonotic pathogens. To understand how a zoonotic disease may have influenced human evolution, we study changes in human expression of anthrax toxin receptor 2 (ANTXR2), which encodes a cell surface protein necessary for Bacillus anthracis virulence toxins to cause anthrax disease. In immune cells, ANTXR2 is 8-fold down-regulated in all available human samples compared to non-human primates, indicating regulatory changes early in the evolution of modern humans. We also observe multiple genetic signatures consistent with recent positive selection driving a European-specific decrease in ANTXR2 expression in multiple tissues affected by anthrax toxins. Our observations fit a model in which humans adapted to anthrax disease following early ecological changes associated with hunting and scavenging, as well as a second period of adaptation after the rise of modern agriculture.
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Evolução Molecular , Regulação da Expressão Gênica , Receptores de Peptídeos/genética , Receptores de Peptídeos/metabolismo , Animais , Antígenos de Bactérias , Bacillus anthracis/genética , Toxinas Bacterianas , Linhagem Celular , Regulação para Baixo , Humanos , Células K562 , Proteínas de Membrana/metabolismo , Virulência , ZoonosesAssuntos
Biópsia/instrumentação , Procedimentos Cirúrgicos Dermatológicos/instrumentação , Países em Desenvolvimento , Acessibilidade aos Serviços de Saúde/organização & administração , Equipamentos Cirúrgicos/provisão & distribuição , Biópsia/estatística & dados numéricos , Estudos Transversais , Procedimentos Cirúrgicos Dermatológicos/estatística & dados numéricos , Instalações de Saúde/provisão & distribuição , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , HumanosRESUMO
Prior research proposed that temporal control over the pattern of operant wheel running on a fixed interval (FI) schedule of sucrose reinforcement is a function of automatic reinforcement generated by wheel running and the experimentally arranged sucrose reinforcement. Two experiments were conducted to assess this prediction. In the first experiment, rats ran for different durations (0, 30, 60, and 180 min) prior to a session of operant wheel running on a FI 120-s schedule. In the second experiment, the concentration of sucrose reinforcement on a FI 180-s schedule was varied across values of 0, 5, 15, and 25%. In Experiment 1, as the duration of pre-operant running increased, the postreinforcement pause before initiation of running lengthened while wheel revolutions in the latter part of the FI interval increased. In Experiment 2, wheel revolutions markedly increased then decreased to a plateau early in the FI interval. Neither manipulation increased temporal control of the pattern of wheel running. Instead, results indicate that operant wheel running is regulated by automatic reinforcement generated by wheel activity and an adjunctive pattern of running induced by the temporal presentation of sucrose. Furthermore, the findings question whether the sucrose contingency regulates wheel running as a reinforcing consequence.
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Condicionamento Operante , Sacarose , Animais , Atividade Motora , Ratos , Esquema de Reforço , Reforço PsicológicoRESUMO
Does the effect of amphetamine on behavior (wheel running) differ depending on the functional role (operant, reinforcement) of that behavior? This study addressed this question using a multiple schedule of reinforcement in which wheel running served as reinforcement for lever pressing in one component and as operant behavior for sucrose reinforcement in the other component. Seven female Long-Evans rats were exposed to a multiple schedule in which pressing a lever on a variable ratio 10 schedule produced the opportunity to run for 15 revolutions in one component and running 15 revolutions produced a drop of 15% sucrose solution in the other component. Doses of 0.5, 1.0, and 2.0 mg/kg D-amphetamine were administered by intraperitoneal injection 20 min prior to a session. As amphetamine dose increased, wheel running decreased in both components - showing no evidence that the effect of the drug on wheel running depended on the function of wheel activity. Notably, lever pressing for wheel-running reinforcement also decreased with amphetamine dose. Drug dose increased the initiation of operant lever pressing, but not the initiation of operant wheel running. We propose that amphetamine dose had common effects on wheel running regardless of its function (reinforcement vs. operant) because wheel-running generates automatic reinforcement and the automatic-reinforcement value of wheel activity is modulated by drug dose.
