Lesions of the ventral hippocampus attenuate the acquisition but not expression of sign‐tracking behavior in rats

Individual variation in the attribution of motivational salience to reward‐related cues is believed to underlie addiction vulnerability. Pavlovian conditioned approach measures individual variation in motivational salience by identifying rats that are attracted to and motivated by reward cues (sign‐trackers) or motivationally fixed on the reward itself (goal‐trackers). Previously, it has been demonstrated that sign‐trackers are more vulnerable to addiction‐like behavior. Moreover, sign‐trackers release more dopamine in the nucleus accumbens than goal‐trackers in response to reward‐related cues, and sign‐ but not goal‐tracking behavior is dopamine‐dependent. In the present study, we investigated whether the ventral hippocampus, a potent driver of dopaminergic activity in the nucleus accumbens, modulates the acquisition and expression of Pavlovian conditioned approach behavior. In Experiment 1, lesions of the ventral, but not dorsal or total hippocampus, decreased sign‐tracking behavior. In Experiment 2, lesions of the ventral hippocampus did not affect the expression of sign‐ or goal‐tracking behaviors nor conditioned reinforcement. In addition, temporary inactivation of the ventral subiculum, the main output pathway of the ventral hippocampus, did not affect the expression of sign‐ or goal‐tracking behaviors. High‐pressure liquid chromatography of nucleus accumbens tissue punches revealed that ventral hippocampal lesions decreased levels of homovanillic acid and the homovanillic acid/dopamine ratio (a marker of dopamine release and metabolism) in only sign‐trackers, and decreased accumbal norepinephrine levels in both sign‐ and goal‐trackers. These results suggest that the ventral hippocampus is important for the acquisition but not expression of sign‐tracking behavior, possibly as a result of altered dopamine and norepinephrine in the nucleus accumbens. © 2016 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134415/1/hipo22619.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134415/2/hipo22619_am.pd

Rats that sign-track are resistant to Pavlovian but not instrumental extinction

Individuals vary in the extent to which they attribute incentive salience to a discrete cue (conditioned stimulus; CS) that predicts reward delivery (unconditioned stimulus; US), which results in some individuals approaching and interacting with the CS (sign-trackers; STs) more than others (goal-trackers; GTs). Here we asked how periods of non-reinforcement influence conditioned responding in STs vs. GTs, in both Pavlovian and instrumental tasks. After classifying rats as STs or GTs by pairing a retractable lever (the CS) with the delivery of a food pellet (US), we introduced periods of non-reinforcement, first by simply withholding the US (i.e., extinction training; experiment 1), then by signaling alternating periods of reward (R) and non-reward (NR) within the same session (experiments 2 and 3). We also examined how alternating R and NR periods influenced instrumental responding for food (experiment 4). STs and GTs did not differ in their ability to discriminate between R and NR periods in the instrumental task. However, in Pavlovian settings STs and GTs responded to periods of non-reward very differently. Relative to STs, GTs very rapidly modified their behavior in response to periods of non-reward, showing much faster extinction and better and faster discrimination between R and NR conditions. These results highlight differences between Pavlovian and instrumental extinction learning, and suggest that if a Pavlovian CS is strongly attributed with incentive salience, as in STs, it may continue to bias attention toward it, and to facilitate persistent and relatively inflexible responding, even when it is no longer followed by reward

Risk, Benefit, and Cost Thresholds for Emergency Department Testing: A Cross‐sectional, Scenario‐based Study

