Biology subjects

Colon-Perez, L.

Publications and source records attributed to Colon-Perez, L..

6 recordsLinked to original sources

bioRxiv2025

Rats Exposed to a Low Resource Environment in Early Life Display Sex Differences in Blood Pressure, Autonomic Activity, and Brain and Kidney Pro-inflammatory Markers During Adulthood

Introduction: Poverty, a low resource state, is a common adverse childhood experience (ACE) and early life stress (ELS). People who experienced childhood poverty are at greater risk for developing hypertension during adulthood, with sex differences. To determine the possible mechanisms of these sex differences, we investigated the alterations in blood pressure (BP), autonomic activity, and inflammation in the brain and kidneys of rats exposed to an impoverished environment during the early postnatal period, by using the limited bedding and nesting (LBN) model. Methods: The LBN model mimics childhood poverty by creating a low resource environment on postnatal days 2-9. After weaning, offspring were separated by sex and LBN exposure and were evaluated at 16-18 weeks of age (Adulthood). Results: LBN males displayed an increase in BP compared to the control (CON), whereas LBN females showed no changes. Sympathetic nerve activity (SNA) was increased in LBN males and females compared to the CON, while only parasympathetic nerve activity (PNA) was increased in LBN vs. CON females. Pro-inflammatory cytokines, IL-17 and TNF-, were decreased in the brains of LBN vs. CON males, with no alterations in females. Conclusion: Adult LBN males have elevated BP, due to increased SNA, while LBN females may be protected from increased BP due to a simultaneous increase in SNA and PNA. The reduction in IL-17 and TNF- in LBN males may serve as a compensatory mechanism to lower BP. This study provides insights into sex differences in BP for adults who experienced childhood poverty.

physiology↗

bioRxiv2025

Developing inhibitors of the guanosine triphosphate hydrolysis accelerating activity of Regulator of G protein Signaling-14

Regulator of G protein Signaling-14 (RGS14), an intracellular inactivator of G protein-coupled receptor (GPCR) signaling, is considered an undruggable protein given its shallow and relatively featureless protein-protein interaction interface combined with a distal allosteric site prone to nonspecific inhibition by thiol-reactive compounds. Here, we identify and validate a tractable chemotype that selectively and non-covalently inhibits RGS14 GTPase-accelerating protein (GAP) activity. Combining structure-guided virtual screening, ligand docking across multiple receptor conformers, and enrichment validation, we progressed from a first-generation active, Z90276197, to over 40 second-generation analogs with improved potency. These inhibitors are predicted to engage the solvent-exposed "canyon" in the RGS14 RGS-box that interacts with the G switch I region. Binding pose predictions underscored the importance of non-polar interactions and shape complementarity over polar interactions in engaging this G-binding canyon and revealed an "ambidextrous" pattern of R1- and R2-group orientations. GAP inhibition was confirmed in fluorescence-based and gold-standard radioactive GTP hydrolysis assays. Two second-generation analogs, Z55660043 and Z55627844, inhibited RGS14 GAP activity in both assays and without measurable cytotoxicity. Deep learning-based scoring of predicted docking poses further supported observed affinity gains from R3-group additions. One analog demonstrated favorable in vivo pharmacokinetics and CNS penetration. Collectively, our findings establish tractable, non-covalent, small molecule inhibition of a G protein regulatory interface and illustrate how machine learning-enhanced docking can guide ligand optimization for shallow protein surfaces. This work opens the door to future development of RGS14 inhibitors as potential therapeutics for central nervous system and metabolic disorders.

pharmacology and toxicology↗

bioRxiv2024

Novel MRI-based Biotypes of Human Neurodevelopment associated with Impulsivity performance