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Anfetamina/farmacologia , Condicionamento Operante/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Animais , Feminino , Ratos , Ratos Long-Evans , Esquema de Reforço , Reforço Psicológico , Sacarose/farmacologiaRESUMO
Sepsis is a complex syndrome characterized by organ dysfunction and a dysregulated immune host response to infection. There is currently no effective treatment for sepsis, but platelets have been proposed as a potential therapeutic target for the treatment of sepsis. We hypothesized that the NLRP3 inflammasome is activated in platelets during sepsis and may be associated with multiorgan injury in response to polymicrobial sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in 12- to 13-week-old male Sprague-Dawley rats. The necrotic cecum was removed at 24 h post-CLP. At 72 h post-CLP, activated platelets were significantly increased in CLP versus Sham rats. Colocalization of NLRP3 inflammasome components was observed in platelets from CLP rats at 72 h post-CLP. Plasma, pulmonary, and renal levels of IL-1ß and IL-18 were significantly higher in CLP rats compared to Sham controls. Soluble markers of endothelial permeability were increased in CLP versus Sham. Renal and pulmonary histopathology were markedly elevated in CLP rats compared to Sham controls. NLRP3 is activated in platelets in response to CLP and is associated with inflammation, endothelial permeability and multiorgan injury. Our results indicate that activated platelets may play a role to cause multiorgan injury in sepsis and may have therapeutic potential for the treatment of sepsis multiorgan injury.
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Plaquetas/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/sangue , Sepse/sangue , Animais , Permeabilidade Capilar/fisiologia , Caspase 1/sangue , Ceco/cirurgia , Células Cultivadas , Endotélio Vascular/fisiologia , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Rim/metabolismo , Ligadura , Lipopolissacarídeos/farmacologia , Pulmão/metabolismo , Masculino , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/metabolismo , Insuficiência de Múltiplos Órgãos/fisiopatologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Ativação Plaquetária/efeitos dos fármacos , Ativação Plaquetária/fisiologia , Ratos Sprague-Dawley , Sepse/complicações , Sepse/fisiopatologiaRESUMO
Previous studies by our lab have established that placental-ischemia stimulated T-helper 17 cells (TH 17s) cause increased cytolytic natural killer (cNK) cell proliferation and activation during pregnancy; however, the exact mechanism is unknown. The objective of this study was to investigate the role of interlukin 17 (IL-17) in inducing cNK cell activation in pregnancy. We infused 150 pg/day of recombinant IL-17 into a subset of normal pregnant (NP) Sprague Dawley rats from gestation day (GD) 12-19 (NP+IL-17). On GD 19, mean arterial pressure (MAP), fetal and placental weights, cytokines, cNK cell activation, cytotoxic enzymes, and vascular reactivity were assessed. MAP significantly increased from 99 ± 3 mmHg in NP to 120 ± 1 mmHg in NP+IL-17 (P < 0.05). Fetal weight significantly decreased from 2.52 ± 0.04 g in NP to 2.32 ± 0.03 g in NP+IL-17 as did placental weight (NP: 0.65 ± 0.03 g; NP+IL-17: 0.54 ± 0.01 g, P < 0.05). Plasma levels of TNF-α increased to 281.4 ± 55.07 pg/mL in NP+IL-17 from 145.3 ± 16.03 pg/mL in NP (P < 0.05) while placental levels of VEGF decreased from 74.2 ± 6.48 pg/mg in NP to 54.2 ± 3.19 pg/mg in NP+IL-17. Total NK cells were increased in the placenta (NP: 14.3 ± 3.49%; NP+IL-17: 29.33 ± 2.76%, P < 0.05) as were cytolytic NK cells (NP: 3.31 ± 1.25%; NP+IL-17: 13.41 ± 1.81%, P < 0.05). A similar trend was observed in circulating NK cells. Plasma granzyme K increased from 3.55 ± 2.29 pg/mL in NP to 20.9 ± 7.76 pg/mL in NP+IL-17 (P < 0.05), and plasma granzyme B increased from 10.95 ± 0.64 pg/mL in NP to 14.9 ± 0.98 pg/mL in NP+IL-17(P < 0.05). In the placenta, both granzyme A (NP: 246.1 ± 16.7 pg/mg; NP+IL-17: 324.3 ± 15.07 pg/mg, P < 0.05) and granzyme B (NP: 15.18 ± 3.79 pg/mg; NP+IL-17: 27.25 ± 2.34 pg/mg, P < 0.05) increased in response to IL-17 infusion. Finally, vascular reactivity of uterine arteries was significantly impaired in response to IL-17 infusion. The results of this study suggest that IL-17 plays a significant role in the activation of cNK cells during pregnancy.
