Biology subjects

Laguesse, S.

Publications and source records attributed to Laguesse, S..

7 recordsLinked to original sources

bioRxiv2025

Loss of Elp3 impairs the maturation tempo of brain ependymal cells

Conditional deletion of Elp3 in the mouse forebrain leads to microcephaly at birth. In this study, we demonstrate that these mice also develop postnatal hydrocephalus, associated with an enlargement of the brain ventricles. In wild-type mice, ependymal motile cilia are properly aligned to facilitate the circulation of cerebrospinal fluid (CSF) within the ventricles. Our findings reveal that Elp3 loss induces endoplasmic reticulum (ER) stress and upregulation of ATF4 expression in ependymal cell progenitors, which compromises Notch signaling and accelerates their maturation. This is accompanied by a disruption in the establishment of rotational and translational polarities of the motile cilia of maturing ependymal cells, resulting in disorganized cilia bundles. Collectively, these molecular abnormalities lead to the premature and abnormal development of ependymal cells, culminating in cilia beating dysfunction, impaired CSF clearance, and the development of hydrocephalus.

neuroscience↗

bioRxiv2023

Paradoxical mTORC1-Dependent microRNA-mediated Translation Repression in the Nucleus Accumbens of Mice Consuming Alcohol Attenuates Glycolysis

mTORC1 promotes protein translation, learning and memory, and neuroadaptations that underlie alcohol use and abuse. We report that activation of mTORC1 in the nucleus accumbens (NAc) of mice consuming alcohol promotes the translation of microRNA (miR) machinery components and the upregulation of microRNAs (miRs) expression including miR-34a-5p. In parallel, we detected a paradoxical mTORC1-dependent repression of translation of transcripts including Aldolase A, an essential glycolytic enzyme. We found that miR-34a-5p in the NAc targets Aldolase A for translation repression and promotes alcohol intake. Our data further suggest that glycolysis is inhibited in the NAc manifesting in an mTORC1-dependent attenuation of L-lactate, the end product of glycolysis. Finally, we show that systemic administration of L-lactate attenuates mouse excessive alcohol intake. Our data suggest that alcohol promotes paradoxical actions of mTORC1 on translation and glycolysis which in turn drive excessive alcohol use.

neuroscience↗

bioRxiv2023

The small G-protein Rac1 in the dorsomedial striatum promotes alcohol-dependent structural plasticity and goal-directed learning in mice

The small G-protein Rac1 promotes the formation of filamentous actin (F-Actin). Actin is a major component of dendritic spines, and we previously found that alcohol alters actin composition and dendritic spine structure in the nucleus accumbens (NAc) and the dorsomedial striatum (DMS). To examine if Rac1 contributes to these alcohol-mediated adaptations, we measured the level of GTP-bound active Rac1 in the striatum of mice following 7 weeks of intermittent access to 20% alcohol. We found that chronic alcohol intake activates Rac1 in the DMS of male mice. In contrast, Rac1 is not activated by alcohol in the NAc and DLS of male mice, or in the DMS of female mice. Similarly, closely related small G-proteins are not activated by alcohol in the DMS, and Rac1 activity is not increased in the DMS by moderate alcohol or natural reward. To determine the consequences of alcohol-dependent Rac1 activation in the DMS of male mice, we inhibited endogenous Rac1 by infecting the DMS of mice with an AAV expressing a dominant negative form of the small G-protein (Rac1-DN). We found that overexpression of AAV-Rac1-DN in the DMS inhibits alcohol-mediated Rac1 signaling and attenuates alcohol-mediated F-actin polymerization, which corresponded with a decrease in dendritic arborization and spine maturation. Finally, we provide evidence to suggest that Rac1 in the DMS plays a role in alcohol-associated goal-directed learning. Together, our data suggest that Rac1 in the DMS plays an important role in alcohol-dependent structural plasticity and aberrant learning. Significance StatementAddiction, including alcohol use disorder, is characterized by molecular and cellular adaptations that promote maladaptive behaviors. We found that Rac1 was activated by alcohol in the dorsomedial striatum (DMS) of male mice. We show that alcohol-mediated Rac1 signaling is responsible for alterations in actin dynamics and neuronal morphology. We also present data to suggest that Rac1 is important for alcohol-associated learning processes. These results suggest that Rac1 in the DMS is an important contributor to adaptations that promote alcohol use disorder.

neuroscience↗

bioRxiv2022

E4F1 COORDINATES PYRUVATE METABOLISM AND THE ACTIVITY OF THE ELONGATOR COMPLEX TO ENSURE PROTEIN TRANSLATION FIDELITY DURING NEURONAL DEVELOPMENT

Pyruvate metabolism defects lead to severe neuropathies such as the Leigh syndrome (LS) but the molecular mechanisms underlying neuronal cell death remain poorly understood. Here, we unravel a connection between pyruvate metabolism and the regulation of the epitranscriptome that is relevant to LS pathogenesis. We identified the transcription factor E4F1 as a key coordinator of AcetylCoenzyme A (AcCoA) production by the pyruvate dehydrogenase complex (PDC) and its utilization as an essential co-factor by the Elongator complex to acetylate tRNAs at the wobble position uridine 34 (U34). E4F1-mediated direct transcriptional regulation of Dlat and Elp3, two genes encoding key subunits of the PDC and of the Elongator complex, respectively, ensured proper translation fidelity and cell survival in the central nervous system (CNS) during mouse embryonic development. Furthermore, analysis of PDH-deficient cells highlighted a crosstalk linking the PDC to ELP3 expression that is perturbed in LS patients.

