Reversal Phase Research Articles

Intracerebroventricular Streptozotocin Induces Obesity and Dementia in Lewis Rats.

Animal models of dementia associated with metabolic abnormalities play an important role in understanding the bidirectional relationships between these pathologies. Rodent strains develop cognitive dysfunctions without alteration of peripheral metabolism following intracerebroventricular administration of streptozotocin (icv-STZ). We aimed to estimate the effect of icv-STZ on cognitive functions and peripheral metabolism in Lewis rats, which are rarely used for the induction of cognitive abnormalities. Inbred adult Lewis rats were treated with single icv-STZ (3 mg/kg). Cognitive functions were assessed using Morris water maze (MWM) test and locomotion by the Open Field test. Metabolic alterations were studied using histological and biochemical analysis of brain and peripheral tissues. The icv-STZ induced rapid weight decline during the first two weeks. Thereafter, the rats showed an accelerated weight gain. Three months after the icv-STZ treatment, the rats were severely obese and revealed fatty liver, pancreatic islet hypertrophy, significantly elevated levels of blood insulin, leptin, and adiponectin, but intact peripheral glucose homeostasis. The icv-STZ rats expressed amyloid-β deposits in blood vessels of leptomeningeal area, microgliosis, astrogliosis, and spongiosis in fimbria-fornix area of hippocampus. Locomotor activities of icv-STZ treated and sham-operated rats were similar. In the MWM test, the icv-STZ treated rats demonstrated severely impaired spatial learning during both acquisition and reversal phases. Icv-STZ treated Lewis rats develop severe dementia associated with obesity and peripheral metabolic abnormalities. This animal model may be useful for exploring the pathophysiological relationship between obesity and dementia and provides a new tool for development of effective therapy.

Strategy set-shifting and response inhibition in adult rats exposed to an environmental polychlorinated biphenyl mixture during adolescence

Converging evidence from studies with animal models and humans suggests that early developmental exposure to polychlorinated biphenyls (PCBs) leads to deficits in cognitive flexibility and inhibitory control. These processes are mediated to a large extent by the prefrontal cortex, thus we examined the effects of PCB exposure during adolescence—a period of robust prefrontal cortical development—on both processes. Specifically, we used operant set-shifting and differential reinforcement of low rates of responding (DRL) tasks to assess cognitive flexibility and response inhibition, respectively. One male and one female pup from each of 14 litters were assigned to each of three treatment groups: 0, 3 or 6mgPCB/kg/day. Rats were dosed orally from postnatal day (PND) 27–50 to capture the whole period of adolescence in rats. At approximately PND 90, they began testing in the set-shifting task which included an initial visual cue discrimination, an extra-dimensional shift to a position discrimination and a reversal of the position discrimination. There were no statistically significant group differences in errors to criterion on visual cue discrimination or on the shift from visual to position discrimination in either males or females. During the position reversal, the 6mg/kg PCB males made significantly fewer errors to reach criterion than control males. The 3mg/kg PCB males showed a trend in the same direction, but this did not reach statistical significance. Interestingly, error analysis revealed that PCB-exposed males made significantly fewer perseverative errors than controls in this phase. No group differences were observed in females. These results suggest a male-specific effect of adolescent PCB-exposure on the reversal phase of the set-shifting task. Following set-shifting, rats progressed to the DRL task in which they were required to withhold responding for a specified period of time (15s) in order to receive a reinforcer. There were no exposure-related group differences in total presses or efficiency ratio in males or in females. In summary, there were subtle sex-specific effects of adolescent PCB exposure on the reversal phase of a set-shifting task, but no effects of exposure on performance on a DRL15 task, suggesting an effect on cognitive flexibility but not response inhibition.

