Rodents monitor their error in self-generated duration on a single trial basis

A fundamental question in neuroscience is what type of internal representation leads to complex, adaptive behavior. When faced with a deadline, individuals’ behavior suggests that they represent the mean and the uncertainty of an internal timer to make near-optimal, time-dependent decisions. Whether this ability relies on simple trial-and-error adjustments or whether it involves richer representations is unknown. Richer representations suggest a possibility of error monitoring, that is, the ability for an individual to assess its internal representation of the world and estimate discrepancy in the absence of external feedback. While rodents show timing behavior, whether they can represent and report temporal errors in their own produced duration on a single-trial basis is unknown. We designed a paradigm requiring rats to produce a target time interval and, subsequently, evaluate its error. Rats received a reward in a given location depending on the magnitude of their timing errors. During the test trials, rats had to choose a port corresponding to the error magnitude of their just-produced duration to receive a reward. High-choice accuracy demonstrates that rats kept track of the values of the timing variables on which they based their decision. Additionally, the rats kept a representation of the mapping between those timing values and the target value, as well as the history of the reinforcements. These findings demonstrate error-monitoring abilities in evaluating self-generated timing in rodents. Together, these findings suggest an explicit representation of produced duration and the possibility to evaluate its relation to the desired target duration.

In neuroscience, a fundamental question is how rich the internal representation of an individual’s experience must be to yield adaptive behavior. Let us consider a hungry individual in need of finding food fast: The individual may adopt a trial-and-error foraging strategy to maximize reward but may also, to maximize its efficiency, represent rich experiential variables, such as how much time it takes to reach a source of food. Both representing elapsed time and monitoring its inherent uncertainty plays an important role in adaptive behavior, learning, and decision making (1). When representing these variables, the sources of uncertainty are both exogenous (stimuli driven) and endogenous (neural implementation). The mapping of exogenous sources of temporal uncertainty has been well described in timing behavior: For instance, mice can adjust their behaviors to the width of the distribution of temporal intervals provided through external stimuli (2). On the other hand, the endogenous sources of uncertainty for time perception are less understood and more difficult to address.Evidence that animals are sensitive and have access to the internal uncertainty of elapsed time comes from a task in which the individual must produce a required target duration using a lever press or a key press (1, 3, 4). In a task in which individuals must produce an interval of fixed duration to obtain a reward (Fig. 1A), a plausible strategy to maximize reward would be to set the produced duration to be longer than the required target duration so as to allow a margin of error [internal target duration; (5)]. This is because the larger an individual’s representational uncertainty, the larger the margin of error to maximize the reward. Consistent with this, studies have shown that the magnitude of error in produced intervals varies with the magnitude of temporal uncertainties (6, 7), and participants with larger temporal uncertainty set larger margins of errors [Fig. 1B and SI Appendix, Fig. S2; (1, 7)]. The observed optimization of timing behavior begs the question of how rich the representation of elapsed time must be.Open in a separate windowFig. 1.The TP task and error-monitoring protocol. (A) Schematic of a box arrangement with a lever available in the middle of the panel and reward ports on the left and right side of the lever. Reward availability was signaled by the port lit, depicted by the lightbulbs. Reward delivery was triggered by rats’ nose poke in the reward port. Depending on the group assignment, rats had to either hold the lever pressed for a minimum of 3.2 s (HOLD group) or press the lever twice with a minimal delay (3.2 s) between two presses (PRESS group). (B) TP performance, in error-monitoring test sessions, follows Weber’s law for both groups, with signatures of optimality. (Upper) Probability density functions over TPs for each individual rat in HOLD (blue) and PRESS (red) groups. Thresholds Θ (blue and red dashed lines for HOLD and PRESS groups, respectively) are plotted for each individual. (Bottom Left) Average probability density functions over TPs for HOLD and PRESS groups superimposed. Note the distribution shift and width shrinkage for HOLD group. (Bottom Right) For each rat, µ(TP) is plotted against σ(TP). Both at the individual and at the group level the PRESS rats showed larger µ(TP) and σ(TP), visible as an upward right shift of the red curve. This pattern indicates that rats make their choices optimally, taking into account their level of TP variability. The results hold within each rat and across sessions (SI Appendix, Fig. S3). (C) Schematic depiction of how rewards were assigned to specific parts of TP distribution. Green color is used for “small error” (SE) trials and orange color for “large error” (LE) trials. Red color indicates TPs that were out of reward range. The arrows indicate probabilistic assignment of TP type (SE or LE) to left and right ports, on training trials. On test trials, the food–port assignments remained, but both ports were available and, thus, the amount of reward was driven by the rat’s choice. (D) Schematic of a trial structure. From the top to bottom, the succession of task events is depicted. They alternate along TP axis (color bar with red, green, and orange) and show different scenarios that are determined by the rats’ performance on TP in single trials. ITI is the last event in a single-trial sequence.A trial-and-error strategy would predict that near-optimal behavior can be parsimoniously explained by adaptation so that timing behavior would fluctuate around the required duration. The representational view would predict that uncertainty and trial-to-trial errors are experiential variables used by the animals to monitor their timing behavior.To settle the question of whether rodents can monitor their timing errors relative to their target on a trial-by-trial basis, we developed a task inspired by human work. Humans required to generate a time interval can also reliably report the magnitude of their errors and their sign (8) (i.e., they can evaluate by how much [magnitude] their generated duration was too short or too long [sign], with respect to the target duration). Humans can also report how confident they are in their timing behavior (9). We tested here these temporal cognitive abilities in rats, which were required to produce a time interval and correctly report, in order to obtain a reward, the magnitude of their timing errors on some test trials. We show that rats correctly reported the magnitude of their timing error, suggesting that their timing behavior uses explicit representations of time intervals together with their uncertainty around the internal target duration.     