BackgroundWhile diagnostic testing is common in the emergency department, the value of some testing is questionable. The purpose of this study was to assess how varying levels of benefit, risk, and costs influenced an individual’s desire to have diagnostic testing.MethodsA survey through Amazon Mechanical Turk presented hypothetical clinical situations: low‐risk chest pain and minor traumatic brain injury. Each scenario included three given variables (benefit, risk, and cost), that was independently randomly varied over four possible values (0.1, 1, 5, and 10% for benefit and risk and $0,$100, $500, and$1,000 for the individual’s personal cost for receiving the test). Benefit was defined as the probability of finding the target disease (traumatic intracranial hemorrhage or acute coronary syndrome).ResultsOne‐thousand unique respondents completed the survey. With an increased benefit from 0.1% to 10%, the percentage of respondents who accepted a diagnostic test went from 28.4% to 53.1%. (odds ratio [OR] = 3.42; 95% confidence interval [CI] = 2.57–4.54). As risk increased from 0.1% to 10%, this number decreased from 52.5% to 28.5%. (OR = 0.33; 95% CI = 0.25–0.44). Increasing cost from $0 to$1,000 had the greatest change of those accepting the test from 61.1% to 21.4%, respectively (OR = 0.15; 95% CI = 0.11–0.2).ConclusionsThe desire for testing was strongly sensitive to the benefits, risks, and costs. Many participants wanted a test when there was no added cost, regardless of benefit or risk levels, but far fewer elected to receive the test as cost increased incrementally. This suggests that out‐of‐pocket costs may deter patients from undergoing diagnostic testing with low potential benefit.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137417/1/acem13148_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137417/2/acem13148.pd

Mechanistic Study of the Effect of Endothelin SNPs in Microvascular Angina – protocol of the PRIZE Endothelin Sub-Study

Introduction Microvascular angina (MVA) is a common cause of ischemia with non-obstructive coronary arteries (INOCA) and limited therapeutic options are available to those affected. Endothelin-1 (ET-1) is a potent vasoconstrictor implicated in the pathophysiology of MVA. A large randomised, double blinded, placebo controlled crossover trial, the PRecIsion medicine with ZibotEntan in microvascular angina (PRIZE) trial is currently underway, investigating an endothelin receptor antagonist – Zibotentan, as a new drug treatment for microvascular angina. The trial uses a 'precision medicine' approach by preferential selection of those with higher ET-1 expression conferred by the PHACTR1 minor G allele single nucleotide polymorphism (SNP). The incidence of this SNP occurs in approximately one third of the population therefore a considerable number of screened patients will be ineligible for randomisation and the treatment phase of the trial. Methods In the PRIZE Endothelin (ET) Sub-Study, patients screened out of the PRIZE trial will be genotyped for other genetic variants in the ET-1 pathway. These will be correlated with phenotypic characteristics including exercise tolerance, angina severity and quantitative measures of microvascular function on cardiovascular MRI as well as mechanistic data on endothelin pathway signalling. Conclusions The study will provide a comprehensive genotype and phenotype bio-resource identifying novel ET-1 genotypes to inform the potential wider use of endothelin receptor antagonists for this indication.Wellcome Trust [WT107715/Z/15/Z, APD], British Heart Foundation [CB, RE/18/6134217], Medical Research Council [CB, MR/S018905/1], ].Jon Moulton Charity Trust [GRA, SPH

South African universities and human development : Towards a theorisation and operationalisation of professional capabilities for poverty reduction

This paper reports on a research project investigating the role of universities in South Africa in contributing to poverty reduction through the quality of their professional education programmes. The focus here is on theorising and the early operationalisation of multi-layered, multi-dimensional transformation based on ideas from Amartya Sen's capability approach. Key features of a professionalism oriented to public service, which in South Africa must mean the needs and lives of the poor, are outlined. These features include: the demand from justice; the expansion of the comprehensive capabilities both of the poor and professional capability formation to be able to act in ‘pro-poor’ ways; and, praxis pedagogies which shape this connected process. This theorisation is then tentatively operationalised in a process of selecting transformation dimensions

Patient Preferences for Diagnostic Testing in the Emergency Department: A Crossâ sectional Study