Circadian disruption affects initial learning but not cognitive flexibility in an automated set-shifting task in adult Long-Evans rats

A sizeable percent of adults are subject to circadian disturbances such as shift work, which involves misalignment of time of light exposure, activity periods, sleep, and eating. Chronic adherence to disruptive circadian schedules can negatively impact cognitive functioning. Developing preclinical models of circadian disruption allow investigation of the relationship and underlying mechanisms between circadian disruption and cognitive functioning. We placed adult Long-Evans rats of both sexes on a 12:12h light:dark schedule in which rats performed an automated operant-behavior task for 3months, with daily testing occurring either 4h after lights-on or lights-off. At the end of this period, rats were tested on an automated set-shifting task to compare the effects of the 2 testing schedules on cognitive flexibility, which is the focus of this report. Over the initial 3-month period, day-tested rats shifted to a diurnal activity schedule, with males shifting more effectively than females, while night-tested rats remained nocturnal. Upon beginning the set-shifting task, night-tested rats took longer to reach criterion performance in the initial, visual-cue detection stage as compared to day-tested rats. The groups did not differ in performance on subsequent egocentric-cue based and reversal phases. Sex-related differences in task performance unrelated to testing schedule, particularly longer latencies to lever press in females, were also detected. One possible explanation for our findings is that the night-tested rats also experienced a form of circadian disruption when they were exposed to ambient light during the daily testing sessions, and that the form they experienced was more detrimental to initial acquisition of the task than testing during the light phase. Subsequent experiments will incorporate a night-tested group that is not exposed to ambient light in order to better understand the effect seen in the night-tested rats in the current study.

Learned expectations and uncertainty facilitate pain during classical conditioning.

Pain spontaneously activates adaptive and dynamic learning processes affecting the anticipation of, and the responses to, future pain. Computational models of associative learning effectively capture the production and ongoing changes in conditioned anticipatory responses (eg, skin conductance response), but the impact of this dynamic process on unconditional pain responses remains poorly understood. Here, we investigated the dynamic modulation of pain and the nociceptive flexion reflex by fear learning in healthy human adult participants undergoing a classical conditioning procedure involving an acquisition, reversal and extinction phase. Conditioned visual stimuli (CS+) coterminated with a noxious transcutaneous stimulation applied to the sural nerve on 50% of trials (unconditioned stimuli). Expected pain probabilities and cue associability were estimated using computational modeling by fitting a hybrid learning model to skin conductance response elicited by the CS+. Multilevel linear regression analyses confirmed that trial-by-trial changes in expected pain and associability positively predict ongoing fluctuations in pain outcomes. Mediation analysis further demonstrated that both expected probability and associability affect pain perception through a direct effect and an indirect effect mediated by descending modulatory mechanisms affecting spinal nociceptive activity. Moderation analyses further showed that hyperalgesic effects of associability were larger in individuals reporting more harm vigilance and less emotional detachment. Higher harm vigilance was also associated with a stronger mediation of hyperalgesic effects by spinal processes. These results demonstrate how dynamic changes in pain can be explained by associative learning theory and that resilient attitudes towards fear/pain can attenuate the adverse impact of adaptive aversive learning processes on pain.

Acquisition and reversal of visual discrimination learning in APPSwDI/Nos2−/− (CVN) mice

Studies of cognitive behavior in rodent models of Alzheimer’s disease (AD) are the mainstay of academic and industrial efforts to find effective treatments for this disorder. However, in the majority of such studies, the nature of rodent behavioral tests is considerably different from the setting associated with cognitive assessments of individuals with AD. The recently developed touchscreen technique provides a more translational way of rodent cognitive testing because the stimulus (images in different locations on the screen) and reaction (touch) are similar to those employed in human test routines, such as the Cambridge Neuropsychological Test Automated Battery. Here, we used Visual Discrimination and Reversal of Visual Discrimination touchscreen tasks to assess cognitive performance of APPSwDI/Nos2−/− (CVN) mice, which express mutated human APP and have a homozygous deletion of the Nos2 gene. We revealed that CVN mice made more first-time errors and received more correction trials than WT mice across both discrimination and reversal phases, although mutation effect size was larger during the latter phase. These results indicate sensitivity of touchscreen-based measurements to AD-relevant mutations in CVN mice and warrant future touchscreen experiments aimed at evaluating other cognitive and motivational phenotypes in this AD mouse model.

