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There is growing evidence that mere exposure to drugs can induce long-term alterations in the neural systems that mediate reward processing, motivation, and behavioral control, potentially causing the pathological pursuit of drugs that characterizes the addicted state. The incentive sensitization theory proposes that drug exposure potentiates the influence of reward-paired cues on behavior. It has also been suggested that drug exposure biases action selection towards the automatic execution of habits and away from more deliberate goal-directed control. The current study investigated whether rats given repeated exposure to peripherally administered cocaine would show alterations in incentive motivation (assayed using the Pavlovian-to-instrumental transfer (PIT) paradigm) or habit formation (assayed using sensitivity to reward devaluation). After instrumental and Pavlovian training for food pellet rewards, rats were given 6 daily injections of cocaine (15 mg/kg, IP) or saline, followed by a 10-d period of rest. Consistent with the incentive sensitization theory, cocaine-treated rats showed stronger cue-evoked lever pressing than saline-treated rats during the PIT test. The same rats were then trained on a new instrumental action with a new food pellet reward before undergoing a reward devaluation testing. Although saline-treated rats exhibited sensitivity to reward devaluation, indicative of goal-directed performance, cocaine-treated rats were insensitive to this treatment, suggesting a reliance on habitual processes. These findings, when taken together, indicate that repeated exposure to cocaine can cause broad alterations in behavioral control, spanning both motivational and action selection processes, and could therefore help explain aberrations of decision-making that underlie drug addiction.

The external globus pallidus (GPe) is a key contributor to motor suppressing pathways in the basal ganglia. The authors show that optogenetic interventions targeted to specific neuronal subpopulations in the GPe can disrupt pathological activity in the basal ganglia and restore movement for hours beyond stimulation. The identification of distinct cell types in the basal ganglia has been critical to our understanding of basal ganglia function and the treatment of neurological disorders. The external globus pallidus (GPe) is a key contributor to motor suppressing pathways in the basal ganglia, yet its neuronal heterogeneity has remained an untapped resource for therapeutic interventions. Here we demonstrate that optogenetic interventions that dissociate the activity of two neuronal populations in the GPe, elevating the activity of parvalbumin (PV)-expressing GPe neurons over that of Lim homeobox 6 (Lhx6)-expressing GPe neurons, restores movement in dopamine-depleted mice and attenuates pathological activity of basal ganglia output neurons for hours beyond stimulation. These results establish the utility of cell-specific interventions in the GPe to target functionally distinct pathways, with the potential to induce long-lasting recovery of movement despite the continued absence of dopamine.

The dorsal striatum has been linked to decision-making under conflict, but the mechanism by which striatal neurons contribute to approach-avoidance conflicts remains unclear. We hypothesized that striatopallidal dopamine D2 receptor (D2R)-expressing neurons promote avoidance, and tested this hypothesis in two exploratory approach-avoidance conflict paradigms in mice: the elevated zero maze and open field. Genetic elimination of D2Rs on striatopallidal neurons (iMSNs), but not other neural populations, increased avoidance of the open areas in both tasks, in a manner that was dissociable from global changes in movement. Population calcium activity of dorsomedial iMSNs was disrupted in mice lacking D2Rs on iMSNs, suggesting that disrupted output of iMSNs contributes to heightened avoidance behavior. Consistently, artificial disruption of iMSN output with optogenetic stimulation heightened avoidance of open areas of these tasks, while inhibition of iMSN output reduced avoidance. We conclude that dorsomedial striatal iMSNs control approach-avoidance conflicts in exploratory tasks, and highlight this neural population as a potential target for reducing avoidance in anxiety disorders.

Background During the last decade, plant biotechnological laboratories have sparked a monumental revolution with the rapid development of next sequencing technologies at affordable prices. Soon, these sequencing technologies and assembling of whole genomes will extend beyond the plant computational biologists and become commonplace within the plant biology disciplines. The current availability of large-scale genomic resources for non-traditional plant model systems (the so-called ‘orphan crops’) is enabling the construction of high-density integrated physical and genetic linkage maps with potential applications in plant breeding. The newly available fully sequenced plant genomes represent an incredible opportunity for comparative analyses that may reveal new aspects of genome biology and evolution. The analysis of the expansion and evolution of gene families across species is a common approach to infer biological functions. To date, the extent and role of gene families in plants has only been partially addressed and many gene families remain to be investigated. Manual identification of gene families is highly time-consuming and laborious, requiring an iterative process of manual and computational analysis to identify members of a given family, typically combining numerous BLAST searches and manually cleaning data. Due to the increasing abundance of genome sequences and the agronomical interest in plant gene families, the field needs a clear, automated annotation tool. Results Here, we present the geneHummus package, an R-based pipeline for the identification and characterization of plant gene families. The impact of this pipeline comes from a reduction in hands-on annotation time combined with high specificity and sensitivity in extracting only proteins from the RefSeq database and providing the conserved domain architectures based on SPARCLE. As a case study we focused on the auxin receptor factors gene (ARF) family in Cicer arietinum (chickpea) and other legumes. Conclusion We anticipate that our pipeline should be suitable for any taxonomic plant family, and likely other gene families, vastly improving the speed and ease of genomic data processing.