Factor analysis of the WISC and WISC-R: A Polish comparison

The factor structures of the WISC and WISC-R were secured for a group of Polish fourth-grade students (N = 30). Consistent with American findings, the WISC Verbal, Performance, and Full Scale IQs were higher than those on the WISC-R. On both measures, factor results favor the two-factor solution, which approximates Wechsler's Verbal and Performance scales. A third factor, which failed to simulate Freedom from Distractibility, accounted for approximately 10% of the explained variance. On this factor, Coding was heavily weighted, but Arithmetic and Digit Span loadings ranged from modest to negative. Results provide support for the application of the Wechsler instruments in cross-cultural settings and for interpreting the third factor according to the dynamics of specific cultures.     

A 2017 update: Challenging the cosmetic procedural delay following oral isotretinoin therapy

For decades it has been widely accepted that elective procedures should be delayed for at least 6-months following completion of isotretinoin therapy. However, numerous 2017 publications demonstrate the need for change in best practice. The evidence has yet to be succinctly summarized in a single article or in a stand-alone quick reference algorithm for physicians. This article’s review of all 2017 publications confirms that the 6-month delay is not necessary for all procedures and provides a simple algorithmic approach to summarize the updated recommendations for procedural delay of cosmetic procedures following systemic isotretinoin therapy. This is a useful tool for clinicians and allows patients to receive the most appropriate and timely cosmetic therapy to minimize the psychosocial impact of the skin condition.     

The Effect of Low Doses of Zearalenone (ZEN) on the Bone Marrow Microenvironment and Haematological Parameters of Blood Plasma in Pre-Pubertal Gilts

The aim of this study was to determine whether low doses of zearalenone (ZEN) influence the carry-over of ZEN and its metabolites to the bone marrow microenvironment and, consequently, haematological parameters. Pre-pubertal gilts (with a body weight of up to 14.5 kg) were exposed to daily ZEN doses of 5 μg/kg BW (group ZEN5, n = 15), 10 μg/kg BW (group ZEN10, n = 15), 15 μg/kg BW (group ZEN15, n = 15), or were administered a placebo (group C, n = 15) throughout the entire experiment. Bone marrow was sampled on three dates (exposure dates 7, 21, and 42—after slaughter) and blood for haematological analyses was sampled on 10 dates. Significant differences in the analysed haematological parameters (WBC White Blood Cells, MONO—Monocytes, NEUT—Neutrophils, LYMPH—Lymphocytes, LUC—Large Unstained Cells, RBC—Red Blood Cells, HGB—Haemoglobin, HCT—Haematocrit, MCH—Mean Corpuscular Volume, MCHC—Mean Corpuscular Haemoglobin Concentrations, PLT—Platelet Count and MPV—Mean Platelet Volume) were observed between groups. The results of the experiment suggest that exposure to low ZEN doses triggered compensatory and adaptive mechanisms, stimulated the local immune system, promoted eryptosis, intensified mycotoxin biotransformation processes in the liver, and produced negative correlations between mycotoxin concentrations and selected haematological parameters.     