Specific muscle synergies in national elite female ice hockey players in response to unexpected external perturbation

ABSTRACTThis study aimed to investigate specific muscle synergies in elite ice hockey players indicating highly developed postural control strategies used to restore balance against unexpected external perturbations. Seven elite athletes (EA) on the women’s national ice hockey team and 7 non-athletes (NA) participated in this study. Based on trajectories of centre of mass (COM), analysis periods were divided into an initial phase (a balance disturbance after perturbation onset) and a reversal phase (a balance recovery response), respectively. Muscle synergies were extracted at each phase by using non-negative matrix factorization. k-means cluster analysis was performed to arrange similar muscle synergies in all participants. EA showed significantly shorter recovery period of COM and smaller body sway than NA. In the initial phase, we identified 2 EA-specific synergies related to ankle plantar flexors or neck extensors. In the case of an NA-specific synergy, co-activation of the ankle plantar flexors and dorsiflexors was found. In the reversal phase, no specific muscle synergies were identified. As the results, EA-specific muscle synergies showed low co-activation strategy of agonists and antagonists in ankle and neck extensors. Our results could provide critical information for rehabilitation strategies in athletes requiring high postural stability.

Effects of Housing on Methamphetamine-Induced Neurotoxicity and Spatial Learning and Memory

Severe stress potentiates methamphetamine (MA) neurotoxicity. However, whether moderate stress increases or decreases the neurotoxic effects of MA is unknown. We assessed the effects of MA (4 × 10 mg/kg at 2 h intervals) in combination with prior barren-cage housing in adult male Sprague-Dawley rats on monoamines and glial fibrillary acid protein (GFAP) in one cohort and spatial learning and memory in the Morris water maze in another cohort. MA reduced dopamine (DA) and serotonin (5-HT) in the neostriatum and nucleus accumbens, 5-HT in the hippocampus, and increased GFAP in neostriatum and nucleus accumbens compared with saline controls. In neostriatum, barren-cage housing protected against MA-induced increases in GFAP, but it did not prevent DA and 5-HT reductions, although it did increase hippocampal norepinephrine. MA impaired spatial learning during acquisition, reversal, and shift phases and impaired reference memory on reversal and shift probe trials. Barren-cage housing enhanced performance during acquisition but not during reversal or shift or on probe trials. The data indicate that prior barren-cage housing moderates MA-induced neostriatal astrogliosis and initial spatial learning, but has no protective effect when the platform is smaller and relocated and therefore requires cognitive flexibility in relearning.

Touch screen assays of behavioural flexibility and error characteristics in Eastern grey squirrels (Sciurus carolinensis)

Behavioural flexibility allows animals to adjust their behaviours according to changing environmental demands. Such flexibility is frequently assessed by the discrimination–reversal learning task. We examined grey squirrels’ behavioural flexibility, using a simultaneous colour discrimination–reversal learning task on a touch screen. Squirrels were trained to select their non-preferred colour in the discrimination phase, and their preferred colour was rewarded in a subsequent reversal phase. We used error rates to divide learning in each phase into three stages (perseveration, chance level and ‘learned’) and examined response inhibition and head-switching during each stage. We found consistent behavioural patterns were associated with each learning stage: in the perseveration stage, at the beginning of each training phase, squirrels showed comparable response latencies to correct and incorrect stimuli, along with a low level of head-switching. They quickly overcame perseveration, typically in one to three training blocks. In the chance-level stage, response latencies to both stimuli were low, but during initial discrimination squirrels showed more head-switches than in the previous stage. This suggests that squirrels were learning the current reward contingency by responding rapidly to a stimulus, but with increased attention to both stimuli. In the learned stage, response latencies to the correct stimulus and the number of head-switches were at their highest, whereas incorrect response latencies were at their lowest, and differed significantly from correct response latencies. These results suggest increased response inhibition and attention allowed the squirrels to minimise errors. They also suggest that errors in the ‘learned’ stage were related to impulsive emission of the pre-potent or previously learned responses.