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Pressão Sanguínea/efeitos dos fármacos , Hipertensão/fisiopatologia , Interleucina-17/administração & dosagem , Células Matadoras Naturais/efeitos dos fármacos , Artéria Uterina/efeitos dos fármacos , Animais , Pressão Sanguínea/fisiologia , Feminino , Granzimas/sangue , Placenta/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/sangue , Artéria Uterina/fisiopatologia , Útero/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
The current study compared the development of response patterns for operant wheel-running and lever-pressing on fixed-interval schedules. Eleven female Long-Evans rats were exposed to fixed-interval (FI) 15-s, 30-s, and 60-s schedules with wheel revolutions as the operant behavior and sucrose solution as reinforcement. Subsequently, a lever was mounted in each wheel and rats responded on an FI-30 s schedule of sucrose reinforcement. Operant lever-pressing on average developed a scalloping pattern of low responding early in the reinforcement interval followed by an increase in pressing to the moment of reinforcement. In contrast, average operant wheel-revolutions peaked early in the reinforcement interval followed by a plateau, a pattern that did not change over sessions. Variation in the FI-schedule value (interval size) with operant wheel-running did not alter the pattern of running throughout the reinforcement interval, but merely parsed this pattern at different points. Cumulative records for the last session showed long postreinforcement pauses (PRP) for lever pressing. Wheel running, however, rose quickly after reinforcement and continued throughout the reinforcement interval. Overall and local wheel-running rates decreased and PRP duration increased as the interval size of the FI schedule increased. We propose that the automatic reinforcement generated by wheel running, but not lever pressing, provides an account of the poor temporal regulation of operant wheel-running in our study.
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Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Esquema de Reforço , Reforço Psicológico , Corrida/psicologia , Sacarose/farmacologia , Animais , Feminino , Ratos , Fatores de TempoRESUMO
Rats responded on a multiple variable-ratio (VR) 10 VR 10 schedule of reinforcement in which lever pressing was reinforced by the opportunity to run in a wheel for 30s in both the changed (manipulated) and unchanged components. To generate positive contrast, the schedule of reinforcement in the changed component was shifted to extinction; to generate negative contrast, the schedule was shifted to VR 3. With the shift to extinction in the changed component, wheel-running and local lever-pressing rates increased in the unchanged component, a result supporting positive contrast; however, the shift to a VR 3 schedule in the changed component showed no evidence of negative contrast in the unaltered setting, only wheel running decreased in the unchanged component. Changes in wheel-running rates across components were consistent in showing a compensation effect, depending on whether the schedule manipulation increased or decreased opportunities for wheel running in the changed component. These findings are the first to demonstrate positive behavioral contrast on a multiple schedule with wheel running as reinforcement in both components.
