Effect of amphetamine dose on wheel-running functioning as reinforcement or operant behavior on a multiple schedule of reinforcement.

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.

Down-regulation of hypothalamic pro-opiomelanocortin (POMC) expression after weaning is associated with hyperphagia-induced obesity in JCR rats overexpressing neuropeptide Y.

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.

Ion implantation of graphene-toward IC compatible technologies.

Doping of graphene via low energy ion implantation could open possibilities for fabrication of nanometer-scale patterned graphene-based devices as well as for graphene functionalization compatible with large-scale integrated semiconductor technology. Using advanced electron microscopy/spectroscopy methods, we show for the first time directly that graphene can be doped with B and N via ion implantation and that the retention is in good agreement with predictions from calculation-based literature values. Atomic resolution high-angle dark field imaging (HAADF) combined with single-atom electron energy loss (EEL) spectroscopy reveals that for sufficiently low implantation energies ions are predominantly substitutionally incorporated into the graphene lattice with a very small fraction residing in defect-related sites.

How degrading! Trapped translation factors get trashed.

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.

Progressive superficial siderosis from Chronic CSF leak as a long-term complication of cervical anterior corpectomy: A case report and review of the literature.

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.

Effects of pre-operant running and sucrose concentration on operant wheel running on a fixed interval schedule of reinforcement.

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.

Multiple stages of evolutionary change in anthrax toxin receptor expression in humans.

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.

Evolution and obesity: resistance of obese-prone rats to a challenge of food restriction and wheel running.

The adaptive hypothesis that an obese-prone genotype confers a fitness advantage when challenged with food restriction and food-related locomotion was tested using a rat model. Juvenile (35-40 days) and adolescent (45-50 days) JCR:LA-cp rats, obese prone (cp/cp) and lean prone (+/?), were exposed to 1.5 h daily meals and 22.5 h of voluntary wheel running, a procedure that normally leads to self-starvation. Genotype had a dramatic effect on survival of rats when exposed to the challenge of food restriction and wheel running. Although similar in initial body weight, obese-prone juveniles survived twice as long, and ran three times as far, as their lean-prone counterparts. Biochemical measures indicated that young obese-prone animals maintained blood glucose and fat mass, whereas lean-prone rats depleted these energy reserves. Corticosterone concentration indicated that obese-prone juveniles exhibited a lower stress response to the survival challenge than lean-prone rats, possibly due to lower energy demands and greater energy reserves. Collectively, the findings support the hypothesis that an obese-prone genotype provides a fitness advantage when food supply is inadequate, but is deleterious during periods of food surfeit, such as the energy-rich food environment of prosperous and developing societies worldwide.

Segmented polyurethane: a new elastomer for biomedical applications.

A segmented polyurethane elastomer, originally developed for elastic thread, is now being used for molded prostheses. Performance of this material when used for components of a heart-assist system warrants a thorough investigation of its effectiveness in a variety of biomedical devices.

Calcification inside artificial hearts: inhibition by warfarin-sodium.

Intracavitary calcium phosphate deposits were observed in smooth, elastomeric blood pump sacs implanted in male calves for periods of 115 to 166 days. These deposits occurred predominantly on the flexing surface of the sacs. In contrast, similar pump sacs remained generally free of mineral deposits for up to 150 days in calves treated with the anticoagulant warfarin-sodium. These results implicate a vitamin K-dependent process in calcium phosphate deposition on elastomeric sacs.

Role of human CYP1A1 and NAT2 in 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced mutagenicity and DNA adducts.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is carcinogenic in multiple organs and numerous species. Bioactivation of PhIP is initiated by PhIP N(2)-hydroxylation catalysed by cytochrome P450s. Following N-hydroxylation, O-acetylation catalysed by N-acetyltransferase 2 (NAT2) is considered a further possible activation pathway. Genetic polymorphisms in NAT2 may modify cancer risk following exposure. Nucleotide excision repair-deficient Chinese hamster ovary (CHO) cells stably transfected with human cytochrome P4501A1 (CYP1A1) and a single copy of either NAT2*4 (rapid acetylator) or NAT2*5B (slow acetylator) alleles were used to test the effect of CYP1A1 and NAT2 polymorphism on PhIP genotoxicity. Cells transfected with NAT2*4 had significantly higher levels of N-hydroxy-PhIP O-acetyltransferase (p = 0.0150) activity than cells transfected with NAT2*5B. Following PhIP treatment, CHO cell lines transfected with CYP1A1, CYP1A1/NAT2*4 and CYP1A1/NAT2*5B each showed concentration-dependent cytotoxicity and hypoxanthine phosphoribosyl transferase (hprt) mutagenesis not observed in untransfected CHO cells. dG-C8-PhIP was the primary DNA adduct formed and levels were dose dependent in transfected CHO cells in the order: CYP1A1 < CYP1A1 and NAT2*5B < CYP1A1 and NAT2*4, although levels did not differ significantly (p > 0.05) following one-way analysis of variance. These results strongly support activation of PhIP by CYP1A1 with little effect of human NAT2 genetic polymorphism on mutagenesis and DNA damage.

