Biology subjects

Escoubas, C. C.

Publications and source records attributed to Escoubas, C. C..

6 recordsLinked to original sources

bioRxiv2025

NOVA: a novel R-package enabling multi-parameter analysis and visualization of neural activity in MEA recordings

Multielectrode array (MEA) technology enables simultaneous recording of electrical signals from neuronal networks, producing complex datasets. Current analytical approaches typically examine a limited number of metrics such as mean firing rate and synchronicity, leaving much of the data underutilized. To address this gap, we created NOVA (Neural Output Visualization and Analysis), an accessible R-based computational tool for comprehensive MEA data interpretation and visualization. NOVA integrates dimensionality reduction through principal component analysis, hierarchical clustering with heatmap generation, and temporal trajectory mapping of network activity patterns. Our code offers both a userfriendly pipeline requiring minimal coding background as well as customizable advanced plotting modules for experienced users. Validation experiments using primary cortical neurons during development and pharmacological manipulation demonstrated NOVAs capacity to detect subtle activity shifts overlooked by conventional methods. Notably, our unbiased approach identified network burst duration as a stronger contributor to activity variance than commonly reported firing rate metrics, exemplifying NOVAs utility for discovering meaningful patterns and generating data-driven hypotheses.

neuroscience↗

bioRxiv2024

Microglial cathepsin B promotes neuronal efferocytosis during brain development

Half of all newborn neurons in the developing brain are removed via efferocytosis - the phagocytic clearance of apoptotic cells. Microglia are brain-resident professional phagocytes that play important roles in neural circuit development including as primary effectors of efferocytosis. While the mechanisms through which microglia recognize potential phagocytic cargo are widely studied, the lysosomal mechanisms that are necessary for efficient digestion are less well defined. Here we show that the lysosomal protease cathepsin B promotes microglial efferocytosis of neurons and restricts the accumulation of apoptotic cells during brain development. We show that cathepsin B is microglia-specific and enriched in brain regions where neuronal turnover is high in both zebrafish and mouse. Myeloid-specific cathepsin B knockdown in zebrafish led to dysmorphic microglia containing undigested dead cells, as well as an accumulation of dead cells in surrounding tissue. These effects where phenocopied in mice globally deficient for Ctsb using markers for apoptosis. We also observed behavioral impairments in both models. Live imaging studies in zebrafish revealed deficits in phagolysosomal fusion and acidification, and live imaging of cultured mouse microglia reveal delayed phagocytosis consistent with impairments in digestion and resolution of phagocytosis rather than initial uptake. These data reveal a novel role for microglial cathepsin B in mediating neuronal efferocytosis during typical brain development.

neuroscience↗

bioRxiv2023

Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior

The innate immune system plays essential roles in brain synaptic development, and immune dysregulation is implicated in neurodevelopmental diseases. Here we show that a subset of innate lymphocytes (group 2 innate lymphoid cells, ILC2s) is required for cortical inhibitory synapse maturation and adult social behavior. ILC2s expanded in the developing meninges and produced a surge of their canonical cytokine Interleukin-13 (IL-13) between postnatal days 5-15. Loss of ILC2s decreased cortical inhibitory synapse numbers in the postnatal period where as ILC2 transplant was sufficient to increase inhibitory synapse numbers. Deletion of the IL-4/IL-13 receptor (Il4ra) from inhibitory neurons phenocopied the reduction inhibitory synapses. Both ILC2 deficient and neuronal Il4ra deficient animals had similar and selective impairments in adult social behavior. These data define a type 2 immune circuit in early life that shapes adult brain function. One sentence summaryType 2 innate lymphoid cells and Interleukin-13 promote inhibitory synapse development.

neuroscience↗

bioRxiv2021

A type I interferon response defines a conserved microglial state required for effective phagocytosis

Microglia are brain resident phagocytes that can engulf synaptic components and extracellular matrix as well as whole neurons. However, whether there are unique molecular mechanisms that regulate these distinct phagocytic states is unknown. Here we define a molecularly distinct microglial subset whose function is to engulf neurons in the developing brain. We transcriptomically identified a cluster of Type I interferon (IFN-I) responsive microglia that expanded 20-fold in the postnatal day 5 somatosensory cortex after partial whisker deprivation, a stressor that accelerates neural circuit remodeling. In situ, IFN-I responsive microglia were highly phagocytic and actively engulfed whole neurons. Conditional deletion of IFN-I signaling (Ifnar1fl/fl) in microglia but not neurons resulted in dysmorphic microglia with stalled phagocytosis and an accumulation of neurons with double strand DNA breaks, a marker of cell stress. Conversely, exogenous IFN-I was sufficient to drive neuronal engulfment by microglia and restrict the accumulation of damaged neurons. IFN-I deficient mice had excess excitatory neurons in the developing somatosensory cortex as well as tactile hypersensitivity to whisker stimulation. These data define a molecular mechanism through which microglia engulf neurons during a critical window of brain development. More broadly, they reveal key homeostatic roles of a canonical antiviral signaling pathway in brain development.

neuroscience↗

bioRxiv2020

AMPK Modulates Associative Learning via Neuronal Mitochondrial Fusion in C. elegans

Loss of metabolic homeostasis is one of the hallmarks of the aging process that might contribute to pathogenesis by creating a permissive landscape over which neurodegenerative diseases can take hold. AMPK, a conserved energy sensor, extends lifespan and is protective in some neurodegenerative models. AMPK regulates mitochondrial homeostasis and morphology, however, whether mitochondrial regulation causally links AMPK to protection against loss of neuronal function with aging and diseases remains unclear. Here we use an associative learning protocol in C. elegans as a readout of neuronal function and show that AMPK activation enhances associative learning and prevents age-related loss of learning capacity. AMPK promotes neuronal mitochondrial fusion and mitochondrial fragmentation via fzo-1 deletion blocks AMPKs effects on associative learning. Restoring mitochondrial fusion capacity specifically in the neurons rescued learning capacity downstream of AMPK. Finally, AMPK activation rescues neuronal A{beta}1-42 induced loss of associative learning. Overall, our results suggest that targeting neuronal metabolic flexibility may be a viable therapeutic option to restore neuronal function in the context of aging and neurodegenerative diseases.

neuroscience↗

bioRxiv2019

Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans

Target of rapamycin complex 1 (TORC1) and AMP-activated protein kinase (AMPK) antagonistically modulate metabolism and aging. However, how they coordinate to determine longevity and if they act via separable mechanisms is unclear. Here, we show that neuronal AMPK is essential for lifespan extension from TORC1 inhibition, and that TORC1 suppression increases lifespan cell non autonomously via distinct mechanisms from global AMPK activation. Lifespan extension by null mutations in genes encoding raga-1 (RagA) or rsks-1 (S6K) is fully suppressed by neuronal-specific rescues. Loss of RAGA-1 increases lifespan via maintaining mitochondrial fusion. Neuronal RAGA-1 abrogation of raga-1 mutant longevity requires UNC-64/syntaxin, and promotes mitochondrial fission cell nonautonomously. Finally, deleting the mitochondrial fission factor DRP-1 renders the animal refractory to the pro-aging effects of neuronal RAGA-1. Our results highlight a new role for neuronal TORC1 in cell nonautonomous regulation of longevity, and suggest TORC1 in the central nervous system might be targeted to promote healthy aging.

genetics↗