Time representation in reinforcement learning models of the basal ganglia

Reinforcement learning (RL) models have been influential in understanding many aspects of basal ganglia function, from reward prediction to action selection. Time plays an important role in these models, but there is still no theoretical consensus about what kind of time representation is used by the basal ganglia. We review several theoretical accounts and their supporting evidence. We then discuss the relationship between RL models and the timing mechanisms that have been attributed to the basal ganglia. We hypothesize that a single computational system may underlie both RL and interval timing—the perception of duration in the range of seconds to hours. This hypothesis, which extends earlier models by incorporating a time-sensitive action selection mechanism, may have important implications for understanding disorders like Parkinson's disease in which both decision making and timing are impaired

Treatment with the PI3K inhibitor LY 294002 or the IGF-1R blocking antibody αIR3 prevents axon formation in adult RGC in culture.

<p>A) Double immunofluorescence showing the distribution of the RGC marker NF200 and the axonal marker Tau-1 in cultured adult RGC. Cells were cultured for 3 days in control conditions or in the presence of 20 nM LY 294002 (LY) or αIR3 (10 mg/ml). Calibration bar = 40 µm. B) Percentage (+/− s.e.m.) of adult RGC cultured for 3 days in the different conditions described above (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054462#pone-0054462-g003" target="_blank">Fig 3A</a>), exhibiting or lacking axons. n = 3 independent experiments. At least 100 cells were scored for each condition. * Significantly different from LY and a IR3 p≤0,0005. C) Cell viability (determined by the criterion of propidium iodide exclusion <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0054462#pone.0054462-Aras1" target="_blank">[52]</a>) after 1 or 4 DIV. n = 3 independent experiments. At least 100 neurons were scored for each condition.</p

Co-transfection of IGF-1R-suppressed adult RGC with a constitutively active form of the PI3k catalytic subunit p-110 restores the ability of the neurons to form axons.

<p>Double immunofluorescence of adult RGC showing the distribution of NF200 (displaying neuronal shape) and myc (marker of transfection with cDNA encoding for a constitutively active form of the PI3K regulatory subunit p110). GFP is a marker of transfection efficiency with the shRNA directed to IGF-1R. Cells were transfected and cultured for 4 days. Calibration bar = 10 µm.</p

Stimulation with IGF-1 triggers the polarized activation of the IGF-1R and PI3K in the axons of adult rat RGC regenerating in culture.

<p>A) Triple immunofluorescence micrographs of a rat adult RGC regenerating in culture after 3 DIV showing the distribution of the RGC marker NF200 (blue), the axonal marker Tau-1 (red) and the phosphorylated (active) form of the IGF-1R (green, pIGF-1R). Cells were cultured for 3 days, deprived of insulin for 4 h and stimulated for 5 min in control medium or medium containing 10 nM IGF-1. Note the significant activation of the IGF-1R, especially at the distal third of the axon (arrow). B) Triple immunofluorescence micrographs of a rat adult RGC regenerating in culture after 3 DIV showing the distribution of the RGC marker NF200 (blue), the axonal marker Tau-1 (red) and the phosphorylated form of the PI3k regulatory subunit p85 (green, p-p85). Cells were treated as described above (Fig. 1A). Note the pronounced activation of PI3K, especially within the distal axon (arrow). Calibration bar = 20 µm.</p

The IGF-1R β subunit is enriched at the distal-most third of the axon in adult RGC regenerating in culture.

<p>A) Western blot of protein from total retina disaggregated cells (RC), a fraction enriched in RGC (RGCF-see methods) and the same fraction after 4 days in culture (RGCF 4DIV) detected using an anti-βgc antibody. Equal amounts of protein from the three different fractions were loaded onto each lane. Note the increased intensity of βgc staining in the RGC 4DIV fraction. Numbers below are the O.D. (arbitrary units) <u>+/−</u> s.e.m. n = 3 independent experiments. B) Western blot prepared as in Fig. 1 A developed using a polyclonal antibody to the IGF-1R β subunit (C20-Santa Cruz Biotechnology). Note the increased intensity of C20 staining in the RGC 4DIV fraction. C) Triple immunofluorescence micrographs of a rat adult RGC regenerating in culture after 3 DIV showing the distribution of the RGC marker NF200 (blue, top panel), the axonal marker Tau-1 (red, second panel) and the β subunit of the IGF-1R (βgc) (green, third panel) in adult RGC neurons regenerating in culture. The lower panel shows a merged image of the three stainings. Note the enrichment of βgc at the distal end of the axon (arrow). Calibration bar = 20 µm.</p

Venous thromboembolism risk and prophylaxis in hospitalised medically ill patients The ENDORSE Global Survey

Limited data are available regarding the risk for venous thromboembolism (VIE) and VIE prophylaxis use in hospitalised medically ill patients. We analysed data from the global ENDORSE survey to evaluate VTE risk and prophylaxis use in this population according to diagnosis, baseline characteristics, and country. Data on patient characteristics, VIE risk, and prophylaxis use were abstracted from hospital charts. VTE risk and prophylaxis use were evaluated according to the 2004 American College of Chest Physicians (ACCP) guidelines. Multivariable analysis was performed to identify factors associated with use of ACCP-recommended prophylaxis. Data were evaluated for 37,356 hospitalised medical patients across 32 countries. VIE risk varied according to medical diagnosis, from 31.2% of patients with gastrointestinal/hepatobiliary diseases to 100% of patients with acute heart failure, active noninfectious respiratory disease, or pulmonary infection (global rate, 41.5%). Among those at risk for VTE, ACCP-recommended prophylaxis was used in 24.4% haemorrhagic stroke patients and 40-45% of cardiopulmonary disease patients (global rate, 39.5%). Large differences in prophylaxis use were observed among countries. Markers of disease severity, including central venous catheters, mechanical ventilation, and admission to intensive care units, were strongly associated with use of ACCP-recommended prophylaxis. In conclusion, VIE risk varies according to medical diagnosis. Less than 40% of at-risk hospitalised medical patients receive ACCP-recommended prophylaxis. Prophylaxis use appears to be associated with disease severity rather than medical diagnosis. These data support the necessity to improve implementation of available guidelines for evaluating VIE risk and providing prophylaxis to hospitalised medical patients

Venous Thromboembolism Risk and Prophylaxis in the Acute Care Hospital Setting (ENDORSE Survey) Findings in Surgical Patients

Objective: To evaluate venous thromboembolism (VTE) risk in patients who underwent a major operation, including the use of, and factors influencing, American College of Chest Physicians-recommended types of VTE prophylaxis