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Comportamento Animal/fisiologia , Condicionamento Operante/fisiologia , Esquema de Reforço , Corrida/fisiologia , Animais , Feminino , Ratos , Ratos Long-Evans , Corrida/psicologiaRESUMO
Obesity and its metabolic complications have emerged as the epidemic of the new millennia. The use of obese rodent models continues to be a productive component of efforts to understand the concomitant metabolic complications of this disease. In 1978, the JCR:LA-cp rat model was developed with an autosomal recessive corpulent (cp) trait resulting from a premature stop codon in the extracellular domain of the leptin receptor. Rats that are heterozygous for the cp trait are lean-prone, while those that are homozygous (cp/cp) spontaneously display the pathophysiology of obesity as well as a metabolic syndrome (MetS)-like phenotype. Over the years, there have been formidable scientific contributions that have originated from this rat model, much of which has been reviewed extensively up to 2008. The premise of these earlier studies focused on characterizing the pathophysiology of MetS-like phenotype that was spontaneously apparent in this model. The purpose of this review is to highlight areas of recent advancement made possible by this model including; emerging appreciation of the "thrifty gene" hypothesis in the context of obesity, the concept of how chronic inflammation may drive obesogenesis, the impact of acute forms of inflammation to the brain and periphery during chronic obesity, the role of dysfunctional insulin metabolism on lipid metabolism and vascular damage, and the mechanistic basis for altered vascular function as well as novel parallels between the human condition and the female JCR:LA-cp rat as a model for polycystic ovary disease (PCOS).
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Plasmons in the visible/UV energy regime have attracted great attention, especially in nano-materials, with regards to applications in opto-electronics and light harvesting; tailored enhancement of such plasmons is of particular interest for prospects in nano-plasmonics. This work demonstrates that it is possible, by adequate doping, to create excitations in the visible/UV regime in nano-carbon materials, i.e., carbon nanotubes and graphene, with choice of suitable ad-atoms and dopants, which are introduced directly into the lattice by low energy ion implantation or added via deposition by evaporation. Investigations as to whether these excitations are of collective nature, i.e., have plasmonic character, are carried out via DFT calculations and experiment-based extraction of the dielectric function. They give evidence of collective excitation behaviour for a number of the introduced impurity species, including K, Ag, B, N, and Pd. It is furthermore demonstrated that such excitations can be concentrated at nano-features, e.g., along nano-holes in graphene through metal atoms adhering to the edges of these holes.
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Rats experiencing sessions of 30min free access to wheel running were assigned to ad-lib and food-deprived groups, and given additional sessions of free wheel activity. Subsequently, both ad-lib and deprived rats lever pressed for 60s of wheel running on fixed ratio (FR) 1, variable ratio (VR) 3, VR 5, and VR 10 schedules, and on a response-initiated variable interval (VI) 30s schedule. Finally, the ad-lib rats were switched to food deprivation and the food-deprived rats were switched to free food, as rats continued responding on the response-initiated VI 30-s schedule. Wheel running functioned as reinforcement for both ad-lib and food-deprived rats. Food-deprived rats, however, ran faster and had higher overall lever-pressing rates than free-feeding rats. On the VR schedules, wheel-running rates positively correlated with local and overall lever pressing rates for deprived, but not ad-lib rats. On the response-initiated VI 30s schedule, wheel-running rates and lever-pressing rates changed for ad-lib rats switched to food deprivation, but not for food-deprived rats switched to free-feeding. The overall pattern of results suggested different sources of control for wheel running: intrinsic motivation, contingencies of automatic reinforcement, and food-restricted wheel running. An implication is that generalizations about operant responding for wheel running in food-deprived rats may not extend to wheel running and operant responding of free-feeding animals.
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Condicionamento Operante , Privação de Alimentos , Esquema de Reforço , Corrida/fisiologia , Corrida/psicologia , Animais , Feminino , Motivação , Atividade Motora/fisiologia , Ratos , Ratos Long-EvansRESUMO
BACKGROUND: Childhood obesity is an important early predictor of adult obesity and associated comorbidities. Common forms of obesity are underpinned by both environmental and genetic factors. However, the rising prevalence of obesity in genetically stable populations strongly suggests that contemporary lifestyle is a premier factor to the disease. In pediatric population, the current treatment/prevention options for obesity are lifestyle interventions such as caloric restriction (CR) and increase physical activity. In obese individuals, CR improves many metabolic parameters in peripheral tissues. Little is known about the effect of CR on the hypothalamus. This study aimed to assess the effect of CR on hypothalamic metabolic gene expression of young obese- and lean-prone animals. METHODS: Male juvenile JCR:LA-cp obese-prone rats were freely fed (Obese-FF) or pair fed (Obese-FR) to lean-prone, free-feeding animals (Lean-FF). A group of lean-prone rats (Lean-FR) were matched for relative average degree of CR to Obese-FR rats. RESULTS: In free-feeding conditions, obese-prone rats consumed more energy than lean-prone rats (P<0.001) and showed greater increases in body weight, fat mass, plasma glucose, insulin and lipids (P<0.01). These metabolic differences were associated with alterations of feeding-related neuropeptides expression in the hypothalamus, as well as pro-inflammatory cytokines and oxidative stress markers. When submitted to the same degree of CR, the two genotypes responded differently; hypothalamic inflammatory and oxidative stress gene expression was improved in Obese-FR, while it was worsened in Lean-FR rats. CONCLUSIONS: We demonstrate in JCR rats that the metabolic and inflammatory response of the brain to CR is genotype dependent.
