Biology subjects

Tovar-Moll, F.

Publications and source records attributed to Tovar-Moll, F..

6 recordsLinked to original sources

bioRxiv2026

Apparent Anatomical Variability Through Rigid Augmentation Enables Reliable Corpus Callosum Segmentation

The corpus callosum is a major white matter bundle responsible for connecting both hemispheres. In mammals, due to a variety of causes, the development of the corpus callosum can be impaired - this brain malformation is known as corpus callosum dysgenesis (CCD). The clinical presentation of CCD varies, with patients exhibiting three morphological phenotypes: agenesis, partial dysgenesis, and hypoplasia. Although the first two presentations are easily detectable on MRI scans, the latter is more challenging, as the structure is fully formed but has a reduced area. In this study, we develop (1) a pipeline to generate synthetic MRI scans with apparent anatomical variation and (2) train a U-Net-based tool to automatically segment the corpus callosum of marmosets in both healthy and disease contexts. Methodologically, a custom script was devised to apply rotation and translation to T1-weighted MRI scans at the volume level. Because the slicing grid remains unchanged, these rigid transformations translate into apparent anatomical variations at the slice level. We compared corpus callosum measurements obtained from automatically segmented masks with those from manually delineated masks. The average Dice score was above 0.90, and the Hausdorff distance was below 0.4 mm. We also stratified our cohort according to phenotype (healthy controls and hypoplastic animals). The magnitude of the effect and the significance level observed between the voxel counts of healthy and hypoplastic animals using manually delineated masks were comparable to those obtained via automatic segmentations. These results show that our pipeline can generate a sufficiently varied training pool to build an accurate U-Net segmentation model with high diagnostic capability.

neuroscience↗

bioRxiv2021

Age-linked suppression of lipoxin A4 mediates cognitive deficits in mice and humans

Age increases the risk for cognitive impairment and is the single major risk factor for Alzheimers disease (AD), the most prevalent form of dementia in the elderly. The pathophysiological processes triggered by aging that render the brain vulnerable to dementia involve, at least in part, changes in inflammatory mediators. Here we show that lipoxin A4 (LXA4), a lipid mediator of inflammation resolution known to stimulate endocannabinoid signaling in the brain, is reduced in the aging central nervous system. We demonstrate that genetic suppression of 5-lipoxygenase (5-LOX), the enzyme mediating LXA4 synthesis, promotes learning impairment in mice. Conversely, administration of exogenous LXA4 attenuated cytokine production and memory loss induced by inflammation in mice. We further show that cerebrospinal fluid LXA4 is reduced in patients with dementia and positively associates with memory performance, brain-derived neurotrophic factor (BDNF), and AD-linked amyloid-. Our findings suggest that reduced LXA4 levels may lead to vulnerability to age-related cognitive disorders and that promoting LXA4 signaling may comprise an effective strategy to prevent early cognitive decline in AD.

neuroscience↗

bioRxiv2021

Quantitative profiling of axonal guidance proteins during the differentiation of human neurospheres

Axon guidance is required for the establishment of brain circuits. Whether much of the molecular basis of axon guidance is known from animal models, the molecular machinery coordinating axon growth and pathfinding in humans remains to be elucidated. The use of induced pluripotent stem cells (iPSC) from human donors has revolutionized in vitro studies of the human brain. iPSC can be differentiated into neuronal stem cells which can be used to generate neural tissue-like cultures, known as neurospheres, that reproduce, in many aspects, the cell types and molecules present in the brain. Here, we analyzed quantitative changes in the proteome of neurospheres during differentiation. Relative quantification was performed at early time points during differentiation using iTRAQ-based labeling and LC-MS/MS analysis. We identified 6,438 proteins, from which 433 were downregulated and 479 were upregulated during differentiation. We show that human neurospheres have a molecular profile that correlates to the fetal brain. During differentiation, upregulated pathways are related to neuronal development and differentiation, cell adhesion, and axonal guidance whereas cell proliferation pathways were downregulated. We developed a functional assay to check for neurite outgrowth in neurospheres and confirmed that neurite outgrowth potential is increased after 10 days of differentiation and is enhanced by increasing cyclic AMP levels. The proteins identified here represent a resource to monitor neurosphere differentiation and coupled to the neurite outgrowth assay can be used to functionally explore neurological disorders using human neurospheres as a model.

neuroscience↗

bioRxiv2019

The cyanobacterial saxitoxin exacerbates neural cell death and brain malformations induced by Zika virus

