Biology subjects

Tapia, A.

Publications and source records attributed to Tapia, A..

3 recordsLinked to original sources

bioRxiv2025

Opposing responses of hippocampal theta oscillations to running and a forelimb-dominated sensorimotor behavior

Hippocampal theta oscillations regulate the timing of neurons to support navigation, memory formation, and sensorimotor integration. Theta is modulated by running speed, breathing, whisking, and jumping and increases in tasks involving memory encoding or retrieval. The positive relationship between theta frequency and running speed is believed stabilize hippocampal representations of space amid movement variability. Here, we incorporated a novel string-pulling task to determine if established relationships between movement and theta hold when progress to a reward is determined by the length of string pulled. This task eliminates many speed-associated inputs, such vestibular, visual, and hindlimb information, and allows an unprecedented level of precision in the analysis of individual paw movements. Given that animals move the string a fixed length to acquire a reward, we predicted that the positive relationship between theta frequency and speed would hold. ApproachFive Sprague Dawley rats (4 mo.) were trained to continuously pull a string a fixed distance of 208 cm using an automated string-pulling system and run on a track for food reward. Local-field data was acquired from electrodes in dorsal CA1. ResultsRelationships between theta and movement speed were distinct during string pulling and running. While theta was robust in both conditions, frequency was significantly reduced during string-pulling and showed no speed-frequency coupling, unlike running. This difference could result from the conflict between hindlimb and forelimb signals, with only forelimb movement signaling advancement. Fine-grained analysis of paw movements during string-pulling (lift, advance, grasp, pull, push) revealed that theta power and frequency peaked during the contralateral paws downward push despite paw speed being low during this action. This suggests that theta frequency and power could respond to effort rather than purely kinematic information. Notably, running-associated theta may similarly reflect both speed and effort as most locomotor tasks conflate these variables. Finally, theta phase aligned from one reach-pull cycle to the next during the downward pull motion - the first action that directly advances the string forward. Since phase-locking has been associated with sensorimotor gating, synchrony at this point could reflect the gating of inputs that are the most causally relevant for reaching the reward, potentially facilitating integration of action-outcome signals for memory encoding and navigation. Taken together, these data support a dual-scale view of hippocampal processing and theta-band activity where macroscale theta activity requires suprathreshold sensory, vestibular, and proprioceptive drive and microscale theta remains sensitive to subsecond limb movements.

neuroscience↗

bioRxiv2025

Endothelial AGO1 Drives Vascular Inflammation and Atherosclerosis via a Non-Canonical Nuclear Mechanism

BACKGROUNDEndothelial cell (EC) dysfunction is a cause and consequence of vascular inflammation and lipid dysregulation in atherosclerosis, yet the molecular drivers linking EC dysfunction to systemic metabolic derangements remain incompletely understood. Moreover, whether inhibiting an endogenous gene in ECs can impact liver function, lipid profile, and the vascular inflammation in the context of atherosclerosis has not been demonstrated. We previously identified Argonaute 1 (AGO1), a component of the RNA-induced silencing complex, as a regulator of EC function in angiogenesis and obesity. However, the role of endothelial AGO1 in vascular inflammation and liver function in the context of hyperlipidemia and atherosclerosis is unknown. METHODSEC-conditional AGO1 knockout (EC-AGO1-KO) and wildtype mice were subjected to pro-atherosclerotic models induced by AAV9-PCSK9 coupled with a Western diet or partial carotid ligation. Metabolic and vascular phenotype and gene expression were analyzed. In human liver sinusoidal and aortic ECs, AGO1 was knocked down using antisense oligonucleotides (ASO), followed by assessment of inflammatory responses (qPCR, RNA-seq, ELISA, and monocyte adhesion assays). To identify the molecular mechanisms linking AGO1 and EC inflammation, Cut&Tag sequencing, chromatin immunoprecipitation, immunofluorescence, proximal ligation assay, and co-immunoprecipitation were performed. The therapeutic effect of AGO1 inhibition was assessed using ASO-delivered via lipid nanoparticle (LNP) for systemic distribution and monocyte membrane-coated nanoparticles (MoNP) to target the inflamed endothelium. RESULTSEC-AGO1-KO mice exhibited improved plasma lipid profiles, reduced hepatic steatosis, inflammation, and fibrosis, and decreased aortic atherosclerotic burden. AGO1 knockdown in ECs attenuated inflammatory responses. Mechanistically, AGO1 interacted with NF-{kappa}B p65 and promoted p65 nuclear translocation and the transcriptional activation of pro-inflammatory genes, including ICAM1 and THBS1. AGO1-ASO delivered through LNP or MoNP achieved the anti-inflammatory, anti-hyperlipidemic, and anti-atherosclerotic effects, recapitulating the phenotypes observed with EC-AGO1-KO. CONCLUSIONSEndothelial AGO1 promotes vascular inflammation and liver dysfunction in the context of hyperlipidemia and atherosclerosis, in part through a non-canonical nuclear action of AGO1 as an NF-{kappa}B coactivator. Inhibition of endothelial AGO1 provides the dual benefits of ameliorating lipid dysregulation and suppressing vascular inflammation. These results highlight EC-AGO1 as a possible therapeutic target for atherosclerosis and cardiometabolic diseases.

pathology↗

bioRxiv2024

Mapping Endothelial-Macrophage Interactions in Diabetic Vasculature: Role of TREM2 in Vascular Inflammation and Ischemic Response

Diabetes mellitus (DM) significantly accelerates vascular diseases like peripheral arterial disease (PAD). Endothelial cells (ECs) and macrophages (M{Phi}s) singularly and synergistically are important contributors to DM-associated vascular dysfunction. Single-cell (sc) profiling technologies are revealing the true heterogeneity of ECs and M{Phi}s, but how this cellular diversity translates to cell-cell interactions, and consequentially vascular function, remains unknown. We leveraged scRNA sequencing and spatial transcriptome (ST) profiling to analyze human mesenteric arteries from non-diabetic (ND) and type 2 diabetic (T2D) donors. We generated a transcriptome and interactome map encompassing the major arterial cells and highlighted Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) as a top T2D-induced gene in mononuclear phagocytes (MPs), with concomitant increases of TREM2 ligands in ECs. We verified DM-associated TREM2 induction in cell and mouse models, and found that TREM2 inhibition decreases pro-inflammatory responses in MPs and ECs, as well as increases EC migration in vitro. Furthermore, TREM2 inhibition using a neutralizing antibody enhanced ischemic recovery and flow reperfusion in DM mice subjected to hindlimb ischemia, suggesting that TREM2 promotes ischemic injury in DM. Finally, in human PAD, co-existing DM was associated with greater expression of TREM2 and its interaction with ECs, with a further increase in ischemic tissue compared to patient-matched non-ischemic tissue. Collectively, our study presents the first atlas of human diabetic vessels with single cell and spatial resolution, and identifies TREM2-EC interaction as a key driver of diabetic vasculopathies, the targeting of which may offer an opportunity to ameliorate vascular dysfunction associated with DM-PAD.

cell biology↗