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Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders in women of reproductive age characterized by ovulatory dysfunction, hyperandrogenism and cardiometabolic risk. The overweight-obese PCOS phenotype appears to have exacerbated reproductive dysfunction and cardiometabolic risk. In overweight-obese adult women with PCOS, exercise and energy restricted diets have shown limited and inconsistent effects on both cardiometabolic indices and reproductive outcomes. We hypothesized that an early lifestyle intervention involving exercise and dietary energy restriction to prevent or reduce the propensity for adiposity would modulate reproductive indices and cardiometabolic risk in an obese PCOS-prone rodent model. Weanling obese PCOS-prone and Lean-Control JCR:LA-cp rodents were given a chow diet ad libitum or an energy-restricted diet combined with or without voluntary exercise (4â h/day) for 8 weeks. Dietary energy restriction and exercise lowered total body weight gain and body fat mass by 30% compared to free-fed sedentary or exercising obese PCOS-prone animals (P<0.01). Energy restriction induced an increase in exercise intensity compared to free-feeding plus exercise conditions. Energy restriction and exercise decreased fasting plasma triglycerides and apoB48 concentrations in obese PCOS-prone animals compared to free-fed and exercise or sedentary groups. The energy restriction and exercise combination in obese PCOS-prone animals significantly increased plasma sex-hormone binding globulin, hypothalamic cocaine-and amphetamine-regulated transcript (CART) and Kisspeptin mRNA expression to levels of the Lean-Control group, and this was further associated with improvements in estrous cyclicity. The combination of exercise and dietary energy restriction when initiated in early life exerts beneficial effects on cardiometabolic and reproductive indices in an obese PCOS-prone rodent model, and this may be associated with normalization of the hypothalamic neuropeptides, Kisspeptin and CART.
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Restrição Calórica , Dieta , Obesidade/metabolismo , Condicionamento Físico Animal/fisiologia , Síndrome do Ovário Policístico/metabolismo , Tecido Adiposo/metabolismo , Animais , Peso Corporal/fisiologia , Modelos Animais de Doenças , Feminino , Resistência à Insulina/fisiologia , Estilo de Vida , Obesidade/prevenção & controle , RatosRESUMO
As a follow up to Belke and Pierce's (2014) study, we assessed the effects of repeated presentation and removal of sucrose solution on the behavior of rats responding on a two-component multiple schedule. Rats completed 15 wheel turns (FR 15) for either 15% or 0% sucrose solution in the manipulated component and lever pressed 10 times on average (VR 10) for an opportunity to complete 15 wheel turns (FR 15) in the other component. In contrast to our earlier study, the components advanced based on time (every 8min) rather than completed responses. Results showed that in the manipulated component wheel-running rates were higher and the latency to initiate running longer when sucrose was present (15%) compared to absent (0% or water); the number of obtained outcomes (sucrose/water), however, did not differ with the presentation and withdrawal of sucrose. For the wheel-running as reinforcement component, rates of wheel turns, overall lever-pressing rates, and obtained wheel-running reinforcements were higher, and postreinforcement pauses shorter, when sucrose was present (15%) than absent (0%) in manipulated component. Overall, our findings suggest that wheel-running rate regardless of its function (operant or reinforcement) is maintained by automatically generated consequences (automatic reinforcement) and is increased as an operant by adding experimentally arranged sucrose reinforcement (extrinsic reinforcement). This additive effect on operant wheel-running generalizes through induction or arousal to the wheel-running as reinforcement component, increasing the rate of responding for opportunities to run and the rate of wheel-running per opportunity.
