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

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

Do Electronic Health Records Help or Hinder Medical Education?

Many countries worldwide are digitizing patients' medical records. What impact will these electronic health records have upon medical education? This debate examines the threats and opportunities

Genetic characterization of outbred Sprague Dawley rats and utility for genome-wide association studies

Sprague Dawley (SD) rats are among the most widely used outbred laboratory rat populations. Despite this, the genetic characteristics of SD rats have not been clearly described, and SD rats are rarely used for experiments aimed at exploring genotype-phenotype relationships. In order to use SD rats to perform a genome-wide association study (GWAS), we collected behavioral data from 4,625 SD rats that were predominantly obtained from two commercial vendors, Charles River Laboratories and Harlan Sprague Dawley Inc. Using double-digest genotyping-by-sequencing (ddGBS), we obtained dense, high-quality genotypes at 291,438 SNPs across 4,061 rats. This genetic data allowed us to characterize the variation present in Charles River vs. Harlan SD rats. We found that the two populations are highly diverged (FST > 0.4). Furthermore, even for rats obtained from the same vendor, there was strong population structure across breeding facilities and even between rooms at the same facility. We performed multiple separate GWAS by fitting a linear mixed model that accounted for population structure and using meta-analysis to jointly analyze all cohorts. Our study examined Pavlovian conditioned approach (PavCA) behavior, which assesses the propensity for rats to attribute incentive salience to reward-associated cues. We identified 46 significant associations for the various metrics used to define PavCA. The surprising degree of population structure among SD rats from different sources has important implications for their use in both genetic and non-genetic studies

Social contact patterns and implications for infectious disease transmission: a systematic review and meta-analysis of contact surveys

Background: Transmission of respiratory pathogens such as SARS-CoV-2 depends on patterns of contact and mixing across populations. Understanding this is crucial to predict pathogen spread and the effectiveness of control efforts. Most analyses of contact patterns to date have focussed on high-income settings. Methods: Here, we conduct a systematic review and individual-participant meta-analysis of surveys carried out in low- and middle-income countries and compare patterns of contact in these settings to surveys previously carried out in high-income countries. Using individual-level data from 28,503 participants and 413,069 contacts across 27 surveys we explored how contact characteristics (number, location, duration and whether physical) vary across income settings. Results: Contact rates declined with age in high- and upper-middle-income settings, but not in low-income settings, where adults aged 65+ made similar numbers of contacts as younger individuals and mixed with all age-groups. Across all settings, increasing household size was a key determinant of contact frequency and characteristics, but low-income settings were characterised by the largest, most intergenerational households. A higher proportion of contacts were made at home in low-income settings, and work/school contacts were more frequent in high-income strata. We also observed contrasting effects of gender across income-strata on the frequency, duration and type of contacts individuals made. Conclusions: These differences in contact patterns between settings have material consequences for both spread of respiratory pathogens, as well as the effectiveness of different non-pharmaceutical interventions

Effect of atorvastatin on C-reactive protein and benefits for cardiovascular disease in patients with type 2 diabetes: analyses from the Collaborative Atorvastatin Diabetes Trial

CARDS was partially funded by Diabetes UK and the National Health Service Research and Development Forum (England)