Biology subjects

Noubary, F.

Publications and source records attributed to Noubary, F..

4 recordsLinked to original sources

bioRxiv2025

Evidence for the Transient Presence of Atypical Astrocytes in Mice Following a Single, Closed-Head Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) affects roughly 42 million people each year, causes a variety of physical, behavioral, and cognitive symptoms, and increases the risk for developing neurological disorders, including post-traumatic headache (PTH) and Alzheimers disease (AD). Multiple molecular and cellular changes occur following mTBI; here we focus on astrocytes - cells that respond to brain injury and are critical to maintaining neuronal and circuit homeostasis. While some astrocytes become reactive after mTBI, others adopt an atypical state characterized by the loss of multiple functional astrocyte proteins, including glutamate transporters (GLT-1, GLAST) and ion channels (Kir4.1), without upregulation of prototypical reactive astrocyte markers (glial fibrillary acidic protein [GFAP]). Previous studies have shown that repeated mTBI causes atypical astrocytes (AtAs) that can persist for months, but we know much less about whether a single mTBI causes similar astrocyte phenotypes. To address this, we employed a closed-head mild traumatic brain injury (chmTBI) model in male and female mice and quantified the abundance of AtAs both acutely (3-days) and chronically (1-month) after a single injury. We found that 3-days after chmTBI, AtAs were present in areas subject to blunt force trauma (BFT), consistent with previous reports, as well as in other brain regions presumably affected by diffuse injury. One month after chmTBI, however, the proportion of AtAs was similar between chmTBI and sham injured mice, thereby suggesting AtAs do not persist long term in this model. Consistent with previous studies, this chmTBI model did not induce significant GFAP-positive reactive astrocytes as assayed using immunohistochemistry, at either timepoint. Overall, we show an increase in AtAs 3-days after a single chmTBI that returns to sham levels when examined 1-month after injury. This suggests that after a single mTBI, AtAs are present but do not persist long term, unlike in repeated mTBI where AtAs persist for months after injury.

neuroscience↗

bioRxiv2023

Traumatic brain injury disrupts state-dependent functional cortical connectivity in a mouse model

Traumatic brain injury (TBI) is the leading cause of death in young people and can cause cognitive and motor dysfunction and disruptions in functional connectivity between brain regions. In human TBI patients and rodent models of TBI, functional connectivity is decreased after injury. Recovery of connectivity after TBI is associated with improved cognition and memory, suggesting an important link between connectivity and functional outcome. We examined widespread alterations in functional connectivity following TBI using simultaneous widefield mesoscale GCaMP7c calcium imaging and electrocorticography (ECoG) in mice injured using the controlled cortical impact (CCI) model of TBI. Combining CCI with widefield cortical imaging provides us with unprecedented access to characterize network connectivity changes throughout the entire injured cortex over time. Our data demonstrate that CCI profoundly disrupts functional connectivity immediately after injury, followed by partial recovery over 3 weeks. Examining discrete periods of locomotion and stillness reveals that CCI alters functional connectivity and reduces theta power only during periods of behavioral stillness. Together, these findings demonstrate that TBI causes dynamic, behavioral state-dependent changes in functional connectivity and ECoG activity across the cortex.

neuroscience↗

bioRxiv2022

Cortical Parvalbumin-positive Interneuron Development and Function are Altered in the APC Conditional Knockout Mouse Model of Infantile Spasm Syndrome

Infantile Spasms syndrome (ISS) is a childhood epilepsy syndrome characterized by infantile or late onset spasms, abnormal neonatal EEG, and epilepsy. Few treatments exist for IS, clinical outcomes are poor, and the molecular and circuit-level etiologies of IS are not well understood. Multiple human ISS risk genes are linked to Wnt/{beta}-catenin signaling, a pathway which controls developmental transcriptional programs and promotes glutamatergic excitation via {beta}-catenins role as a synaptic scaffold. We previously showed that deleting adenomatous polyposis coli (APC), a component of the {beta}-catenin destruction complex, in excitatory neurons (APC cKO mice, APCfl/fl x CaMKIICre) in mice increased {beta}-catenin levels in developing glutamatergic neurons and led to infantile behavioral spasms, abnormal neonatal EEG, and adult epilepsy. Here, we tested the hypothesis that the development of inhibitory GABAergic interneurons (INs) is disrupted in APC cKOs. IN dysfunction is implicated in human ISS, is a feature of other rodent models of ISS and may contribute to the manifestation of spasms and seizures. We found that parvalbumin positive INs (PV+INs), an important source of cortical inhibition, were decreased in number, underwent disproportionate developmental apoptosis, and had altered dendrite morphology at P9, the peak time of behavioral spasms. PV+INs received excessive excitatory input and their intrinsic ability to fire action potentials was reduced at all timepoints examined (P9, P14, P60). Subsequently, synaptic inhibition of pyramidal neurons was uniquely altered in the somatosensory cortex of APC cKO mice at all ages, with both decreased inhibition at P14 and enhanced inhibition at P9 and P60. These results indicate that inhibitory circuit dysfunction occurs in APC cKOs and, along with known changes in excitation, may contribute to ISS-related phenotypes. Significance StatementInfantile spasms syndrome (ISS) is a devastating epilepsy with limited treatment options and poor clinical outcomes. The molecular, cellular, and circuit disruptions that cause infantile spasms and seizures are largely unknown, but inhibitory GABAergic interneuron dysfunction has been implicated in rodent models of ISS and may contribute to human ISS. Here, we utilize a rodent model of ISS, the APC cKO mouse, in which {beta}-catenin signaling is increased in excitatory neurons. This results in altered parvalbumin-positive GABAergic interneuron development and inhibitory synaptic dysfunction throughout life, showing that pathology arising in excitatory neurons can initiate long-term interneuron dysfunction. Our findings further implicate GABAergic dysfunction in ISS, even when pathology is initiated in other neuronal types.

neuroscience↗

bioRxiv2018

Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury

Traumatic brain injury (TBI) causes cortical dysfunction and can lead to post-traumatic epilepsy. Multiple studies demonstrate that GABAergic inhibitory network function is compromised following TBI, which may contribute to hyperexcitability and motor, behavioral, and cognitive deficits. Preserving the function of GABAergic interneurons, therefore, is a rational therapeutic strategy to preserve cortical function after TBI and prevent long-term clinical complications. Here, we explored an approach based on the ketogenic diet, a neuroprotective and anticonvulsant dietary therapy which results in reduced glycolysis and increased ketosis. Utilizing a pharmacologic inhibitor of glycolysis (2-deoxyglucose, or 2-DG), we found that acute in vitro glycolytic inhibition decreased the excitability of excitatory neurons, but not inhibitory interneurons, in cortical slices from naive mice. Employing the controlled cortical impact (CCI) model of TBI in mice, we found that in vitro 2-DG treatment rapidly attenuated epileptiform activity seen in acute cortical slices 3-5 weeks after TBI. One week of in vivo 2-DG treatment immediately after TBI prevented the development of epileptiform activity, restored excitatory and inhibitory synaptic activity, and attenuated loss of parvalbumin-positive inhibitory interneurons. In summary, inhibition of glycolysis with 2-DG may have therapeutic potential to restore network function following TBI.\n\nOne Sentence SummaryFollowing traumatic brain injury in mice, in vivo treatment with the glycolytic inhibitor 2-deoxyglucose prevented cortical network pathology including cortical hyperexcitability, changes in synaptic activity, and loss of parvalbumin-expressing GABAergic interneurons.

neuroscience↗