Drug addiction is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling that are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the current study, we tested this hypothesis using fast-scan cyclic voltammetry to monitor phasic DA signaling in the nucleus accumbens core of cocaine-pretreated (6 once-daily injections of 15 mg/kg, i.p.) and drug-naive rats during a test of cue-evoked incentive motivation for food-the Pavlovian-to-instrumental transfer task. We found that prior cocaine exposure augmented both reward seeking and DA release triggered by the presentation of a reward-paired cue. Furthermore, cue-evoked DA signaling positively correlated with cue-evoked food seeking and was found to be a statistical mediator of this behavioral effect of cocaine. Taken together, these findings provide support for the hypothesis that repeated cocaine exposure enhances cue-evoked incentive motivation through augmented phasic mesolimbic DA signaling. This work sheds new light on a fundamental neurobiological mechanism underlying motivated behavior and its role in the expression of compulsive reward seeking.

The extent to which neuroanatomical variability associated with early substance involvement, which is associated with subsequent risk for substance use disorder development, reflects preexisting risk and/or consequences of substance exposure remains poorly understood. To examine neuroanatomical features associated with early substance use initiation and to what extent associations may reflect preexisting vulnerability. Cohort study using data from baseline through 3-year follow-up assessments of the ongoing longitudinal Adolescent Brain Cognitive Development Study. Children aged 9 to 11 years at baseline were recruited from 22 sites across the US between June 1, 2016, and October 15, 2018. Data were analyzed from February to September 2024. Substance use initiation through 3-year follow-up (ie, age <15 years). Self-reported alcohol, nicotine, cannabis, and other substance use initiation and baseline magnetic resonance imaging (MRI)-derived estimates of brain structure (ie, global and regional cortical volume, thickness, surface area, sulcal depth, and subcortical volume). Covariates included family (eg, familial relationships), pregnancy (eg, prenatal exposure to substances), child (eg, sex and pubertal status), and MRI (eg, scanner model) variables. Among 9804 children (mean [SD] baseline age, 9.9 [0.6] years; 5160 boys [52.6%]; 213 Asian [2.2%], 1474 Black [15.0%], 514 Hispanic/Latino [5.2%], 29 American Indian [0.3%], 10 Pacific Islander [0.1%], 7463 White [76.1%], and 75 other [0.7%]) with nonmissing baseline neuroimaging and covariate data, 3460 (35.3%) reported substance use initiation before age 15. Initiation of any substance or alcohol use was associated with thinner cortex in prefrontal regions (eg, rostral middle frontal gyrus, β = -0.03; 95% CI, -0.02 to -0.05; P = 6.99 × 10-6) but thicker cortex in all other lobes, larger globus pallidus and hippocampal volumes, as well as greater global indices of brain structure (eg, larger whole brain volume, β = 0.05; 95% CI, 0.03 to 0.06; P = 2.80 × 10-8) following Bonferroni or false discovery rate multiple testing correction. Cannabis use initiation was associated with lower right caudate volume (β = -0.03; 95% CI, -0.01 to -0.05; P = .002). Post hoc examinations restricting to postbaseline initiation suggested that the majority of associations, including thinner prefrontal cortex and greater whole brain volume, preceded initiation. In this cohort study of children, preexisting neuroanatomical variability was associated with substance use initiation. In addition to putative neurotoxic effects of substance exposure, brain structure variability may reflect predispositional risk for initiating substance use earlier in life with potential cascading implications for development of later problems.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Extra TFIIIC (ETC) sites are chromosomal locations bound in vivo by the RNA polymerase III (Pol III) transcription factor III C (TFIIIC) complex, but are not necessarily associated with Pol III transcription. Although the location of ETC sequences are conserved in budding yeast, and similar sites are found in other organisms, their functions are largely unstudied. One such site, ETC6 in Saccharomyces cerevisiae, lies upstream of TFC6, a gene encoding a subunit of the TFIIIC complex itself. Promoter analysis shows that the ETC6 B-box sequence is involved in autoregulation of the TFC6 promoter. Mutation of ETC6 increases TFC6 mRNA levels, whereas mutation immediately upstream severely weakens promoter activity. A temperature-sensitive mutation in TFC3 that weakens DNA binding of TFIIIC also results in increased TFC6 mRNA levels; however, no increase is observed in mutants of TFIIIB or Pol III subunits, demonstrating a specific role for the TFIIIC complex in TFC6 promoter regulation. Chromatin immunoprecipitation shows an inverse relationship of TFIIIC occupancy at ETC6 versus TFC6 mRNA levels. Overexpression of TFC6 increases association of TFIIIC at ETC6 (and other loci) and results in reduced expression of a TFC6 promoter-URA3 reporter gene. Both of these effects are dependent on the ETC6 B-box. These results demonstrate that the TFC6 promoter is directly regulated by the TFIIIC complex, a demonstration of an RNA polymerase II promoter being directly responsive to a core Pol III transcription factor complex. This regulation could have implications in controlling global tRNA expression levels.

