Caffeine-induced protein kinase A activation restores cognitive deficits induced by sleep deprivation by regulating O-GlcNAc cycling in adult zebrafish.

Sleep deprivation (SD) is widely acknowledged as a significant risk factor for cognitive impairment. In this study, intraperitoneal caffeine administration significantly ameliorated the learning and memory (L/M) deficits induced by SD and reduced aggressive behaviors in adult zebrafish. SD led to a reduction in protein kinase A (PKA) phosphorylation, phosphorylated-cAMP response element-binding protein (p-CREB), and c-Fos expression in zebrafish brain. Notably, these alterations were effectively reversed by caffeine. In addition, caffeine mitigated neuroinflammation induced by SD, as evident from suppression of the SD-mediated increase in glial fibrillary acidic protein (GFAP) and nuclear factor-κB (NF-κB) activation. Caffeine restored normal O-GlcNAcylation and O-GlcNAc transferase (OGT) levels while reversing the increased expression of O-GlcNAcase (OGA) in zebrafish brain after SD. Intriguingly, rolipram, a selective phosphodiesterase 4 (PDE4) inhibitor, effectively mitigated cognitive deficits, restored p-CREB and c-Fos levels, and attenuated the increase in GFAP in brain induced by SD. In addition, rolipram reversed the decrease in O-GlcNAcylation and OGT expression as well as elevation of OGA expression following SD. Treatment with H89, a PKA inhibitor, significantly impaired the L/M functions of zebrafish compared with the control group, inducing a decrease in O-GlcNAcylation and OGT expression and, conversely, an increase in OGA expression. The H89-induced changes in O-GlcNAc cycling and L/M dysfunction were effectively reversed by glucosamine treatment. H89 suppressed, whereas caffeine and rolipram promoted O-GlcNAc cycling in Neuro2a cells. Our collective findings underscore the interplay between PKA signaling and O-GlcNAc cycling in the regulation of cognitive function in the brain, offering potential therapeutic targets for cognitive deficits associated with SD.NEW & NOTEWORTHY Our observation highlights the intricate interplay between cAMP/PKA signaling and O-GlcNAc cycling, unveiling a novel mechanism that potentially governs the regulation of learning and memory functions. The dynamic interplay between these two pathways provides a novel and nuanced perspective on the molecular foundation of learning and memory regulation. These insights open avenues for the development of targeted interventions to treat conditions that impact cognitive function, including SD.

Combined docking and machine learning identify key molecular determinants of ligand pharmacological activity on ß2 adrenoceptor.

G protein-coupled receptors (GPCRs) are valuable therapeutic targets for many diseases. A central question of GPCR drug discovery is to understand what determines the agonism or antagonism of ligands that bind them. Ligands exert their action via the interactions in the ligand binding pocket. We hypothesized that there is a common set of receptor interactions made by ligands of diverse structures that mediate their action and that among a large dataset of different ligands, the functionally important interactions will be over-represented. We computationally docked ~2700 known ß2AR ligands to multiple ß2AR structures, generating ca 75 000 docking poses and predicted all atomic interactions between the receptor and the ligand. We used machine learning (ML) techniques to identify specific interactions that correlate with the agonist or antagonist activity of these ligands. We demonstrate with the application of ML methods that it is possible to identify the key interactions associated with agonism or antagonism of ligands. The most representative interactions for agonist ligands involve K972.68×67 , F194ECL2 , S2035.42×43 , S2045.43×44 , S2075.46×641 , H2966.58×58 , and K3057.32×31 . Meanwhile, the antagonist ligands made interactions with W2866.48×48 and Y3167.43×42 , both residues considered to be important in GPCR activation. The interpretation of ML analysis in human understandable form allowed us to construct an exquisitely detailed structure-activity relationship that identifies small changes to the ligands that invert their pharmacological activity and thus helps to guide the drug discovery process. This approach can be readily applied to any drug target.

REM Sleep Deprivation Impairs Learning and Memory by Decreasing Brain O-GlcNAc Cycling in Mouse.

Rapid eye movement (REM) sleep is implicated learning and memory (L/M) functions and hippocampal long-term potentiation (LTP). Here, we demonstrate that REM sleep deprivation (REMSD)-induced impairment of contextual fear memory in mouse is linked to a reduction in hexosamine biosynthetic pathway (HBP)/O-GlcNAc flux in mouse brain. In mice exposed to REMSD, O-GlcNAcylation, and O-GlcNAc transferase (OGT) were downregulated while O-GlcNAcase was upregulated compared to control mouse brain. Foot shock fear conditioning (FC) induced activation of protein kinase A (PKA) and cAMP response element binding protein (CREB), which were significantly inhibited in brains of the REMSD group. Intriguingly, REMSD-induced defects in L/M functions and FC-induced PKA/CREB activation were restored upon increasing O-GlcNAc cycling with glucosamine (GlcN) or Thiamet G. Furthermore, Thiamet G restored the REMSD-induced decrease in dendritic spine density. Suppression of O-GlcNAcylation by the glutamine fructose-6-phosphate amidotransferase (GFAT) inhibitor, 6-diazo-5-oxo-L-norleucine (DON), or OGT inhibitor, OSMI-1, impaired memory function, and inhibited FC-induced PKA/CREB activation. DON additionally reduced the amplitude of baseline field excitatory postsynaptic potential (fEPSP) and magnitude of long-term potentiation (LTP) in normal mouse hippocampal slices. To our knowledge, this is the first study to provide comprehensive evidence of dynamic O-GlcNAcylation changes during the L/M process in mice and defects in this pathway in the brain of REM sleep-deprived mice. Our collective results highlight HBP/O-GlcNAc cycling as a novel molecular link between sleep and cognitive function.

Sexual awareness and cognitive social capital among high school students: a cross-sectional study in rural Vietnam / Journal of Rural Medicine

Objective: Since the late 1980s, Vietnam has seen numerous social changes, likely leading to changes in adolescent sexual awareness. Adolescents are currently exposed to a plethora of sexual information without adequate sex education and knowledge. Globally, researchers have identified sexual knowledge and self-esteem as determinants of adolescent sexual awareness and behavior, but little is known about the role of social capital, especially in rural areas. This study aimed to clarify the relationship between sexual awareness and cognitive social capital among high school students in rural Vietnam.Materials and Methods: We conducted a questionnaire-based survey assessing sexual knowledge, sexual awareness, perceptions of peers’ sexual experience, structural and cognitive social capital, and self-esteem (Rosenberg Self-Esteem Scale) in March 2017 among 1,583 11th graders at four public high schools in Hai Duong Province, Vietnam.Results: The final sample comprised 1,517 students (95.8% of total responses): 609 boys (40.1%) and 908 girls (59.9%). Multiple logistic regression analysis was performed with intolerance toward premarital sex as the dependent variable. In the first model, the independent variables were self-esteem, knowledge of proper timing for condom use, and perception that many peers are sexually experienced. The second model added an indicator of cognitive social capital. In the first model, self-esteem, knowledge of proper timing for condom use, and perception that many peers are sexually experienced were all significantly associated with intolerance toward premarital sex for both boys and girls. In the second model, for both boys and girls, only cognitive social capital was significantly associated with intolerance toward premarital sex.Conclusion: The results of this study regarding the effect of social capital in rural Vietnam are consistent with previous findings in urban areas. Social capital should be emphasized in efforts to improve sexual awareness and, in turn, sexual and reproductive health among adolescents in rural areas.