Biology subjects
Publications and source records attributed to de Almeida, C..
The claustrum regulates reward processing, but its role in feeding remains unknown. We report that palatable food recruits claustral neurons and a claustrum-to-medial prefrontal cortex circuit whose activation reduces high-fat diet intake. These findings identify the claustrum as a key regulator of appetitive feeding, with potential implications for metabopsychiatric disorders.
Messenger ribonucleoproteins (mRNPs) acquire distinct protein compositions as they move from the nucleus to the cytoplasm, yet how this transition is coordinated and how inefficient remodeling affects downstream mRNA metabolism remains poorly understood. Here, we identify PAIP1 as a metazoan cofactor of the mRNA export ATPase DDX19. By binding a conserved N-terminal motif in DDX19, PAIP1 is recruited to the nuclear pore, where it promotes exchange of the nuclear poly(A)-binding protein PABPN1 for cytoplasmic PABPC1, thereby coupling mRNA export to cytoplasmic mRNP maturation. PAIP1 depletion alters cytoplasmic mRNP composition, mRNA stability and poly(A)-tail homeostasis. In Drosophila embryos, where poly(A)-tail regulation of maternal mRNAs directs early development, maternal PAIP1 depletion shortens poly(A)-tails, delays zygotic genome activation, and causes severe developmental defects. Our findings identify an export-coupled mRNP maturation pathway linking PABP exchange to downstream mRNA metabolism.
DEAD-box RNA helicases remodel RNA structures in many cellular pathways, yet how their activity is spatially controlled in cells remains poorly understood. The Drosophila germline helicase Vasa functions in ovaries only when localized to cytoplasmic granules, a process mediated by eLOTUS-domain proteins. Here, we define the mechanism by which eLOTUS domains activate Vasa. Biochemical analyses reveal that Vasa alone is largely inactive. eLOTUS domains bind the open conformation of Vasa and promote formation of the closed RNA- and ATP-bound state by accelerating RNA engagement. This stimulation requires a positively charged intrinsically disordered sequence within eLOTUS that increases RNA association. Mutations in this element abolish Vasa stimulation while preserving binding. We demonstrate that Vasa activation is essential in vivo. Together, these findings reveal a localization-dependent mechanism for regulating the DEAD-box helicase Vasa, in which enzymatic activity is gated by a spatially restricted cofactor.
Background and PurposeObesity involves profound disruptions in neuronal circuits, neuroendocrine communication and the endocannabinoid system (ECS). While global cannabinoid type-1 receptor (CB1R) blockade improves metabolism, its clinical use is limited by neuropsychiatric side effects. Peripherally restricted CB1R antagonists offer a safer alternative, yet the neural pathways, specifically the role of the gut-brain vagal axis, mediating their effects remain unclear. Experimental ApproachWe investigated the metabolic and neural effects of peripheral inhibition of CB1R (JD5037 and AM6545) in lean and diet-induced obese (DIO). Metabolic parameters were assessed using indirect calorimetry, and neuronal activation was mapped by cFos immunoreactivity. The requirement for vagal signaling was examined using subdiaphragmatic vagotomy (SDV) and pharmacological blockade of cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1) receptors. Key ResultsPeripheral CB1R inhibition suppressed food intake and shifted nutrient partitioning toward fatty acid oxidation in DIO, but not lean, mice. Obesity upregulated CB1R expression in the nodose ganglia. In DIO mice, peripheral CB1R inhibition robustly activated satiety-related brainstem (NTS, AP, PBN) and hypothalamic (ARC, PVN) nuclei. SDV abolished brainstem activation but failed to blunt hypothalamic recruitment or the anorexigenic and metabolic benefits. Furthermore, antagonism of CCK or GLP-1 receptors did not prevent the feeding-suppressive effects of JD5037. Conclusions and ImplicationsOur findings reveal a dual-mechanism model: vagal pathways mediate brainstem engagement, while hypothalamic recruitment and metabolic improvements occur via vagal-independent signaling. These results demonstrate that peripherally restricted CB1R antagonists indirectly engage central homeostatic circuits, supporting their therapeutic potential for obesity even in conditions with impaired vagal signaling. Bullet point summaryO_ST_ABS What is already knownC_ST_ABSO_LIObesity is associated with elevated circulating endocannabinoids, reflecting chronic overactivation of the peripheral