IntroductionAdequate neurodevelopment is critical to the proper advancement of cognitive and emotional processing; however, variation in neurodevelopment has emerged as a potential risk factor for subsequent drug use. The Adolescent Brain Cognitive Development (ABCD) Study is an ongoing and longitudinal study to determine the developmental trajectories of the brain and how experiences impact brain development, which makes it an ideal framework study to determine proper neurodevelopmental trajectories associated with healthy executive function behavioral development and their neurobiology. MethodBased on the availability of ABCD (Release 5.1) tabulated data, we selected 1368 subjects with neuroimaging records on multiple time points. To focus on the frontal cortex, we preprocess 20 ROIs (including ten regions with right and left cerebral hemispheres) cortical thickness measurements for SuStaIn. Once SuStaIn determined the potential control and phenotype (subtypes) group, we conducted t-tests between the control and phenotype groups on their delay discounting measurements. To overserve possible trajectories, we also investigated the correlation of the thickness measurements with delay discounting under the suggested phenotype by SuStaIn. ResultsSuStaIn identified four subtypes and one potential control group, validated by cross-validation test as the optimal solution for balancing model accuracy and complexity. Among the t-tests on delay discounting results between the control group and each subtype, subtype1 tends to show low significance on the 3-month indifference point (p=0.067), subtype 2 identifies a significant reduction in impulsivity on the 1-month indifference point (p=0.017), subtype 4 stands significant reduction at on 3-month indifference point (p=0.0092) and significance on 1-year indifference point (p=0.00418). For the correlations between each selected ROI, we identified a negative correlation (R=-0.18, p=0.0095) between the thickness of the left hemisphere caudal-anterior-cingulate and delay discounting indifference point at 3 months. ConclusionWe successfully identified four subtypes of the ABCD, which may be putative abnormal trajectories of executive function accelerated development. Three of the four subtypes reflect impulsive behavioral phenotype, and one displays an association with cortical thinning. Overall, we present evidence that there are putative neurobiological signs of potential executive function disruption as early as nine years of age.

neuroscience↗

bioRxiv2024

Gut Microbiota and DTI Microstructural Brain Alterations in Rodents Due to Morphine Self-Administration

The opioid epidemic is an evolving health crisis in need of interventions that target all domains of maladaptive changes due to chronic use and abuse. Opioids are known for their effects on the opioid and dopaminergic systems, in addition to neurocircuitry changes that mediate changes in behavior; however, new research lines are looking at complementary changes in the brain and gut. The gut-brain axis (GBA) is a bidirectional signaling process that permits feedback between the brain and gut and is altered in subjects with opioid use disorders. In this work, we determine longitudinal, non-invasive, and in-vivo complementary changes in the brain and gut in rodents trained to self-administer morphine for two weeks using MRI and 16S rDNA analysis of fecal matter. We assess the changes occurring during both an acute phase (early in the self-administration process, after two days of self-administration) and a chronic phase (late in the self-administration process, after two weeks of self-administration), with all measurements benchmarked against baseline (naive, non-drug state). Rats were surgically implanted with an intravenous jugular catheter for self-administration of morphine. Rats were allowed to choose between an active lever, which delivers a single infusion of morphine (0.4 mg/kg/infusion), or an inactive lever, which had no consequence upon pressing. Animals were scanned in a 7T MRI scanner three times (baseline, acute, and chronic), and before scanning, fecal matter was collected from each rat. After the last scan session, a subset of animals was euthanized, and brains were preserved for immunohistochemistry analysis. We found early changes in gut microbiota diversity and specific abundance as early as the acute phase that persisted into the chronic phase. In MRI, we identified alterations in diffusivity indices both within subjects and between groups, showing a main effect in the striatum, thalamus, and somatosensory cortex. Finally, immunohistochemistry analyses revealed increased neuroinflammatory markers in the thalamus of rats exposed to morphine. Overall, we demonstrate that morphine self-administration shapes the brain and gut microbiota. In conclusion, gut changes precede the anatomical effects observed in MRI features, with neuroinflammation emerging as a crucial link mediating communication between the gut and the brain. This highlights neuroinflammation as a potential target in addressing the impacts of opioid use.