Oscillatory stratified flow over supercritical topography: Wave energetics and turbulence

Topographic features with steep, supercritical slope on the ocean bottom are sites of large energy conversion from the oscillating tide to internal waves according to linear theory. At the same time, they are also sites with potentially large local energy loss as is suggested by nonlinear waves and overturns found in field observations and two-dimensional simulations. Here, we investigate the internal wave dynamics and turbulence at an isolated supercritical obstacle using three-dimensional, high resolution large-eddy simulations (LES) conducted with a body conforming grid. An obstacle with a smoothed triangular shape having supercritical slope is considered as a laboratory-scale model for a two-dimensional ocean ridge. Three simulations are performed with constant Reynolds number and an excursion number (Ex) that varies from 0.066 to unity, corresponding to a large obstacle and a small obstacle, respectively. The dominant nonlinear flow feature is a downslope jet with intensified velocity whose length and thickness increase with increasing Ex. During the flow reversal phase, the downward jet encounters upward flow along the slope and the interaction creates a rebounding jet which distorts the density resulting in convective instability. Turbulence is generated predominantly by shear in the jet, convective instabilities from the rebounding jet, and breaking of transient lee waves. The active region of turbulence grows as Ex increases although the local normalized turbulent kinetic energy becomes smaller. Analysis of the baroclinic energy budget shows that, with increasing Ex, there is a substantial decrease of energy conversion (C) to the wave field as well as a substantial increase in local energy loss (q).

P27kip1 Is Required for Functionally Relevant Adult Hippocampal Neurogenesis in Mice.

We asked whether cell-cycle associated protein p27kip1 might be involved in the transition of precursor cells to postmitotic maturation in adult hippocampal neurogenesis. p27kip1 was expressed throughout the dentate gyrus with a strong nuclear expression in early postmitotic, calretinin-positive neurons and neuronally determined progenitor cells (type-3 and some type-2b), lower or absent expression in radial glia-like precursor cells (type-1) and type-2a cells and essentially no expression in granule cells. This suggested a transitory role in late proliferative and early postmitotic phases of neurogenesis. Inconsistent with a role limited to cell cycle arrest the acute stimuli, voluntary wheel running (RUN), environmental enrichment (ENR) and kainate-induced seizures increased p27kip1 expressing cells. Sequential short-term combination of RUN and ENR yielded more p27kip1 cells than either stimulus alone, indicating an additive effect. In vitro, p27kip1 was lowly expressed by proliferating precursor cells but increased upon differentiation. In p27kip1-/- mice neurogenesis was reduced in vivo, whereas the number of proliferating cells was increased. Accordingly, the microdissected dentate gyrus of p27kip1-/- mice generated more colonies in the neurosphere assay and an increased number of larger spheres with the differentiation potential unchanged. In p27kip1-/- monolayer cultures, proliferation was increased and cell cycle genes were upregulated. In the Morris water maze p27kip1-/- mice learned the task but were specifically impaired in the reversal phase explainable by the decrease in adult neurogenesis. We conclude that p27kip1 is involved in the decisive step around cell-cycle exit and plays an important role in activity-regulated and functionally relevant adult hippocampal neurogenesis. Stem Cells 2017;35:787-799.

Global Sensitivity Analysis of Transient Code Output Applied to a Reflood Experiment Model Using the TRACE Code

