Biology subjects

Giroux, M.

Publications and source records attributed to Giroux, M..

5 recordsLinked to original sources

bioRxiv2022

Amphetamine disrupts dopamine axon growth in adolescence by a sex-specific mechanism

Initiating drug use during adolescence increases the risk of developing addiction and psychiatric disorders later in life, with long-term outcomes varying according to sex and exact timing of use. Even though most individuals begin experimenting with drugs of abuse in adolescence, to date, the cellular and molecular underpinnings explaining differential sensitivity to detrimental drug effects remain unknown. The Netrin-1/DCC guidance cue system plays a critical role in the adolescent development of mesocorticolimbic dopamine circuitry, segregating the cortical and limbic pathways. Adolescent experiences, including exposure to drugs of abuse, can regulate Dcc expression in male mice, placing Netrin-1/DCC signaling as a potential molecular link between experience and enduring changes to circuitry and behavior. Here we show that exposure to a recreational-like regimen of amphetamine (AMPH) in adolescence induces sex- and age-specific alterations in Dcc expression in the ventral tegmental area. Female mice are protected against the deleterious long-term effects of AMPH-induced Dcc regulation by compensatory changes in the expression of its binding partner, Netrin-1. AMPH induces targeting errors in mesolimbic dopamine axons and triggers their ectopic growth to the prefrontal cortex, only in early-adolescent male mice, underlying a male-specific vulnerability to its enduring cognitive effects. Upregulating DCC receptor expression in dopamine neurons in adolescent males using a neuron-optimized CRISPR/dCas9 Activation System induces female-like protection against the persistent effects of AMPH in early adolescence on inhibitory control. Netrin-1/DCC signaling is therefore a molecular switch which can be differentially regulated in response to the same experience as function of age and sex of the individual, leading to divergent long-term outcomes associated with vulnerable or resilient phenotypes.

neuroscience↗

bioRxiv2020

miR-218 in adolescence predicts and mediates vulnerability to stress

Adolescence is a period of increased vulnerability to psychiatric disorders including depression. Discovering novel biomarkers to identify individuals who are at high risk is very much needed. Our previous work shows that the microRNA miR-218 mediates susceptibility to stress and depression in adulthood, by targeting the Netrin-1 guidance cue receptor gene Dcc (Deleted in colorectal cancer) in the medial prefrontal cortex (mPFC). Here we investigated whether miR-218 regulates Dcc expression in adolescence and could serve as an early predictor of lifetime stress vulnerability. miR-218 expression in the mPFC increases from early adolescence to adulthood and correlates negatively with Dcc levels. In blood, postnatal miR-218 expression parallels changes occurring in the mPFC. Notably, circulating miR-218 levels in adolescence associate with vulnerability to social defeat stress in adulthood, with high levels associated with social avoidance severity. Indeed, downregulation of miR-218 in the mPFC in adolescence promotes resilience to stress in adulthood, indicating that adolescent miR-218 expression may serve both as a marker of risk and as a target for early interventions.

neuroscience↗

bioRxiv2019

Cell population effects in a mouse tauopathy model identified by single cell sequencing

Neurodegenerative disorders are complex multifactorial diseases that have poorly understood selective vulnerabilities among discrete cell populations. We performed single cell RNA sequencing of whole hippocampi from the rTg4510 mouse tauopathy model, which expresses a P301L MAPT mutation at two time points--before and after the onset of pathology. One population of neurons showed a robust size reduction in both the young and the old transgenic animals. Differential expression of genes expressed in this group of neurons suggested an enrichment in granule cell neurons. We identified genes that characterize this population of neurons using Pareto optimization of the specificity and precision of gene pairs for the population of interest. The resulting optimal marker genes were overwhelmingly associated with neuronal projections and their expression was enriched in the dentate gyrus suggesting that the rTg4510 mouse is a good model for Picks disease. This observation suggested that the tau mutation affects the population of neurons associated with neuronal projections even before overt tau inclusions can be observed. Out of the optimal pairs of genes identified as markers of the population of neurons of interest, we selected Purkinje cell protein 4 (Pcp4+) and Syntaxin binding protein 6 (Stxbp6+) for experimental validation. Single-molecule RNA fluorescence in situ hybridization confirmed preferential expression of these markers and localized them to the dentate gyrus.

cell biology↗

bioRxiv2018

Farnesyl Transferase Inhibition for the Treatment of Tauopathies

Tau inclusions are a shared feature of many neurodegenerative conditions and tau mutations lead to frontotemporal dementia. Approaches to treatment of these conditions have focused directly on the tau protein by targeting its post-translational modifications, its levels and its tendency to aggregate. We discovered a novel regulatory pathway for tau degradation that operates through the Rhes protein, a GTPase. Rhes is farnesylated and treatment with the farnesyl transferase inhibitor, lonafarnib, reduced Rhes, attenuated behavioral abnormalities, significantly reduced atrophy, tau inclusions, sumoylation and ubiquitination, as well as microgliosis in the rTg4510 tauopathy mouse. Direct reduction of Rhes levels reproduced the results observed with lonafarnib. The mechanism of lonafarnib action, as mediated by Rhes to reduce tau pathology, operates through the lysosome without involvement of the proteasome. Finally we show that the developmental increase in Rhes levels can be homeostatically regulated in the presence of tau mutations as a protective mechanism through which cells sense abnormal tau before any pathology is present. The extensive human trials of lonafarnib for other conditions, makes this drug ideal for repurposing to treat tauopathies.\n\nOne-sentence summaryVia a mechanism that involves targeting Rhes, lonafarnib can induce lysosomal-mediated tau degradation and prevent pathology in a tau mouse model

neuroscience↗

bioRxiv2017

Enhanced neuronal regeneration in the CAST/Ei mouse strain is linked to expression of differentiation markers after injury

Peripheral nerve regeneration after injury requires a broad program of transcriptional changes. We investigated the basis for the enhanced nerve regenerative capacity of the CAST/Ei mouse strain relative to C57BL/6 mice. RNA sequencing of dorsal root ganglia (DRG) showed a CAST/Ei specific upregulation of Ascl1 after injury. Ascl1 overexpression in C57BL/6 mice DRG neurons enhanced their neurite outgrowth. Ascl1 is regulated by miR-7048-3p, which is down-regulated in CAST/Ei mice. Inhibition of miR-7048-3p enhances neurite outgrowth. Following injury, CAST/Ei neurons largely retained their mature neuronal profile as determined by single cell RNAseq, whereas the C57BL/6 neurons acquired an immature profile. These findings suggest that one facet of the enhanced regenerative phenotype is preservation of neuronal identity in response to injury.

molecular biology↗