Environmental enrichment facilitates cocaine-cue extinction, deters reacquisition of cocaine self-administration and alters AMPAR GluA1 expression and phosphorylation

This study investigated the combination of environmental enrichment (EE) with cocaine‐cue extinction training on reacquisition of cocaine self‐administration. Rats were trained under a second‐order schedule for which responses were maintained by cocaine injections and cocaine‐paired stimuli. During three weekly extinction sessions, saline was substituted for cocaine but cocaine‐paired stimuli were presented. Rats received 4‐h periods of EE at strategic time points during extinction training, or received NoEE. Additional control rats received EE or NoEE without extinction training. One week later, reacquisition of cocaine self‐administration was evaluated for 15 sessions, and then GluA1 expression, a cellular substrate for learning and memory, was measured in selected brain regions. EE provided both 24 h before and immediately after extinction training facilitated extinction learning and deterred reacquisition of cocaine self‐administration for up to 13 sessions. Each intervention by itself (EE alone or extinction alone) was ineffective, as was EE scheduled at individual time points (EE 4 h or 24 h before, or EE immediately or 6 h after, each extinction training session). Under these conditions, rats rapidly reacquired baseline rates of cocaine self‐administration. Cocaine self‐administration alone decreased total GluA1 and/or pSer845GluA1 expression in basolateral amygdala and nucleus accumbens. Extinction training, with or without EE, opposed these changes and also increased total GluA1 in ventromedial prefrontal cortex and dorsal hippocampus. EE alone increased pSer845GluA1 and EE combined with extinction training decreased pSer845GluA1 in ventromedial prefrontal cortex. EE might be a useful adjunct to extinction therapy by enabling neuroplasticity that deters relapse to cocaine self‐administration.The authors declare no competing financial interests. These studies were supported by NSF grant SMA-0835976 to the CELEST Science of Learning Center at Boston University and by NIH grants DA024315 (KMK) and MH079407 (HYM). We thank Iris Mile, Zachary Silber, Sharone Moverman and Enjana Bylykbashi for expert technical assistance. (SMA-0835976 - NSF; DA024315 - NIH; MH079407 - NIH)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4798903/Published versio

Persistent Homology in Sparse Regression and its Application to Brain Morphometry

Sparse systems are usually parameterized by a tuning parameter that determines the sparsity of the system. How to choose the right tuning parameter is a fundamental and difficult problem in learning the sparse system. In this paper, by treating the the tuning parameter as an additional dimension, persistent homological structures over the parameter space is introduced and explored. The structures are then further exploited in speeding up the computation using the proposed soft-thresholding technique. The topological structures are further used as multivariate features in the tensor-based morphometry (TBM) in characterizing white matter alterations in children who have experienced severe early life stress and maltreatment. These analyses reveal that stress-exposed children exhibit more diffuse anatomical organization across the whole white matter region.Comment: submitted to IEEE Transactions on Medical Imagin

Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics

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Uniformity of large-area bilayer graphene grown by chemical vapor deposition

Graphene grown by chemical vapour deposition (CVD) on copper foils is a viable method for large area films for transparent conducting electrode (TCE) applications. We examine the spatial uniformity of large area films on the centimeter scale when transferred onto both Si substrates with 300nm oxide and flexible transparent PET substrates. A difference in the quality of graphene, as measured by the sheet resistance and transparency, is found for the areas at the edges of large sheets that depends on the supporting boat used for the CVD growth. Bilayer graphene is grown with uniform properties on the centimeter scale when a flat support is used for CVD growth. The flat support provides consistent delivery of precursor to the copper catalyst for graphene growth. These results provide important insights into the upscaling of CVD methods for growing high quality graphene and its transfer onto flexible substrates for potential applications as a TCE

