Hippocampal BDNF regulates a shift from flexible, goal-directed to habit memory system function following cocaine abstinence.

The transition from recreational drug use to addiction involves pathological learning processes that support a persistent shift from flexible, goal-directed to habit behavioral control. Here, we examined the molecular mechanisms supporting altered function in hippocampal (HPC) and dorsolateral striatum (DLS) memory systems following abstinence from repeated cocaine. After 3 weeks of cocaine abstinence (experimenter- or self-administered), we tested new behavioral learning in male rats using a dual-solution maze task, which provides an unbiased approach to assess HPC- versus DLS-dependent learning strategies. Dorsal hippocampus (dHPC) and DLS brain tissues were collected after memory testing to identify transcriptional adaptations associated with cocaine-induced shifts in behavioral learning. Our results demonstrate that following prolonged cocaine abstinence rats show a bias toward the use of an inflexible, habit memory system (DLS) in lieu of a more flexible, easily updated memory system involving the HPC. This memory system bias was associated with upregulation and downregulation of brain-derived neurotrophic factor (BDNF) gene expression and transcriptionally permissive histone acetylation (acetylated histone H3, AcH3) in the DLS and dHPC, respectively. Using viral-mediated gene transfer, we overexpressed BDNF in the dHPC during cocaine abstinence and new maze learning. This manipulation restored HPC-dependent behavioral control. These findings provide a system-level understanding of altered plasticity and behavioral learning following cocaine abstinence and inform mechanisms mediating the organization of learning and memory more broadly

Hydrophobic Ligand Binding by Zn-α_2-glycoprotein, a Soluble Fat-depleting Factor Related to Major Histocompatibility Complex Proteins

Zn-alpha2-glycoprotein (ZAG) is a member of the major histocompatibility complex (MHC) class I family of proteins and is identical in amino acid sequence to a tumor-derived lipid-mobilizing factor associated with cachexia in cancer patients. ZAG is present in plasma and other body fluids, and its natural function, like leptin's, probably lies in lipid store homeostasis. X-ray crystallography has revealed an open groove between the helices of ZAG's alpha1 and alpha2 domains, containing an unidentified small ligand in a position similar to that of peptides in MHC proteins (Sanchez, L. M., Chirino, A. J., and Bjorkman, P. J. (1999) Science 283, 1914-1919). Here we show, using serum-derived and bacterial recombinant protein, that ZAG binds the fluorophore-tagged fatty acid 11-(dansylamino)undecanoic acid (DAUDA) and, by competition, natural fatty acids such as arachidonic, linolenic, eicosapentaenoic, and docosahexaenoic acids. Other MHC class I-related proteins (FcRn, HFE, HLA-Cw*0702) showed no such evidence of binding. Fluorescence and isothermal calorimetry analysis showed that ZAG binds DAUDA with Kd in the micromolar range, and differential scanning calorimetry showed that ligand binding increases the thermal stability of the protein. Addition of fatty acids to ZAG alters its intrinsic (tryptophan) fluorescence emission spectrum, providing a strong indication that ligand binds in the expected position close to a cluster of exposed tryptophan side chains in the groove. This study therefore shows that ZAG binds small hydrophobic ligands, that the natural ligand may be a polyunsaturated fatty acid, and provides a fluorescence-based method for investigating ZAG-ligand interactions

Cell-Extrinsic Defective Lymphocyte Development in Lmna-/- Mice

Background: Mutations in the LMNA gene, which encodes all A-type lamins, result in a variety of human diseases termed laminopathies. Lmna-/- mice appear normal at birth but become runted as early as 2 weeks of age and develop multiple tissue defects that mimic some aspects of human laminopathies. Lmna-/- mice also display smaller spleens and thymuses. In this study, we investigated whether altered lymphoid organ sizes are correlated with specific defects in lymphocyte development. Principal Findings: Lmna-/- mice displayed severe age-dependent defects in T and B cell development which coincided with runting. Lmna-/- bone marrow reconstituted normal T and B cell development in irradiated wild-type recipients, driving generation of functional and self-MHC restricted CD4 + and CD8 + T cells. Transplantation of Lmna-/- neonatal thymus lobes into syngeneic wild-type recipients resulted in good engraftment of thymic tissue and normal thymocyte development. Conclusions: Collectively, these data demonstrate that the severe defects in lymphocyte development that characterize Lmna-/- mice do not result directly from the loss of A-type lamin function in lymphocytes or thymic stroma. Instead, the immune defects in Lmna-/- mice likely reflect indirect damage, perhaps resulting from prolonged stress due to the striate