The northeast (NE) region of Brazil commonly goes through drought periods, which favor cyanobacterial blooms, capable of producing neurotoxins with implications for human and animal health. The most severe dry spell in the history of Brazil occurred between 2012 and 2016. Coincidently, the highest incidence of microcephaly associated with the Zika virus (ZIKV) outbreak was described in the NE region of Brazil during the same years. In this work, we tested the hypothesis that saxitoxin (STX), a neurotoxin produced in South America by the freshwater cyanobacteria Raphidiopsis raciborskii, could have contributed to the most severe Congenital Zika Syndrome (CZS) profile described worldwide. Quality surveillance showed higher cyanobacteria amounts and STX occurrence in human drinking water supplies of NE compared to other regions of Brazil. Experimentally, we described that STX doubled the amount of ZIKV-induced neural cell death in progenitor areas of human brain organoids, while the chronic ingestion of water contaminated with STX before and during gestation caused brain abnormalities in offspring of ZIKV-infected immunocompetent C57BL/6J mice. Our data indicate that saxitoxin-producing cyanobacteria is overspread in water reservoirs of the NE and might have acted as a co-insult to ZIKV infection in Brazil. These results raise a public health concern regarding the consequences of arbovirus outbreaks happening in areas with droughts and/or frequent freshwater cyanobacterial blooms.\n\nAuthor summaryThe uncontrolled spreading of cyanobacteria in drinking water reservoirs has been the cause of serious public health problems worldwide. Toxin-producing cyanobacterial blooms commonly occur during drought periods in the northeast (NE) region of Brazil. During Zika Virus (ZIKV) outbreak in 2015-16, Brazilian NE showed disproportionately higher microcephaly incidence. Here, we test the hypothesis that the cyanotoxin saxitoxin (STX) may act as a co-insult for ZIKV. Water quality surveillance data showed increased cyanobacteria population and higher STX amount in NE region during 2014-2018. In vitro, we observed that neural progenitor cell death was doubled after STX exposure to ZIKV-infected brain organoids. In vivo, chronic ingestion of STX during gestational period potentiated ZIKV-derived brain abnormalities in newborn mice. Our study provides new insights that may explain the discrepancies among Brazilian regions regarding CZS severity. Moreover, the data highlight the importance of cyanobacteria and cyanotoxin freshwater monitoring for future arbovirus outbreaks.

neuroscience↗

bioRxiv2018

Changes in thalamocortical connectivity as a potential mechanism of cross-modal plasticity in congenitally blind individuals

Cross-modal plasticity in blind individuals has been reported over the past decades showing that non-visual information is carried and processed by visual brain structures. However, the structural underpinnings of cross-modal plasticity in congenitally blind individuals remain unclear despite multiple efforts. We mapped thalamocortical connectivity and assessed cortical thickness and integrity of white matter of ten congenitally blind individuals and ten sighted controls. We hypothesized an aberrant thalamocortical pattern of connectivity taking place in the absence of visual stimuli from birth as a potential mechanism of cross-modal plasticity. In addition to the increased cortical thickness of the primary visual cortex and reduced integrity of visual white matter bundles, we observed structural connectivity changes between the thalamus and occipital and temporal cortices. Specifically, the thalamic territory dedicated to connections with the occipital cortex was smaller and displayed weaker connectivity in congenitally blind individuals. In contrast, those connecting with the temporal cortex showed greater volume and increased connectivity compared to sighted controls. The abnormal pattern of thalamocortical connectivity included the lateral and medial geniculate nuclei and the pulvinar nucleus. For the first time in humans, a remapping of structural thalamocortical connections involving both unimodal and multimodal thalamic nuclei has been demonstrated, shedding light on the possible mechanisms of cross-modal plasticity in humans. The present findings may help understand the functional adaptations commonly observed in congenitally blind individuals.

neuroscience↗

bioRxiv2018

Computational fluid dynamic analysis reveals the underlying physical forces playing a role in 3D multiplex brain organoid cultures

Organoid cultivation in suspension culture requires agitation at low shear stress to allow for nutrient diffusion, which preserves tissue structure. Multiplex systems for organoid cultivation have been proposed, but whether they meet similar shear stress parameters as the regularly used spinner flask and its correlation with the successful generation of brain organoids, has not been determined. Herein, we used computational fluid dynamics (CFD) analysis to compare two multiplex culture conditions: steering plates on an orbital shaker and the use of a previously described bioreactor. The bioreactor had low speed and high shear stress regions that may affect cell aggregate growth, depending on volume, whereas the CFD parameters of the steering plates were closest to the parameters of the spinning flask. Our protocol improves the initial steps of the standard brain organoid formation, and organoids produced therefrom displayed regionalized brain structures, including retinal pigmented cells. Overall, we conclude that suspension culture on orbital steering plates is a cost-effective practical alternative to previously described platforms for the cultivation of brain organoids for research and multiplex testing.\n\nHighlightsO_LIImprovements to organoid preparation protocol\nC_LIO_LIMultiplex suspension culture protocol successfully generate brain organoids\nC_LIO_LIComputational fluid dynamics (CFD) reveals emerging properties of suspension cultures\nC_LIO_LICFD of steering plates is equivalent to that of spinner flask cultures\nC_LI

bioengineering↗