One of the most common types of skin breakdown in ageing populations is skin tears. The International Skin Tear Advisory Panel advocates for special attention to be paid to dressing selection related to skin tear management. The panel recommends choosing dressings that will promote the maintenance of moisture balance, suit the local wound environment, protect peri‐wound skin, control or manage exudate and infection, and optimise caregiver time. It is paramount that dressings protect the fragile nature of the skin associated with those who at heightened risk for skin tear development. To compare the effectiveness of soft silicone dressings (a contact layer and/or foam) for the healing of skin tears with local practices that do not include soft silicone dressings. The study was a pragmatic randomised controlled prospective study. One hundred and twenty‐six individuals from two long‐term care facilities in Ontario Canada who presented with skin tears were randomised into the treatment group using either soft silicone dressings (a contact layer and/or foam) or the control group using non‐adhesive dressings. The current study demonstrated that 96.9% (n = 63) of skin tears in the treatment group healed over a 3‐week period compared with 34.4% (n = 21) in the control group. The proportion of wound healing experienced at week 2 was 89.2% (n = 58) in the treatment group compared with 27.9% (n = 17) in the control group. There was a significantly greater reduction in wound surface area relative to baseline in the treatment group (2.9 cm2) compared with the control group (0.6 cm2) (χ2 = 21.792 P < .0001) at week 1. Survival analysis data supported that skin tears healed 50% faster in the treatment group (11 days) compared with the control group (22 days) (χ2 = 59.677 P < .0001). The expected healing trajectory of acute wounds, including skin tears, if proper wound bed preparation is realised and infection is controlled, is 7 to 21 days. Results of this study suggest the use of silicone dressings support wound healing and aid in wound closure within the expected healing trajectory, with faster complete wound closure and mean healing times compared with non‐silicone dressing for the treatment of STs.

Background The majority of undiagnosed diseases manifest with objective findings that warrant further investigation. The Undiagnosed Diseases Network (UDN) receives applications from patients whose symptoms and signs have been intractable to diagnosis; however, many UDN applicants are affected primarily by subjective symptoms such as pain and fatigue. We sought to characterize presenting symptoms, referral sources, and demographic factors of applicants to the UDN to identify factors that may determine application outcome and potentially differentiate between those with undiagnosed diseases (with more objective findings) and those who are less likely to have an undiagnosed disease (more subjective symptoms). Methods We used a systematic retrospective review of 151 consecutive Not Accepted and 50 randomly selected Accepted UDN applications. The primary outcome was whether an applicant was Accepted, or Not Accepted, and, if accepted, whether or not a diagnosis was made. Objective and subjective symptoms and information on prior specialty consultations were collected from provider referral letters. Demographic data and decision data on network acceptance were gathered from the UDN online portal. Results Fewer objective findings and more subjective symptoms were found in the Not Accepted applications. Not Accepted referrals also were from older individuals, reported a shorter period of illness, and were referred to the UDN by their primary care physicians. All of these differences reached statistical significance in comparison with Accepted applications. The frequency of subspecialty consults for diagnostic purposes prior to UDN application was similar in both groups. Conclusions The preponderance of subjective and lack of objective findings in the Not Accepted applications distinguish these from applicants that are accepted for evaluation and diagnostic efforts through the UDN. Not Accepted applicants are referred primarily by their primary care providers after multiple specialist consultations fail to yield answers. Distinguishing between patients with undiagnosed diseases with objective findings and those with primarily subjective findings can delineate patients who would benefit from further diagnostic processes from those who may have functional disorders and need alternative pathways for management of their symptoms. Trial registration clinicaltrials.gov NCT02450851 , posted May 21st 2015.