PSMC5, a 19S Proteasomal ATPase, Regulates Cocaine Action in the Nucleus Accumbens

ΔFosB is a stable transcription factor which accumulates in the nucleus accumbens (NAc), a key part of the brain’s reward circuitry, in response to chronic exposure to cocaine or other drugs of abuse. While ΔFosB is known to heterodimerize with a Jun family member to form an active transcription factor complex, there has not to date been an open-ended exploration of other possible binding partners for ΔFosB in the brain. Here, by use of yeast two-hybrid assays, we identify PSMC5—also known as SUG1, an ATPase-containing subunit of the 19S proteasomal complex—as a novel interacting protein with ΔFosB. We verify such interactions between endogenous ΔFosB and PSMC5 in the NAc and demonstrate that both proteins also form complexes with other chromatin regulatory proteins associated with gene activation. We go on to show that chronic cocaine increases nuclear, but not cytoplasmic, levels of PSMC5 in the NAc and that overexpression of PSMC5 in this brain region promotes the locomotor responses to cocaine. Together, these findings describe a novel mechanism that contributes to the actions of ΔFosB and, for the first time, implicates PSMC5 in cocaine-induced molecular and behavioral plasticity.National Institutes of Health (U.S.)National Institute on Drug AbuseIshibashi FoundationJapan Society for the Promotion of Science (KAKENHI 24591735)Japan Society for the Promotion of Science (KAKENHI 26290064)Japan Society for the Promotion of Science (KAKENHI 25116010

Rationale for and protocol of a multi-national population-based bacteremia surveillance collaborative

<p>Abstract</p> <p>Background</p> <p>Bloodstream infections are frequent causes of human illness and cause major morbidity and death. In order to best define the epidemiology of these infections and to track changes in occurrence, adverse outcome, and resistance rates over time, population based methodologies are optimal. However, few population-based surveillance systems exist worldwide, and because of differences in methodology inter-regional comparisons are limited. In this report we describe the rationale and propose first practical steps for developing an international collaborative approach to the epidemiologic study and surveillance for bacteremia.</p> <p>Findings</p> <p>The founding collaborative participants represent six regions in four countries in three continents with a combined annual surveillance population of more than 8 million residents.</p> <p>Conclusion</p> <p>Future studies from this collaborative should lead to a better understanding of the epidemiology of bloodstream infections.</p

Class I HDAC Inhibition Blocks Cocaine-Induced Plasticity Through Targeted Changes in Histone Methylation

Induction of histone acetylation in the nucleus accumbens (NAc), a key brain reward region, promotes cocaine-induced alterations in gene expression. Histone deacetylases (HDACs) tightly regulate the acetylation of histone tails, but little is known about the functional specificity of different HDAC isoforms in the development and maintenance of cocaine-induced plasticity, and prior studies of HDAC inhibitors report conflicting effects on cocaine-elicited behavioral adaptations. Here, we demonstrate that specific and prolonged blockade of HDAC1 in NAc of mice increased global levels of histone acetylation, but also induced repressive histone methylation and antagonized cocaine-induced changes in behavior, an effect mediated in part via a chromatin-mediated suppression of GABAA receptor subunit expression and inhibitory tone on NAc neurons. Our findings suggest a novel mechanism by which prolonged and selective HDAC inhibition can alter behavioral and molecular adaptations to cocaine and inform the development of novel therapeutics for cocaine addiction

Safety, tolerability, and efficacy of maralixibat in adults with primary sclerosing cholangitis: Open-label pilot study