Chronic infusion of interleukin-17 promotes hypertension, activation of cytolytic natural killer cells, and vascular dysfunction in pregnant rats.

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.

NLRP3 inflammasome activation in platelets in response to sepsis.

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.

Automatic reinforcement from operant wheel-running undermines temporal control by fixed-interval schedules of reinforcement.

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.

Acrolein induces selective protein carbonylation in synaptosomes.

Acrolein, the most reactive of the alpha,beta-unsaturated aldehydes, is endogenously produced by lipid peroxidation, and has been found increased in the brain of patients with Alzheimer's disease. Although it is known that acrolein increases total protein carbonylation and impairs the function of selected proteins, no study has addressed which proteins are selectively carbonylated by this aldehyde. In this study we investigated the effect of increasing concentrations of acrolein (0, 0.005, 0.05, 0.5, 5, 50 microM) on protein carbonylation in gerbil synaptosomes. In addition, we applied proteomics to identify synaptosomal proteins that were selectively carbonylated by 0.5 microM acrolein. Acrolein increased total protein carbonylation in a dose-dependent manner. Proteomic analysis (two-dimensional electrophoresis followed by mass spectrometry) revealed that tropomyosin-3-gamma isoform 2, tropomyosin-5, beta-actin, mitochondrial Tu translation elongation factor (EF-Tu(mt)) and voltage-dependent anion channel (VDAC) were significantly carbonylated by acrolein. Consistent with the proteomics studies that have identified specifically oxidized proteins in Alzheimer's disease (AD) brain, the proteins identified in this study are involved in a wide variety of cellular functions including energy metabolism, neurotransmission, protein synthesis, and cytoskeletal integrity. Our results suggest that acrolein may significantly contribute to oxidative damage in AD brain.

Functional proteomic analysis of protein kinase C epsilon signaling complexes in the normal heart and during cardioprotection.

Using two-dimensional electrophoresis, mass spectrometry, immunoblotting, and affinity pull-down assays, we found that myocardial protein kinase C epsilon (PKCepsilon) is physically associated with at least 36 known proteins that are organized into structural proteins, signaling molecules, and stress-responsive proteins. Furthermore, we found that the cardioprotection induced by activation of PKCepsilon is coupled with dynamic modulation and recruitment of PKCepsilon-associated proteins. The results suggest heretofore-unrecognized functions of PKCepsilon and provide an integrated framework for the understanding of PKCepsilon-dependent signaling architecture and cardioprotection.

Reinforcement value and substitutability of sucrose and wheel running: implications for activity anorexia.

Choice between sucrose and wheel-running reinforcement was assessed in two experiments. In the first experiment, ten male Wistar rats were exposed to concurrent VI 30 s VI 30 s schedules of wheel-running and sucrose reinforcement. Sucrose concentration varied across concentrations of 2.5, 7.5, and 12.5%. As concentration increased, more behavior was allocated to sucrose and more reinforcements were obtained from that alternative. Allocation of behavior to wheel running decreased, but obtained wheel-running reinforcement did not change. Overall, the results suggested that food-deprived rats were sensitive to qualitative changes in food supply (sucrose concentration) while continuing to defend a level of physical activity (wheel running). In the second study, 15 female Long Evans rats were exposed to concurrent variable ratio schedules of sucrose and wheel-running, wheel-running and wheel-running, and sucrose and sucrose reinforcement. For each pair of reinforcers, substitutability was assessed by the effect of income-compensated price changes on consumption of the two reinforcers. Results showed that, as expected, sucrose substituted for sucrose and wheel running substituted for wheel running. Wheel running, however, did not substitute for sucrose; but sucrose partially substituted for wheel running. We address the implications of the interrelationships of sucrose and wheel running for an understanding of activity anorexia.

Evidence for positive, but not negative, behavioral contrast with wheel-running reinforcement on multiple variable-ratio schedules.

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.

Wheel-running reinforcement in free-feeding and food-deprived rats.

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.