Appropriate model assessment requires proper understanding of the impact of variations of model parameters and their interactions on results. However, in many thermal-hydraulic (TH) simulations, the code often predicts time-dependent output where the impact of model parameter variations on the overall transient is not easily discernible from quantities of interest (QoIs) based on the maximum, minimum, or average over space and/or time. This work proposes a methodology to analyze transient code output in a more comprehensive manner and coupled with established global sensitivity analysis (SA) methods.This paper first describes how the particularities of transient output variations can be characterized through application of functional data analysis (FDA) techniques. The convoluted amplitude and phase variations in the output are separated first by using a registration technique. The high-dimensional transient output is then projected in reduced dimension by using principal component analysis. Based on this, innovative QoIs that capture the variation over the whole course of the transient are finally derived.The subsequent global SA is a two-step process. First, the noninfluential parameters are identified using the efficient Morris screening method. The exclusion of these parameters reduces the size of the problem and decreases the cost of the downstream analysis. Second, the sensitivity of the influential model parameters with respect to a selected QoI is computed using the Sobol’ method. The method gives a set of sensitivity indices quantifying the contributions of input variations to the QoI variation considering possible interactions among the parameters.The applicability of the proposed methodology is demonstrated by analyzing a 26-parameter reflood experiment simulation model with the TRAC/RELAP Computational Engine (TRACE) TH system code. The FDA-derived QoI on the time-dependent cladding temperature was able to give a deeper insight on particular modes of variations exhibited by the model over the whole course of the reflood transient. That is, the variations in the cladding temperature transient could be simply divided into two modes: the reversal phase (from heatup until shortly after the temperature turnaround) and the descent phase (onward until quenching). The applied SA method was then able to attribute the variation of these two modes to the variation of the model parameters. It was found that the model was additive during the temperature reversal phase with dispersed flow film boiling—related parameters contributing to most of the model output variation, consistent with the adopted phenomenological model. Yet, the variation during the temperature descent could only be explained through parameter interactions indicating a more complex input/output relationship.Through study of this particular case, it is shown that if different QoIs based on the same time-dependent output variable are used—thus inspecting functional aspects of the output—the model might behave differently, being additive with respect to one QoI and interacting with respect to another, thus revealing more information on the model behavior, which might be overlooked in a SA based on extreme or time-averaged QoIs.

Lipid-Modifying Efficacy and Tolerability of Anacetrapib Added to Ongoing Statin Therapy in Patients with Hypercholesterolemia or Low High-Density Lipoprotein Cholesterol

To assess the effects of anacetrapib added to statin ± other lipid-modifying therapies in patients with hypercholesterolemia and not at their low-density lipoprotein cholesterol (LDL-C) goal (as per National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] guidelines) and in those with low high-density lipoprotein cholesterol (HDL-C). Patients on a stable dose of moderate/high-intensity statin ± other lipid-modifying therapies with LDL-C ≥70, ≥100, ≥130, or ≥160mg/dl for very high, high, moderate, and low coronary heart disease risk, respectively, or at LDL-C goal with HDL-C ≤40mg/dl, were randomized 1:1:1, stratified by background therapy use, to anacetrapib 100mg (n= 153), anacetrapib 25mg (n= 152), or placebo (n= 154) for 24weeks, followed by a 12-week off-drug reversal phase. The primary end points were percent change from baseline in LDL-C (beta-quantification method) and HDL-C, as well as the safety profile of anacetrapib. Both doses of anacetrapib reduced LDL-C, non-HDL-C, apolipoprotein (Apo) B, and lipoprotein a and increased HDL-C and Apo AI versus placebo (p <0.001 for all). There were no meaningful differences between the anacetrapib 25mg, 100mg, and placebo groups in the proportions of discontinuations due to drug-related adverse events (0.7%, 1.3% vs 1.3%) or in abnormalities in liver enzymes (0%, 0% vs 0.7%), creatine kinase elevations overall (0%, 0.7% vs 0%) or with muscle symptoms (none seen), blood pressure, electrolytes, or adjudicated cardiovascular events (0.7%, 0.7% vs 1.3%). In conclusion, treatment with anacetrapib resulted in substantial reductions in LDL-C and increases in HDL-C and was generally well tolerated.

Magnetization Reversal and Glassy Behavior in Tb0.7Sr0.3MnO3

Magnetization reversal and glassy phase in Tb0.7Sr0.3MnO3 are reported. Polycrystalline samples of Tb0.7Sr0.3MnO3 are prepared by solid-state synthesis. This material crystallizes in orthorhombic Pbnm space group with lattice parameters: a = 5.471(1)A, b = 7.608(2)A, and c = 5.398(2)A. Field-cooled/zero field-cooled magnetization measurements show two magnetic transitions, one at 40 K and another at 8 K. The transition at 40 K is due to magnetic ordering of Mn while that at 8 K arises due to Tb ordering. Low field-cooled measurements reveal magnetization reversal at low temperature. The temperature at which this occurs increases with decrease in field strength. The observed magnetization reversal is attributed to the competition between interacting Mn (3 d) and Tb (4 f) magnetic sublattices which makes the system ferrimagnetic. The glassy magnetic behavior below 50 K and absence of long-range order in Tb0.7Sr0.3MnO3 is confirmed through ac susceptibility studies.