BACKGROUND: Primary sclerosing cholangitis (PSC) is frequently associated with pruritus, which significantly impairs quality of life. Maralixibat is a selective ileal bile acid transporter (IBAT) inhibitor that lowers circulating bile acid (BA) levels and reduces pruritus in cholestatic liver diseases. This is the first proof-of-concept study of IBAT inhibition in PSC. METHODS: This open-label study evaluated the safety and tolerability of maralixibat ≤10 mg/d for 14 weeks in adults with PSC. Measures of pruritus, biomarkers of BA synthesis, cholestasis, and liver function were also assessed. RESULTS: Of 27 enrolled participants, 85.2% completed treatment. Gastrointestinal treatment-emergent adverse events (TEAEs) occurred in 81.5%, with diarrhea in 51.9%. TEAEs were mostly mild or moderate (63.0%); 1 serious TEAE (cholangitis) was considered treatment related. Mean serum BA (sBA) levels decreased by 16.7% (-14.84 µmol/L; 95% CI, -27.25 to -2.43; p = 0.0043) by week 14/early termination (ET). In participants with baseline sBA levels above normal (n = 18), mean sBA decreased by 40.0% (-22.3 µmol/L, 95% CI, -40.38 to -4.3; p = 0.004) by week 14/ET. Liver enzyme elevations were not significant; however, increases of unknown clinical significance in conjugated bilirubin levels were observed. ItchRO weekly sum scores decreased from baseline to week 14/ET by 8.4% (p = 0.0495), by 12.6% (p = 0.0275) in 18 participants with pruritus at baseline, and by 70% (p = 0.0078) in 8 participants with ItchRO daily average score ≥3 at baseline. CONCLUSIONS: Maralixibat was associated with reduced sBA levels in adults with PSC. In participants with more severe baseline pruritus, pruritus improved significantly from baseline. TEAEs were mostly gastrointestinal related. These results support further investigation of IBAT inhibitors for adults with PSC-associated pruritus. ClinicalTrials.gov: NCT02061540

A Precision Treatment Model for Internet-Delivered Cognitive Behavioral Therapy for Anxiety and Depression among University Students:A Secondary Analysis of a Randomized Clinical Trial

Importance: Guided internet-delivered cognitive behavioral therapy (i-CBT) is a low-cost way to address high unmet need for anxiety and depression treatment. Scalability could be increased if some patients were helped as much by self-guided i-CBT as guided i-CBT. Objective: To develop an individualized treatment rule using machine learning methods for guided i-CBT vs self-guided i-CBT based on a rich set of baseline predictors. Design, Setting, and Participants: This prespecified secondary analysis of an assessor-blinded, multisite randomized clinical trial of guided i-CBT, self-guided i-CBT, and treatment as usual included students in Colombia and Mexico who were seeking treatment for anxiety (defined as a 7-item Generalized Anxiety Disorder [GAD-7] score of ≥10) and/or depression (defined as a 9-item Patient Health Questionnaire [PHQ-9] score of ≥10). Study recruitment was from March 1 to October 26, 2021. Initial data analysis was conducted from May 23 to October 26, 2022. Interventions: Participants were randomized to a culturally adapted transdiagnostic i-CBT that was guided (n = 445), self-guided (n = 439), or treatment as usual (n = 435). Main Outcomes and Measures: Remission of anxiety (GAD-7 scores of ≤4) and depression (PHQ-9 scores of ≤4) 3 months after baseline. Results: The study included 1319 participants (mean [SD] age, 21.4 [3.2] years; 1038 women [78.7%]; 725 participants [55.0%] came from Mexico). A total of 1210 participants (91.7%) had significantly higher mean (SE) probabilities of joint remission of anxiety and depression with guided i-CBT (51.8% [3.0%]) than with self-guided i-CBT (37.8% [3.0%]; P =.003) or treatment as usual (40.0% [2.7%]; P =.001). The remaining 109 participants (8.3%) had low mean (SE) probabilities of joint remission of anxiety and depression across all groups (guided i-CBT: 24.5% [9.1%]; P =.007; self-guided i-CBT: 25.4% [8.8%]; P =.004; treatment as usual: 31.0% [9.4%]; P =.001). All participants with baseline anxiety had nonsignificantly higher mean (SE) probabilities of anxiety remission with guided i-CBT (62.7% [5.9%]) than the other 2 groups (self-guided i-CBT: 50.2% [6.2%]; P =.14; treatment as usual: 53.0% [6.0%]; P =.25). A total of 841 of 1177 participants (71.5%) with baseline depression had significantly higher mean (SE) probabilities of depression remission with guided i-CBT (61.5% [3.6%]) than the other 2 groups (self-guided i-CBT: 44.3% [3.7%]; P =.001; treatment as usual: 41.8% [3.2%]; P &lt;.001). The other 336 participants (28.5%) with baseline depression had nonsignificantly higher mean (SE) probabilities of depression remission with self-guided i-CBT (54.4% [6.0%]) than guided i-CBT (39.8% [5.4%]; P =.07). Conclusions and Relevance: Guided i-CBT yielded the highest probabilities of remission of anxiety and depression for most participants; however, these differences were nonsignificant for anxiety. Some participants had the highest probabilities of remission of depression with self-guided i-CBT. Information about this variation could be used to optimize allocation of guided and self-guided i-CBT in resource-constrained settings. Trial Registration: ClinicalTrials.gov Identifier: NCT04780542.</p