Circulating endothelial cells in essential thrombocythemia and polycythemia vera: correlation with JAK2-V617F mutational status,angiogenic factors and coagulation activation markers

Angiogenesis plays an important role in the biology of hematological malignancies, including essential thrombocythemia (ET) and polycythemia vera (PV). Some data suggests that it has a role in the pathogenesis of thrombosis, the major clinical problem in ET and PV. The number of different subpopulations of circulating endothelial cells (CECs), plasma levels of vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor 1 and 2 (sVEGFR-1,2) and placenta growth factor (PlGF) were determined in 30 patients with ET and 16 patients with PV. Correlations between angiogenesis and JAK2-V617F mutational status, risk factors for thrombosis and coagulation activation markers were also assessed. The number of CEC subpopulations, were markedly higher in ET and PV patients, irrespective of JAK2-V617F status, when compared to the control group. The median values of activated CECs were markedly higher in PV patients with WBC >8.7 (×10⁹/l). Significantly higher VEGF plasma levels were found in ET patients and a similar trend was seen in PV patients in relation to healthy volunteers. The plasma levels of sVEGFR-1 were significantly higher, and PlGF levels markedly lower, in the ET and PV group than in controls. Our study also demonstrated markedly increased levels of D-dimer and TAT complexes in the patient groups. In conclusion, we found that angiogenesis, as measured by CEC numbers, is increased in ET and PV patients regardless of JAK2-V617F mutational status. Our results demonstrated that angiogenic cytokines interact with known thrombotic risk factors. We confirmed the coagulation activation in ET and PV patients but found no differences in levels of coagulation activation markers in relation to JAK2-V617F mutational status.     

Epistatic relationship between the cancer susceptibility genes CHEK2 and p27.

We studied the effects of p27 and CHEK2 variants on prostate and colon cancer risk in a case-control study. Modest effects on prostate cancer risk were observed for both CHEK2 missense and truncating variants. However, the excess cancer risk was restricted to the subgroup of men who were homozygous for the VV genotype in codon 109 of the p27 gene. Among men with the VV p27 genotype, the odds ratios associated with truncating and missense CHEK2 mutations were 3.1 (P < 0.0001) and 1.9 (P < 0.0001), respectively. Among men with other p27 genotypes (GG and VG), the odds ratios were 1.5 and 1.2 for truncating and missense CHEK2 mutations, respectively, and were not statistically significant. The interaction between CHEK2 and p27 was confirmed in a group of patients with colon cancer. Thus, it seems that the clinical expression of CHEK2 variant alleles on prostate and colon cancer risk may be restricted to individuals with a specific genotype (VV) of the p27 gene. Two-gene models provide numerous challenges for gene identification and cancer risk assessment.     

Classical Prognostic Factors for Survival and Loco-Regional Control in Breast Cancer Patients Treated with Radical Mastectomy Alone

A retrospective analysis of clinical and pathological prognostic factors was performed in 1 068 breast cancer patients treated with radical mastectomy alone in 1952-1980. Three endpoints were considered: 10-year survival, 10-year disease-free survival and 10-year loco-regional relapse-free survival. Both univariate and multivariate analyses confirmed the prognostic significance of tumour size, histological type and grade (Bloom classification) and involvement of axillary nodes for all three endpoints. Additionally, young age appeared to be a significant risk factor for loco-regional disease-free survival. Prognostic subgroups were defined by the use of 3 main indicators. In node negative patients with T1 tumours the prognosis seemed to be good regardless of histological grade (80-90% 10-year disease-free survival), in T2 tumours the survival was significantly dependent on histological type and grade. In node positive patients increasing number of involved nodes and higher histological grade had an independent adverse effect on all three endpoints. The study demonstrates that classical, commonly available prognostic factors clearly distinguish subgroups with different prognosis, which may be helpful when deciding on the use of adjuvant local and/or systemic therapies.     

The effect of monocytes on early activation of lymphocytes T among children with idiopathic uveitis

PURPOSE: We have investigated T Lymphocytes ability for CD69 molecule induction in presence and absence of monocytes in idiopathic uveitis. MATERIAL AND METHODS: Twenty-five children with idiopathic uveitis were studied. The control group consisted of 12 healthy children. Peripheral blood mononuclear cells (PBMCs) were isolated from heparinised venous blood, by density gradient centrifugation. CD69 expression was cytometrically assessed on freshly isolated and cultured T lymphocytes. RESULTS: CD69 expression on freshly isolated peripheral blood T lymphocytes was low in both studied groups. LPS-stimulated monocytes added to cultures of T lymphocytes induced increase in CD69 expression but significantly lower in children with idiopathic uveitis compare to healthy children.