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Condicionamento Operante/efeitos dos fármacos , Condicionamento Físico Animal , Reforço Psicológico , Corrida , Sacarose/administração & dosagem , Animais , Feminino , Ratos , Ratos Long-Evans , Esquema de ReforçoRESUMO
We hypothesized the cannabinoid-1 receptor and leptin receptor (ObR) operate synergistically to modulate metabolic, neuroendocrine, and behavioral responses of animals exposed to a survival challenge (food restriction and wheel running). Obese-prone (OP) JCR:LA-cp rats, lacking functional ObR, and lean-prone (LP) JCR:LA-cp rats (intact ObR) were assigned to OP-C and LP-C (control) or CBR1-antagonized (SR141716, 10 mg/kg body wt in food) OP-A and LP-A groups. After 32 days, all rats were exposed to 1.5-h daily meals without the drug and 22.5-h voluntary wheel running, a survival challenge that normally culminates in activity-based anorexia (ABA). Rats were removed from the ABA protocol when body weight reached 75% of entry weight (starvation criterion) or after 14 days (survival criterion). LP-A rats starved faster (6.44 ± 0.24 days) than LP-C animals (8.00 ± 0.29 days); all OP rats survived the ABA challenge. LP-A rats lost weight faster than animals in all other groups (P < 0.001). Consistent with the starvation results, LP-A rats increased the rate of wheel running more rapidly than LP-C rats (P = 0.001), with no difference in hypothalamic and primary neural reward serotonin levels. In contrast, OP-A rats showed suppression of wheel running compared with the OP-C group (days 6-14 of ABA challenge, P < 0.001) and decreased hypothalamic and neural reward serotonin levels (P < 0.01). Thus there is an interrelationship between cannabinoid-1 receptor and ObR pathways in regulation of energy balance and physical activity. Effective clinical measures to prevent and treat a variety of disorders will require understanding of the mechanisms underlying these effects.
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Comportamento Animal/fisiologia , Metabolismo Energético/fisiologia , Neurotransmissores/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptores para Leptina/metabolismo , Animais , Peso Corporal/fisiologia , Restrição Calórica/métodos , Ingestão de Alimentos/fisiologia , Alimentos , Hipotálamo/metabolismo , Masculino , Ratos , Corrida , Transdução de Sinais/fisiologiaRESUMO
The current study investigated the effect of motivational manipulations on operant wheel running for sucrose reinforcement and on wheel running as a behavioral consequence for lever pressing, within the same experimental context. Specifically, rats responded on a two-component multiple schedule of reinforcement in which lever pressing produced the opportunity to run in a wheel in one component of the schedule (reinforcer component) and wheel running produced the opportunity to consume sucrose solution in the other component (operant component). Motivational manipulations involved removal of sucrose contingent on wheel running and providing 1h of pre-session wheel running. Results showed that, in opposition to a response strengthening view, sucrose did not maintain operant wheel running. The motivational operations of withdrawing sucrose or providing pre-session wheel running, however, resulted in different wheel-running rates in the operant and reinforcer components of the multiple schedule; this rate discrepancy revealed the extrinsic reinforcing effects of sucrose on operant wheel running, but also indicated the intrinsic reinforcement value of wheel running across components. Differences in wheel-running rates between components were discussed in terms of arousal, undermining of intrinsic motivation, and behavioral contrast.
