Biology subjects

Madrid, A.

Publications and source records attributed to Madrid, A..

3 recordsLinked to original sources

bioRxiv2021

Gene by environment interaction mouse model reveals a functional role for 5-hydroxymethylcytosine in neurodevelopmental disorders

Mouse knockouts of Cntnap2 exhibit altered neurodevelopmental behavior and a genome-wide disruption of 5-hydroxymethylcytosine (5hmC). Here we examined whether adult Cntnap2 heterozygous mice (Cntnap2+/-, lacking behavioral or neuropathological abnormalities) subjected to a prenatal stress would have disruptions in brain 5hmC levels and exhibit altered behaviors similar to the knockout mice. Adult prenatally stressed Cntnap2+/- female mice showed repetitive behaviors and altered sociability, similar to the homozygote phenotype. Genomic profiling revealed disruptions in hippocampal and striatal 5hmC levels that were correlated to altered transcript levels of genes linked to these phenotypes (e.g., Reln, Dst, Trio and Epha5). Chromatin-immunoprecipitation coupled with high-throughput sequencing and hippocampal nuclear lysate pull-down data indicated that 5hmC abundance alters the binding of the transcription factor CLOCK near the promoters of differentially expressed genes (e.g., Palld, Gigyf1, and Fry), providing a mechanistic role for 5hmC (disruption of transcription factor binding) in gene regulation of developmentally important genes.

genetics↗

bioRxiv2020

Neuroinflammation alters the phenotype of lymphangiogenic vessels near the cribriform plate.

Meningeal lymphatic vessels residing in the dural layer surrounding the dorsal regions of the brain, basal regions, and near the cribriform plate have all been implicated in the management of neuroinflammation and edema. Interestingly, only the lymphatic vessels near the cribriform plate undergo functional lymphangiogenesis in a mouse model of Multiple Sclerosis, suggesting these particular lymphatics uniquely undergo dynamic changes in response to neuroinflammation and may have distinct access to pro-lymphangiogenic factors in the CNS. However, it is unknown if these newly formed lymphangiogenic vessels are functionally similar to steady-state or if they have any other functional changes during neuroinflammation. In this study, we generated a novel protocol to isolate lymphatic endothelial cells from the cribriform plate for single cell analysis. We demonstrate that neuroinflammation-induced lymphangiogenic vessels undergo unique changes, including the capture of CNS-derived antigens, upregulation of adhesion and immune-modulatory molecules to interact with dendritic cells, and display IFN-{gamma} dependent changes in response to the microenvironment. Single-cell trajectory analysis showed that cribriform plate lymphangiogenic vessels are post-proliferative and not generated from trans-differentiation of myeloid cells. Additionally, we show that these lymphangiogenic vessels have access to a CSF reservoir, express the water pore Aquaporin-1, and may have direct access to the CSF due to gaps in the arachnoid epithelial layer separating the dura from the subarachnoid space. These data characterize cribriform plate lymphatics and demonstrate that these vessels are dynamic structures that engage in leukocyte interactions, antigen sampling, and undergo expansion to drain excess fluid during neuroinflammation. Neuroinflammation not only induces efficient drainage of CSF but also alters the functions of lymphatic vessels near the cribriform plate.

immunology↗

bioRxiv2018

Highly Predictive Transdiagnostic Features Shared across Schizophrenia, Bipolar Disorder, and ADHD Identified Using a Machine Learning Based Approach

The Diagnostic and Statistical Manual of Mental Disorders (DSM) is the standard for diagnosing psychiatric disorders in the United States. However, evidence has suggested that symptoms in psychiatric disorders are not restricted to the boundaries between DSM categories, implying an underlying latent transdiagnostic structure of psychopathology. Here, we applied an importance-guided machine learning technique for model selection to item-level data from self-reported instruments contained within the Consortium for Neuropsychiatric Phenomics dataset. From 578 questionnaire items, we identified a set of features which consisted of 85 items that were shared across diagnoses of schizophrenia (SCZ), bipolar disorder (BD), and attention deficit/hyperactivity disorder (ADHD). A classifier trained on the transdiagnostic features reliably distinguished the patient group as a whole from healthy controls (classification AUC = 0.95) and only 10 items were needed to attain the performance level of AUC being 0.90. A sum score created from the items produced high separability between patients and healthy controls (Cohens d = 2.85), and it outperformed predefined sum scores and sub-scores within the instruments (Cohens d ranging between 0.13 and 1.21). The transdiagnostic features comprised both symptom domains (e.g. dysregulated mood, attention deficit, and anhedonia) and personality traits (e.g. neuroticism, impulsivity, and extraversion). Moreover, by comparing the features that were common across the three patient groups with those that were most predictive of a single patient category, we can describe the unique features for each patient group superimposed on the transdiagnostic feature structure. Overall, our results reveal a latent transdiagnostic symptom/behavioral phenotypic structure shared across SCZ, BD, and ADHD and present a new perspective to understand insights offered by self-report psychiatric instruments.

pathology↗