neuroscience↗

bioRxiv2024

Macro- and Micro-Structural Alterations in the Midbrain in Early Psychosis

IntroductionEarly psychosis (EP) is a critical period in the course of psychotic disorders during which the brain is thought to undergo rapid and significant functional and structural changes 1. Growing evidence suggests that the advent of psychotic disorders is early alterations in the brains functional connectivity and structure, leading to aberrant neural network organization. The Human Connectome Project (HCP) is a global effort to map the human brains connectivity in healthy and disease populations; within HCP, there is a specific dataset that focuses on the EP subjects (i.e., those within five years of the initial psychotic episode) (HCP-EP), which is the focus of our study. Given the critically important role of the midbrain function and structure in psychotic disorders (cite), and EP in particular (cite), we specifically focused on the midbrain macro- and micro-structural alterations and their association with clinical outcomes in HCP-EP. MethodsWe examined macro- and micro-structural brain alterations in the HCP-EP sample (n=179: EP, n=123, Controls, n=56) as well as their associations with behavioral measures (i.e., symptoms severity) using a stepwise approach, incorporating a multimodal MRI analysis procedure. First, Deformation Based Morphometry (DBM) was carried out on the whole brain 3 Tesla T1w images to examine gross brain anatomy (i.e., seed-based and voxel-based volumes). Second, we extracted Fractional Anisotropy (FA), Axial Diffusivity (AD), and Mean Diffusivity (MD) indices from the Diffusion Tensor Imaging (DTI) data; a midbrain mask was created based on FreeSurfer v.6.0 atlas. Third, we employed Tract-Based Spatial Statistics (TBSS) to determine microstructural alterations in white matter tracts within the midbrain and broader regions. Finally, we conducted correlation analyses to examine associations between the DBM-, DTI- and TBSS-based outcomes and the Positive and Negative Syndrome Scale (PANSS) scores. ResultsDBM analysis showed alterations in the hippocampus, midbrain, and caudate/putamen. A DTI voxel-based analysis shows midbrain reductions in FA and AD and increases in MD; meanwhile, the hippocampus shows an increase in FA and a decrease in AD and MD. Several key brain regions also show alterations in DTI indices (e.g., insula, caudate, prefrontal cortex). A seed-based analysis centered around a midbrain region of interest obtained from freesurfer segmentation confirms the voxel-based analysis of DTI indices. TBSS successfully captured structural differences within the midbrain and complementary alterations in other main white matter tracts, such as the corticospinal tract and cingulum, suggesting early altered brain connectivity in EP. Correlations between these quantities in the EP group and behavioral scores (i.e., PANSS and CAINS tests) were explored. It was found that midbrain volume noticeably correlates with the Cognitive score of PA and all DTI metrics. FA correlates with the several dimensions of the PANSS, while AD and MD do not show many associations with PANSS or CAINS. ConclusionsOur findings contribute to understanding the midbrain-focused circuitry involvement in EP and complimentary alteration in EP. Our work provides a path for future investigations to inform specific brain-based biomarkers of EP and their relationships to clinical manifestations of the psychosis course.

neuroscience↗

bioRxiv2022

StandardRat: A multi-center consensus protocol to enhance functional connectivity specificity in the rat brain

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows comparison with invasive or terminal procedures. To date, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. We introduce StandardRat, a consensus rat functional MRI acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired in rats from 46 centers. We developed a reproducible pipeline for the analysis of rat data acquired with diverse protocols and determined experimental and processing parameters associated with a more robust functional connectivity detection. We show that the standardized protocol enhances biologically plausible functional connectivity patterns, relative to pre-existing acquisitions. The protocol and processing pipeline described here are openly shared with the neuroimaging community to promote interoperability and cooperation towards tackling the most important challenges in neuroscience.

neuroscience↗