BackgroundDiagnostic testing is common during emergency department (ED) visits. Little is understood about patient preferences for such testing. We hypothesized that a patient’s willingness to undergo diagnostic testing is influenced by the potential benefit, risk, and personal cost.MethodsWe conducted a cross sectional survey among ED patients for diagnostic testing in two hypothetical scenarios: chest pain (CP) and mild traumatic brain injury (mTBI). Each scenario defined specific risks, benefits, and costs of testing. The odds of a participant desiring diagnostic testing were calculated using a series of nested multivariable logistic regression models.ResultsParticipants opted for diagnostic testing 68.2% of the time, including 69.7% of CP and 66.7% of all mTBI scenarios. In the CP scenario, 81% of participants desired free testing versus 59% when it was associated with a $100 copay (difference = 22$100 copayment (difference = 17%, 95% CI = 11% to 24%). Benefit and risk had mixed effects across the scenarios. In fully adjusted models, the association between cost and desire for testing persisted in the CP (odds ratio [OR] = 0.33, 95% CI = 0.23 to 0.47) and adult mTBI (OR = 0.47, 95% CI = 0.33 to 0.67) scenarios.ConclusionsIn this EDâ based study, patient preferences for diagnostic testing differed significantly across levels of risk, benefit, and cost of diagnostic testing. Cost was the strongest and most consistent factor associated with decreased desire for testing.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144652/1/acem13404.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144652/2/acem13404_am.pd

Divergent effects of repeated cocaine and novel environment exposure on locus coeruleus c‐fos expression and brain catecholamine concentrations in rats

IntroductionChronic administration of cocaine causes a disinhibited, hyperexploratory response to novel environments. As the norepinephrine (NE) system regulates exploration and is dysregulated following cocaine exposure, we hypothesized that this cocaine‐mediated hyperexploratory response is associated with increased locus coeruleus (LC) reactivity.MethodsTo test this hypothesis, we used dual fluorescent in situ hybridization immunofluorescence to analyze novelty‐induced c‐fos and tyrosine hydroxylase expression in the LC and high‐pressure liquid chromatography to measure dopamine (DA) and NE concentrations in key catecholamine projection regions following exposure to cocaine.ResultsRepeated cocaine exposure followed by a 14‐day drug‐free period increased exploration of novel environments, replicating previous findings. Novelty exposure increased LC c‐fos expression, increased anterior cingulate NE, and decreased ventral tegmental area DA. Cocaine exposure decreased amygdala (AMY) DA, but had no effect on LC c‐fos expression or NE in any tested brain region. No interactions between cocaine and novelty were found. Open arm exploration was positively correlated with LC c‐fos expression and NE concentrations in both the anterior cingulate and nucleus accumbens, and negatively correlated with AMY DA concentration.ConclusionsOur findings confirm that exposure to novel environments increases LC activity and NE in the anterior cingulate cortex, that long‐term exposure to cocaine dysregulates AMY DA, and that disinhibited exploration in novel environments correlates with NE and DA in regions that modulate risk‐taking and avoidance behavior. Further studies investigating the effects of cocaine on brain catecholamine systems are important in understanding the long‐lasting effects of cocaine on brain function.Chronic cocaine exposure causes a long‐lasting, disinhibited, hyperexploratory phenotype. This effect may be partially driven by changes in locus coeruleus (LC) function, as LC activation in response to novel environments is correlated with this disinhibited exploratory behavior.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148353/1/brb31222_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148353/2/brb31222.pd

Simulating spatial and temporal evolution of multiple wing cracks around faults in crystalline basement rocks

Fault zones are structurally highly spatially heterogeneous and hence extremely complex. Observations of fluid flow through fault zones over several scales show that this structural complexity is reflected in the hydrogeological properties of faults. Information on faults at depth is scarce, hence, it is highly valuable to understand the controls on spatial and temporal fault zone development. In this paper we increase our understanding of fault damage zone development in crystalline rocks by dynamically simulating the growth of single and multiple splay fractures produced from failure on a pre-existing fault. We present a new simulation model, MOPEDZ (Modeling Of Permeability Evolution in the Damage Zone surrounding faults), that simulates fault evolution through solution of Navier's equation with a combined Mohr-Coulomb and tensile failure criteria. Simulations suggest that location, frequency, mode of failure and orientation of splay fractures are significantly affected both by the orientation of the fault with respect to the maximum principal compressive stress and the conditions of differential stress. Model predictions compare well with published field outcrop data, confirming that this model produces realistic damage zone geometries