endocannabinoid system. C_LIO_LIClinical and preclinical studies indicate that peripheral CB1R inhibition ameliorates obesity-related dysfunctions. C_LI What this study addsO_LIPeripheral CB1R inhibition suppresses food intake and promotes fatty acid oxidation in obese but not lean conditions. C_LIO_LIPeripheral CB1R inhibition engages brainstem nuclei via vagal signaling and hypothalamic nuclei via vagal-independent mechanisms. C_LI Clinical significanceO_LIMetabolic state-dependent CB1R responsiveness must be considered when designing endocannabinoids-targeted obesity therapies. C_LIO_LIPeripheral CB1R antagonists engage central homeostatic circuits via body-brain pathways, warranting surveillance of CNS outcomes. C_LI
Reward-related processes have traditionally been ascribed to neural circuits centered on the dopamine (DA) system. While exteroceptive stimuli, such as food and drugs of abuse, are well-established activators of DA-neuron activity, growing evidence indicates that interoceptive signals also play a critical role in modulating reward. Among these, the gut-brain vagal axis has emerged as a key pathway, yet its precise contribution to mesolimbic DA-dependent signaling, dynamics and behaviors remains poorly defined. Here, we combine complementary ex vivo and in vivo approaches across multiple scales to investigate how the gut-brain vagal axis regulates DA dynamics and reward-related behaviors. We show that gut-brain vagal tone is essential for gating mesolimbic DA system activity and functions, modulating DA-dependent molecular and cellular processes, and scaling both food- and drugs-induced reinforcement. These findings challenge the traditional brain-centric view of reward processing, supporting a more unified and integrated model in which gut-derived and vagus-mediated interoceptive signals are pivotal in intrinsically shaping motivation and reinforcement. By uncovering the influence of gut-brain vagal communication on mesolimbic DA functions, this work offers new insights into the neurobiological mechanisms underlying both adaptive and maladaptive reward processes, with broad implications for eating disorders and addiction.
Spinal cord injury (SCI) is a debilitating disease resulting in an estimated 18,000 new cases in the United States on an annual basis. Significant behavioral research on animal models has led to a large amount of data, some of which has been catalogued in the Open Data Commons for Spinal Cord Injury (ODC-SCI). More recently, high throughput sequencing experiments have been utilized to understand molecular mechanisms associated with SCI, with nearly 6,000 samples from over 90 studies available in the Sequence Read Archive. However, to date, no resource is available for efficiently mining high throughput sequencing data from SCI experiments. Therefore, we have developed a protocol for processing RNA-Seq samples from high-throughput sequencing experiments related to SCI resulting in both raw and normalized data that can be efficiently mined for comparisons across studies as well as homologous discovery across species. We have processed 1,196 publicly available RNA-seq samples from 50 bulk RNA-Seq studies across nine different species, resulting in an SQLite database that can be used by the SCI research community for further discovery. We provide both the database as well as a web-based front-end that can be used to query the database for genes of interest, differential gene expression, genes with high variance, and gene set enrichments.
Uridylation is a widespread modification destabilizing eukaryotic mRNAs. Yet, molecular mechanisms underlying TUTase-mediated mRNA degradation remain mostly unresolved. Here, we report that the Arabidopsis TUTase URT1 participates in a molecular network connecting several translational repressors/decapping activators. URT1 directly interacts with DECAPPING 5 (DCP5), the Arabidopsis ortholog of human LSM14 and yeast Scd6, and this interaction connects URT1 to additional decay factors like DDX6/Dhh1-like RNA helicases. Nanopore direct RNA sequencing reveals a global role of URT1 in shaping poly(A) tail length, notably by preventing the accumulation of excessively deadenylated mRNAs. Based on in vitro and in planta data, we propose a model that explains how URT1 could reduce the accumulation of oligo(A)-tailed mRNAs both by favoring their degradation and because 3 terminal uridines intrinsically hinder deadenylation. Importantly, preventing the accumulation of excessively deadenylated mRNAs avoids the biogenesis of illegitimate siRNAs that silence endogenous mRNAs and perturb Arabidopsis growth and development.