Nicotine replacement therapy versus control for smoking cessation

Background: Nicotine replacement therapy (NRT) aims to temporarily replace much of the nicotine from cigarettes to reduce motivation to smoke and nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence. Objectives: To determine the effectiveness and safety of nicotine replacement therapy (NRT), including gum, transdermal patch, intranasal spray and inhaled and oral preparations, for achieving long-term smoking cessation, compared to placebo or 'no NRT' interventions. Search methods: We searched the Cochrane Tobacco Addiction Group trials register for papers mentioning 'NRT' or any type of nicotine replacement therapy in the title, abstract or keywords. Date of most recent search is July 2017. Selection criteria: Randomized trials in people motivated to quit which compared NRT to placebo or to no treatment. We excluded trials that did not report cessation rates, and those with follow-up of less than six months, except for those in pregnancy (where less than six months, these were excluded from the main analysis). We recorded adverse events from included and excluded studies that compared NRT with placebo. Studies comparing different types, durations, and doses of NRT, and studies comparing NRT to other pharmacotherapies, are covered in separate reviews. Data collection and analysis: Screening, data extraction and 'Risk of bias' assessment followed standard Cochrane methods. The main outcome measure was abstinence from smoking after at least six months of follow-up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. We calculated the risk ratio (RR) for each study. Where appropriate, we performed meta-analysis using a Mantel-Haenszel fixed-effect model. Main results: We identified 136 studies; 133 with 64,640 participants contributed to the primary comparison between any type of NRT and a placebo or non-NRT control group. The majority of studies were conducted in adults and had similar numbers of men and women. People enrolled in the studies typically smoked at least 15 cigarettes a day at the start of the studies. We judged the evidence to be of high quality; we judged most studies to be at high or unclear risk of bias but restricting the analysis to only those studies at low risk of bias did not significantly alter the result. The RR of abstinence for any form of NRT relative to control was 1.55 (95% confidence interval (CI) 1.49 to 1.61). The pooled RRs for each type were 1.49 (95% CI 1.40 to 1.60, 56 trials, 22,581 participants) for nicotine gum; 1.64 (95% CI 1.53 to 1.75, 51 trials, 25,754 participants) for nicotine patch; 1.52 (95% CI 1.32 to 1.74, 8 trials, 4439 participants) for oral tablets/lozenges; 1.90 (95% CI 1.36 to 2.67, 4 trials, 976 participants) for nicotine inhalator; and 2.02 (95% CI 1.49 to 2.73, 4 trials, 887 participants) for nicotine nasal spray. The effects were largely independent of the definition of abstinence, the intensity of additional support provided or the setting in which the NRT was offered. A subset of six trials conducted in pregnant women found a statistically significant benefit of NRT on abstinence close to the time of delivery (RR 1.32, 95% CI 1.04 to 1.69; 2129 participants); in the four trials that followed up participants post-partum the result was no longer statistically significant (RR 1.29, 95% CI 0.90 to 1.86; 1675 participants). Adverse events from using NRT were related to the type of product, and include skin irritation from patches and irritation to the inside of the mouth from gum and tablets. Attempts to quantitatively synthesize the incidence of various adverse effects were hindered by extensive variation in reporting the nature, timing and duration of symptoms. The odds ratio (OR) of chest pains or palpitations for any form of NRT relative to control was 1.88 (95% CI 1.37 to 2.57, 15 included and excluded trials, 11,074 participants). However, chest pains and palpitations were rare in both groups and serious adverse events were extremely rare. Authors' conclusions: There is high-quality evidence that all of the licensed forms of NRT (gum, transdermal patch, nasal spray, inhalator and sublingual tablets/lozenges) can help people who make a quit attempt to increase their chances of successfully stopping smoking. NRTs increase the rate of quitting by 50% to 60%, regardless of setting, and further research is very unlikely to change our confidence in the estimate of the effect. The relative effectiveness of NRT appears to be largely independent of the intensity of additional support provided to the individual. Provision of more intense levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT. NRT often causes minor irritation of the site through which it is administered, and in rare cases can cause non-ischaemic chest pain and palpitations

Mediator and cohesin connect gene expression and chromatin architecture

Transcription factors control cell-specific gene expression programs through interactions with diverse coactivators and the transcription apparatus. Gene activation may involve DNA loop formation between enhancer-bound transcription factors and the transcription apparatus at the core promoter, but this process is not well understood. Here we report that mediator and cohesin physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with cohesin, which can form rings that connect two DNA segments. The cohesin-loading factor Nipbl is associated with mediator–cohesin complexes, providing a means to load cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by mediator and cohesin. Mediator and cohesin co-occupy different promoters in different cells, thus generating cell-type-specific DNA loops linked to the gene expression program of each cell.National Institutes of Health (U.S.) (Fellowship)Canadian Institutes of Health Research (Research Fellowship)National Institutes of Health (U.S.) (Grant R01 HG002668