developmental biology↗

bioRxiv2020

Adolescent Alcohol Binge-Drinking Insidiously Impairs Adult Behavior In Mice

Adolescence is a developmental period characterized by significant changes in brain architecture and behavior. The immaturity of the adolescent brain is associated with heightened vulnerability to exogenous agents, including alcohol. Alcohol is the most consumed drug among teenagers, and binge-drinking during adolescence is a major public health concern. Studies have suggested that adolescent alcohol exposure (AAE) may interfere with the maturation of frontal brain regions and lead to long-lasting behavioral consequences. In this study, we used a mouse model of AAE in which adolescent mice reach high blood alcohol concentration after voluntary binge-drinking. In order to assess short- and long-term consequences of AAE, a battery of behavioral tests was performed during late adolescence and during adulthood. We showed that AAE had no short-term effect on young mice behavior but rather increased anxiety- and depressive-like behaviors, as well as alcohol consumption during adulthood. Moreover, alcohol binge-drinking during adolescence dramatically decreased recognition memory performances and behavioral flexibility in both adult males and females. Furthermore, we showed that voluntary consumption of alcohol during adolescence did not trigger any major activation of the innate immune system in the prefrontal cortex (PFC). Together, our data suggest that voluntary alcohol binge-drinking in adolescent mice induces a delayed appearance of behavioral impairments in adulthood.

animal behavior and cognition↗

bioRxiv2019

Differential Correlation of Serum BDNF and microRNA Content in Rats with Rapid or Late Onset of Heavy Alcohol Use

Heavy alcohol use reduces the levels of the brain-derived neurotrophic factor (BDNF) in the prefrontal cortex of rodents through the upregulation of microRNAs targeting BDNF mRNA. In humans, an inverse correlation exists between circulating blood levels of BDNF and the severity of psychiatric disorders including alcohol abuse. Here, we set out to determine whether a history of heavy alcohol use produces comparable alterations in the blood of rats. We used an intermittent access to 20% alcohol using the 2-bottle choice paradigm (IA20%2BC), and measured circulating levels of BDNF protein and microRNAs in the serum of Long-Evans rats before and after 8-weeks of excessive alcohol intake. We observed that the drinking profile of heavy alcohol users is not unified; Whereas 70% of the rats gradually escalate their alcohol intake (Late Onset), 30% of alcohol users exhibit a very Rapid Onset of drinking (Rapid Onset). We found that serum BDNF levels are negatively correlated with alcohol intake in both Rapid Onset and Late Onset rats. In contrast, increased expression of the microRNAs (miRs) targeting BDNF, miR30a-5p, miR-195-5p, miR191-5p and miR206-3p, was detected only in the Rapid Onset rats. Finally, we report that the alcohol-dependent molecular changes are not due to alterations in platelet number. Our data suggest that rats exhibit both Late and Rapid Onset of alcohol intake. We further show that heavy alcohol use produces comparable changes in BDNF protein levels in both groups. However, circulating microRNAs are responsive to alcohol only in the Rapid Onset rats.

neuroscience↗

bioRxiv2019

mTORC1 IN THE ORBITOFRONTAL CORTEX PROMOTES HABITUAL ALCOHOL SEEKING

The mammalian target of rapamycin complex 1 (mTORCl) plays an important role in dendritic translation, synaptic plasticity, and learning and memory. We previously showed that heavy alcohol use activates mTORC1 in the orbitofrontal cortex (OFC) of rodents. Here, we set out to determine the consequences of alcohol-dependent mTORC1 activation in the OFC. We found that although inhibition of mTORC1 in the OFC does not alter rat alcohol intake per se, it attenuates alcohol seeking. We then tested whether mTORC1 in the OFC is required for goal-directed or habitual alcohol seeking. To do so, rats were trained self-administer alcohol under a random ratio (RR) or a random interval (RI) schedule of reinforcement, which biases toward goal-directed or habitual responding, respectively, and tested whether mTORC1 inhibition alters lever presses following alcohol devaluation. We found that pharmacological inhibition of mTORC1 or knockdown of the adaptor protein, Raptor, did not affect goal-directed alcohol responding but restored sensitivity to devaluation in RI-trained rats. In contrast, habitual responding for sucrose was unaltered by mTORC1 inhibition. These data suggest that mTORC1 in the OFC drives alcohol habit. We then elucidate the mechanism by which mTORC1 is activated by alcohol, and found that the recruitment of GluN2B during alcohol withdrawal stimulates mTORC1 in OFC cFos-positive neurons. Finally, we show that inhibition of GluN2B in the OFC attenuates both alcohol seeking and habitual responding for alcohol. Together, our data suggest that alcohol withdrawal promotes an NMDAR-dependent activation of mTORC1 which in turn drives habitual alcohol seeking.

neuroscience↗