Biology subjects

Newbern, J.

Publications and source records attributed to Newbern, J..

5 recordsLinked to original sources

bioRxiv2026

Differential sex-dependent responses of circulating steroid hormones and cortical gene expression in a preclinical traumatic brain injury model

Accumulating evidence supports sex differences in traumatic brain injury (TBI) outcomes, however the underlying processes that lead to sex differences are not well understood. TBI results in the initiation of molecular and cellular responses that facilitate the progression of neurodegeneration. Importantly, little is known about how the circulating hormone profile is altered in response to TBI, and whether sex differences in endocrine responses might shape secondary injury pathologies. Using intact male and female mice in a preclinical TBI model, we assessed changes in plasma hormone concentrations and cortical gene expression at 24 and 72 hours after TBI. We demonstrate that males and females exhibit sex-specific alterations in circulating levels of progesterone, testosterone, androstenedione, estradiol and dehydroepiandrosterone (DHEA) in response to TBI. We also identified sex differences in the expression of genes that are involved in immune responses and tissue remodeling after injury. Moreover, we report divergent circulating hormone and gene expression correlations between sexes.

neuroscience↗

bioRxiv2023

Hyperactivation of MEK1 in cortical glutamatergic neurons results in projection axon deficits and aberrant motor learning

Abnormal Extracellular Regulated Kinase 1/2 (ERK1/2) signaling is linked to multiple neurodevelopmental diseases, especially the RASopathies, which typically exhibit ERK1/2 hyperactivation in neurons and non-neuronal cells. To better understand how excitatory neuron-autonomous ERK1/2 activity regulates the development of the mouse motor cortex, we conditionally expressed a hyperactive MEK1S217/221E variant using Nex/NeuroD6:Cre. Our results show that MEK1S217/221E expression led to persistent hyperactivation of ERK1/2 in neocortical axons, but not excitatory neuron somas or nuclei. We noted reduced axonal arborization of multiple subcortical target domains in mutants and reduced cortical expression of the activity dependent gene, ARC. These changes did not coincide with significant differences in voluntary locomotor activity or motor performance in the accelerating rotarod task. However, motor learning in a single-pellet retrieval task was significantly diminished in Nex/NeuroD6:Cre; MEK1S217/221E mutants. Restriction of MEK1S217/221E expression to layer V cortical neurons recapitulated axonal outgrowth deficits, however, had no effect on motor learning. Collectively, these results indicate that within the cortex, glutamatergic neuron-autonomous hyperactivation of MEK1 is sufficient to drive deficits in axon outgrowth, activity dependent gene expression, and skilled motor learning. Summary statementMEK-ERK1/2 hyperactivation in developing cortical excitatory neurons is sufficient to decrease long-range axonal outgrowth, which coincides with reduced Arc expression and deficits in aspects of skilled motor learning by adulthood.

neuroscience↗

bioRxiv2020

Accumbens cholinergic interneurons mediate cue-induced nicotine seeking and associated glutamatergic plasticity

Nicotine, the primary addictive substance in tobacco, is widely abused. Relapse to cues associated with nicotine results in increased glutamate release within nucleus accumbens core (NAcore), modifying synaptic plasticity of medium spiny neurons (MSNs) which contributes to reinstatement of nicotine seeking. However, the role of cholinergic interneurons (ChIs) within the NAcore in mediating these neurobehavioral processes in unknown. ChIs represent less than 1% of the accumbens neuronal population yet are activated during drug seeking and reward-predicting events. Thus, we hypothesized that ChIs may play a significant role in mediating glutamatergic plasticity that underlies nicotine seeking behavior. Using chemogenetics transgenic rats that express Cre under the control of the choline acetyltransferase (ChAT) promoter, ChIs were bi-directionally manipulated prior to cue-induced reinstatement. Following nicotine self-administration and extinction training, ChIs were activated or inhibited prior to a cue reinstatement session. Following reinstatement, whole-cell electrophysiology from NAcore MSNs was used to assess changes in plasticity, measured via -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) / N-Methyl-D-Aspartate (NMDA) (A/N) ratios. Chemogenetic inhibition of ChIs inhibited cued nicotine seeking and resulted in decreased A/N, whereas activation of ChIs had no effect, demonstrating that ChI inhibition prevents transient synaptic potentiation (t-SP) associated with cue-induced nicotine seeking. To assess potential underlying mechanisms, accumbens 4{beta}2- and 7-containing nicotinic ACh receptors (nAChRs) were pharmacologically inhibited and MSN synaptic morphology was assessed following reinstatement. Inhibition of both nAChR subtypes prevented cue-induced nicotine seeking and t-SP (measured via changes in spine head diameter). Together, these results demonstrate that these neurons mediate cue-induced nicotine reinstatement and underlying synaptic plasticity within the NAcore.

neuroscience↗

bioRxiv2019

Sex-dependent macromolecule and nanoparticle delivery in experimental brain injury

Development of effective therapeutics for brain disorders is challenging, in particular, the blood-brain barrier (BBB) severely limits access of the therapeutics into the brain parenchyma. Traumatic brain injury (TBI) may lead to transient BBB permeability that affords a unique opportunity for therapeutic delivery via intravenous administration ranging from macromolecules to nanoparticles (NP) for developing precision therapeutics. In this regard, we address critical gaps in understanding the range/size of therapeutics, delivery window(s), and moreover the potential impact of biological factors for optimal delivery parameters. Here we show, for the first time, to the best of our knowledge, that 24 h post-focal TBI female mice exhibit a heightened macromolecular tracer and NP accumulation compared to male mice, indicating sex-dependent differences in BBB permeability. Furthermore, we report for the first time the potential to deliver NP-based therapeutics within 3 d after focal injury in both female and male mice. The delineation of injury-induced BBB permeability with respect to sex and temporal profile is essential to more accurately tailor time-dependent precision and personalized nanotherapeutics.

bioengineering↗

bioRxiv2019

Consecutive signaling pathways are activated in progression of Duchenne muscular dystrophy in C. elegans

BackgroundDuchenne muscular dystrophy (DMD) is a lethal, X-linked disease characterized by progressive muscle degeneration. The condition is driven by nonsense and missense mutations in the dystrophin gene, but the resulting changes in muscle-specific gene expression that take place in dystrophins absence remain uncharacterized, as they are potentially obscured by the chronic inflammation elicited by muscle damage in humans. C. elegans possess a mild inflammatory response that allows for the characterization of the transcriptome rearrangements affecting disease progression independently of inflammation. ResultsIn effort to better understand these dynamics we have isolated and sequenced body muscle-specific transcriptomes from C. elegans lacking functional dystrophin at distinct stages of disease progression. We have identified two consecutively altered gene networks, which are also disrupted in the dystrophin deficient mdx mouse model. We found an upregulation of genes involved in mitochondrial function early in disease progression, and an upregulation of genes related to muscle fibre repair in later stages. This suggests that dystrophin may have a signaling role early in development, and its absence may activate compensatory mechanisms that counteract muscle degradation caused by loss of dystrophin. We have also developed a temperature-based screening method for synthetic paralysis that can be used to rapidly identify genetic partners of dystrophin. ConclusionsOur results allow for the comprehensive identification of transcriptome rearrangements that potentially serve as independent drivers of disease progression and may in turn allow for the identification of new therapeutic targets for the treatment of DMD. One Sentence SummaryA tissue specific transcriptome analysis of dystrophin deficient muscle in C. elegans reveals that dystrophin has distinct, dynamic signaling roles in early and late stage progression of Duchenne muscular dystrophy.

genetics↗