A computational study on the effect of the orifice size on the performance of a turbulent jet ignition system

Fully three-dimensional computational fluid dynamic simulations with detailed combustion chemistry of a turbulent jet ignition system installed in a rapid compression machine are presented. The turbulent jet ignition system is a prechamber-initiated combustion system intended to allow lean-burn combustion in spark ignition internal-combustion engines. In the presented configuration, the turbulent jet ignition prechamber has a volume that is 2% of the volume of the main combustion chamber in the rapid compression machine and is separated from the main chamber by a nozzle containing a single orifice. Four simulations with orifice diameters of 1.0 mm, 1.5 mm, 2.0 mm, and 3.0 mm respectively are presented in order to demonstrate the effect of the orifice diameter on the combustion behavior of the turbulent jet ignition process. Data generated by the simulations is shown including combustion chamber pressures, temperature fields, jet velocities and mass fraction burn durations. From the combustion pressure trace, the jet velocity, and other field data, five distinct phases of the turbulent jet ignition process are identified. These phases are called the compression phase, the prechamber combustion initiation phase, the cold jet phase, the hot jet phase, and the flow reversal phase. The four simulations show that the orifice diameter of 1.5 mm provides the fastest ignition and the fastest overall combustion as reflected in the 0–10% and 10–90% mass fraction burn duration data generated. Meanwhile, the simulation for the orifice diameter of 1.0 mm produces the highest jet velocity and has the shortest delay between the spark and the exit of a jet of hot gases into the main chamber but produces a slower burn duration than the simulation for the larger orifice diameter of 1.5 mm. The simulations for orifice diameters of 2.0 mm and 3.0 mm demonstrate that the combustion speed is reduced as the orifice diameter increases above 1.5 mm. Finally, a discussion is given which examines the implications that the results generated have in regard to implementation of the turbulent jet ignition system in an internal-combustion engine.

The human-specificCASP4gene product contributes to Alzheimer-related synaptic and behavioural deficits

Recent studies have indicated that innate immune signalling molecules are involved in late-onset Alzheimer's disease (LOAD) risk. Amyloid beta (Aβ) accumulates in AD brain, and has been proposed to act as a trigger of innate immune responses. Caspase-4 is an important part of the innate immune response. We recently characterized transgenic mice carrying human CASP4, and observed that the mice manifested profound innate immune responses to lipopolysaccharide (LPS). Since these inflammatory processes are important in the aetiology of AD, we have now analysed the correlation of expression of caspase-4 in human brain with AD risk genes, and studied caspase-4 effects on AD-related phenotypes in APPswe/PS1deltaE9 (APP/PS1) mice. We observed that the expression of caspase-4 was strongly correlated with AD risk genes including TYROBP, TREM2, CR1, PSEN1, MS4A4A and MS4A6A in LOAD brains. Caspase-4 expression was upregulated in CASP4/APP/PS1 mice in a region-specific manner, including hippocampus and prefrontal cortex. In APP/PS1 mice, caspase-4 expression led to impairments in the reversal phase of a Barnes maze task and in hippocampal synaptic plasticity, without affecting soluble or aggregated Aβ levels. Caspase-4 was expressed predominantly in microglial cells, and in the presence of CASP4, more microglia were clustered around amyloid plaques. Furthermore, our data indicated that caspase-4 modulates microglial cells in a manner that increases proinflammatory processes. We propose that microglial caspase-4 expression contributes to the cognitive impairments in AD, and that further study of caspase-4 will enhance our understanding of AD pathogenesis and may lead to novel therapeutic targets in AD.