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Condicionamento Operante/efeitos dos fármacos , Reforço Psicológico , Corrida/psicologia , Sacarose/farmacologia , Edulcorantes/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Motivação/efeitos dos fármacos , Ratos , Ratos Long-Evans , Esquema de Reforço , RecompensaRESUMO
We hypothesised that hypothalamic feeding-related neuropeptides are differentially expressed in obese-prone and lean-prone rats and trigger overeating-induced obesity. To test this hypothesis, in the present study, we measured energy balance and hypothalamic neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) mRNA expressions in male JCR:LA-cp rats. We compared, in independent cohorts, free-feeding obese-prone (Obese-FF) and lean-prone (Lean-FF) rats at pre-weaning (10 d old), weaning (21-25 d old) and early adulthood (8-12 weeks). A group of Obese-pair-feeding (PF) rats pair-fed to the Lean-FF rats was included in the adult cohort. The body weights of 10-d-old Obese-FF and Lean-FF pups were not significantly different. However, when the pups were shifted from dams' milk to solid food (weaning), the obese-prone rats exhibited more energy intake over the days than the lean-prone rats and higher body and fat pad weights and fasting plasma glucose, leptin, insulin and lipid levels. These differences were consistent with higher energy consumption and lower energy expenditure. In the young adult cohort, the differences between the Obese-FF and Lean-FF rats became more pronounced, yielding significant age effects on most of the parameters of the metabolic syndrome, which were reduced in the Obese-PF rats. The obese-prone rats displayed higher NPY expression than the lean-prone rats at pre-weaning and weaning, and the expression levels did not differ by age. In contrast, POMC expression exhibited significant age-by-genotype differences. At pre-weaning, there was no genotype difference in POMC expression, but in the weanling cohort, obese-prone pups exhibited lower POMC expression than the lean-prone rats. This genotype difference became more pronounced at adulthood. Overall, the development of hyperphagia-induced obesity in obese-prone JCR rats is related to POMC expression down-regulation in the presence of established NPY overexpression.
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Núcleo Arqueado do Hipotálamo/metabolismo , Regulação para Baixo , Regulação da Expressão Gênica no Desenvolvimento , Hiperfagia/metabolismo , Neuropeptídeo Y/biossíntese , Obesidade/etiologia , Pró-Opiomelanocortina/metabolismo , Adiposidade , Animais , Comportamento Animal , Restrição Calórica , Ingestão de Energia , Metabolismo Energético , Hiperfagia/fisiopatologia , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/prevenção & controle , Neurônios/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Obesidade/prevenção & controle , Pró-Opiomelanocortina/genética , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Mutantes , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , DesmameRESUMO
Oxytocin is a major neuropeptide that modulates the brain functions involved in social behaviour and interaction. Despite of the importance of oxytocin for the neural control of social behaviour, little is known about the molecular mechanism(s) by which oxytocin secretion in the brain is regulated. Pro-oxytocin is synthesised in the cell bodies of hypothalamic neurones in the supraoptic and paraventricular nuclei and processed to a 9-amino-acid mature form during post-Golgi transport to the secretion sites at the axon terminals and somatodendritic regions. Oxytocin secreted from the somatodendritic regions diffuses throughout the hypothalamus and its neighbouring brain regions. Some oxytocin-positive axons innervate and secrete oxytocin to the brain regions distal to the hypothalamus. Brain oxytocin binds to its receptors in the brain regions involved in social behaviour. Oxytocin is also secreted from the axon terminal at the posterior pituitary gland into the blood circulation. We have discovered a new molecular complex consisting of annexin A1 (ANXA1), A-kinase anchor protein 150 (AKAP150) and microtubule motor that controls the distribution of oxytocin vesicles between the axon and the cell body in a protein kinase A (PKA)- and protein kinase C (PKC)-sensitive manner. ANXA1 showed significant co-localisation with oxytocin vesicles. Activation of PKA enhanced the association of kinesin-2 with ANXA1, thus increasing the axon-localisation of oxytocin vesicles. Conversely, activation of PKC decreased the binding of kinesin-2 to ANXA1, thus attenuating the axon-localisation of oxytocin vesicles. The result of the present study suggest that ANXA1 complex coordinates the actions of PKA and PKC to control the distribution of oxytocin vesicles between the axon and the cell body.