Associations of emotional arousal, dissociation and symptom severity with operant conditioning in borderline personality disorder

Those with borderline personality disorder (BPD) display altered evaluations regarding reward and punishment compared to others. The processing of rewards is basal for operant conditioning. However, studies addressing operant conditioning in BPD patients are rare. In the current study, an operant conditioning task combining learning acquisition and reversal was used. BPD patients and matched healthy controls (HCs) were exposed to aversive and neutral stimuli to assess the influence of emotion on learning. Picture content, dissociation, aversive tension and symptom severity were rated. Error rates were measured. Results showed no group interactions between aversive versus neutral scenes. The higher emotional arousal, dissociation and tension, the worse the acquisition, but not reversal, scores were for BPD patients. Scores from the Borderline Symptom List were associated with more errors in the reversal, but not the acquisition phase. The results are preliminary evidence for impaired acquisition learning due to increased emotional arousal, dissociation and tension in BPD patients. A failure to process punishment in the reversal phase was associated with symptom severity and may be related to neuropsychological dysfunctioning involving the ventromedial prefrontal cortex. Conclusions are limited due to the correlational study design and the small sample size.

Dopamine D3 Receptor Availability Is Associated with Inflexible Decision Making.

Dopamine D2/3 receptor signaling is critical for flexible adaptive behavior; however, it is unclear whether D2, D3, or both receptor subtypes modulate precise signals of feedback and reward history that underlie optimal decision making. Here, PET with the radioligand [(11)C]-(+)-PHNO was used to quantify individual differences in putative D3 receptor availability in rodents trained on a novel three-choice spatial acquisition and reversal-learning task with probabilistic reinforcement. Binding of [(11)C]-(+)-PHNO in the midbrain was negatively related to the ability of rats to adapt to changes in rewarded locations, but not to the initial learning. Computational modeling of choice behavior in the reversal phase indicated that [(11)C]-(+)-PHNO binding in the midbrain was related to the learning rate and sensitivity to positive, but not negative, feedback. Administration of a D3-preferring agonist likewise impaired reversal performance by reducing the learning rate and sensitivity to positive feedback. These results demonstrate a previously unrecognized role for D3 receptors in select aspects of reinforcement learning and suggest that individual variation in midbrain D3 receptors influences flexible behavior. Our combined neuroimaging, behavioral, pharmacological, and computational approach implicates the dopamine D3 receptor in decision-making processes that are altered in psychiatric disorders. Flexible decision-making behavior is dependent upon dopamine D2/3 signaling in corticostriatal brain regions. However, the role of D3 receptors in adaptive, goal-directed behavior has not been thoroughly investigated. By combining PET imaging with the D3-preferring radioligand [(11)C]-(+)-PHNO, pharmacology, a novel three-choice probabilistic discrimination and reversal task and computational modeling of behavior in rats, we report that naturally occurring variation in [(11)C]-(+)-PHNO receptor availability relates to specific aspects of flexible decision making. We confirm these relationships using a D3-preferring agonist, thus identifying a unique role of midbrain D3 receptors in decision-making processes.

Vascular Risk Factors and Diseases Modulate Deficits of Reward-Based Reversal Learning in Acute Basal Ganglia Stroke.

BackgroundBesides motor function, the basal ganglia have been implicated in feedback learning. In patients with chronic basal ganglia infarcts, deficits in reward-based reversal learning have previously been described.MethodsWe re-examined the acquisition and reversal of stimulus-stimulus-reward associations and acquired equivalence in eleven patients with acute basal ganglia stroke (8 men, 3 women; 57.8±13.3 years), whose performance was compared eleven healthy subjects of comparable age, sex distribution and education, who were recruited outside the hospital. Eleven hospitalized patients with a similar vascular risk profile as the stroke patients but without stroke history served as clinical control group.ResultsIn a neuropsychological assessment 7±3 days post-stroke, verbal and spatial short-term and working memory and inhibition control did not differ between groups. Compared with healthy subjects, control patients with vascular risk factors exhibited significantly reduced performance in the reversal phase (F[2,30] = 3.47; p = 0.044; post-hoc comparison between risk factor controls and healthy controls: p = 0.030), but not the acquisition phase (F[2,30] = 1.01; p = 0.376) and the acquired equivalence (F[2,30] = 1.04; p = 0.367) tasks. In all tasks, the performance of vascular risk factor patients closely resembled that of basal ganglia stroke patients. Correlation studies revealed a significant association of the number of vascular risk factors with reversal learning (r = -0.33, p = 0.012), but not acquisition learning (r = -0.20, p = 0.121) or acquired equivalence (r = -0.22, p = 0.096).ConclusionsThe previously reported impairment of reward-based learning may be attributed to vascular risk factors and associated diseases, which are enriched in stroke patients. This study emphasizes the necessity of appropriate control subjects in cognition studies.

Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib in Japanese patients with heterozygous familial hypercholesterolemia

Background and aimsThis multicenter, randomized, double-blind, placebo-controlled study assessed the lipid-modifying efficacy/safety profile of anacetrapib 100 mg added to ongoing statin ± other lipid-modifying therapies (LMT) in Japanese patients with heterozygous familial hypercholesterolemia (HeFH). MethodsPatients 18–80 years with a genotype-confirmed/clinical diagnosis of HeFH who were on a stable dose of statin ± other LMT for ≥6 weeks and with an LDL-C concentration ≥100 mg/dL were randomized to anacetrapib 100 mg (n = 34) or placebo (n = 34) for 12 weeks, followed by a 12-week off-drug reversal phase. The primary endpoints were percent change from baseline in LDL-C (beta-quantification method [BQ]) and safety/tolerability. ResultsAt Week 12, treatment with anacetrapib reduced LDL-C (BQ) compared to placebo and resulting in a between-group difference of 29.8% (95% CI: −38.6 to −21.0; p < 0.001) favoring anacetrapib. Anacetrapib also reduced non-HDL-C (23. 6%; p < 0.001), ApoB (14.1%; p < 0.001) and Lp(a) (48.7%; p < 0.001), and increased HDL-C (110.0%; p < 0.001) and ApoA1 (48.2%; p < 0.001) versus placebo. Anacetrapib 100 mg added to ongoing therapy with statin ± other LMT for 12 weeks was generally well-tolerated. There were no differences between the groups in the proportion of patients who discontinued drug due to an adverse event or abnormalities in liver enzymes, creatinine kinase, blood pressure, electrolytes or adjudicated cardiovascular events. ConclusionsIn Japanese patients with HeFH, treatment with anacetrapib 100 mg for 12 weeks resulted in substantial reductions in LDL-C and increases in HDL-C and was well tolerated.(ClinicalTrials.govNCT01824238)

Does litter size affect emotionality, spatial learning and memory in piglets?

Average litter size has steadily increased over the past decades in the pig farming industry. Large litters are associated with an increase of piglets born with a lower birth weight and reduced overall piglet viability. The aim of our study was to investigate whether litter size affects emotionality, learning and memory in pigs. Ten piglets from large litters (≥18 piglets) were compared with ten piglets from small litters (≤13 piglets). Piglets from two different suppliers, using different breeds, (hereafter called: Source) were tested. Effects were determined of Litter size and Source on birth weights and growth rates, on emotionality of the piglets measured in an open field test (OFT) at 5 weeks of age, and on effects of OFT-induced stress as indicated by salivary cortisol. The effects of Litter size and Source on spatial learning and memory in a holeboard task were assessed between 9 and 14 weeks of age. Small litter piglets from Source 1 grew faster than large litter piglets from the same source. This effect of Litter size was not found in piglets from Source 2. In the OFT, no effects of Litter size on behaviours were found. However, piglets from Source 1 had lower baseline cortisol levels, made more escape attempts and showed higher locomotor activity during the OFT than piglets from Source 2. During the acquisition phase of the holeboard task, piglets from Source 2 learned the reference memory component faster and reached a higher overall working memory level in the reversal phase than piglets from Source 1. Our results show that Source (i.e. supplier and/or breed) influenced performance in behavioural tasks, and that the occurrence of litter size effects was supplier or breed dependent.