Biology subjects

Lavigne, M.

Publications and source records attributed to Lavigne, M..

6 recordsLinked to original sources

bioRxiv2025

Motivational control is implemented by a cingulo-prefrontal pathway

The neuronal connections between the midcingulate cortex (MCC) and the dorsolateral prefrontal cortex (dlPFC) are associated with multiple cognitive functions, including rapid and long-term adaptive processes. Here we show that DREADD-mediated activation of MCC to dlPFC projection in macaques led to increased engagement in a foraging task, but did not alter their trial-to-trial adaptive strategy. We conclude that a critical role for MCC-dlPFC pathway is in the temporally extended control of behaviour rather than in rapid adaptation.

neuroscience↗

bioRxiv2024

Setdb1 regulates proper differentiation of adult intestinal stem cells via restraining permissive chromatin structure and transcriptional variability

The histone methylase Setdb1 plays a pivotal role in embryonic stem cell maintenance and developmental lineage specification. However, its function in adult stem cells remains elusive. Here we show that conditional inactivation of Setdb1 in Lgr5+ intestinal stem cells alters the transcriptional programs of the progeny cell types and results in increased cell-to-cell transcriptional variability. Loss of Setdb1 blocked differentiation towards the absorptive enterocyte lineage, while the secretory cell types were only marginally affected due to the activation of alternative developmental trajectories. Setdb1 inactivation did not affect global H3K9 methylation at large heterochromatin domains but led to altered distribution of transposase-accessible chromatin regions, aberrant exposure of transcription factor binding sites and premature activation of differentiation-specific genes. The results demonstrate that Setdb1 regulates intestinal stem cell differentiation by fine-tuning chromatin accessibility in open euchromatin regions thereby controlling transcriptional variability between cells.

cell biology↗

bioRxiv2022

Noradrenergic cross-modular reciprocal inhibition within the Locus Coeruleus.

The Locus Coeruleus (LC) is the primary noradrenergic nucleus in the brain with widespread projections driving changes in cognitive state and animal behaviour. The LC is composed of multiple "modules" with specific efferent target domains enabling discretional neuromodulation. LC neuronal activity releases noradrenaline within the nucleus as a local feedback mechanism, but it is not known how this influences modular output. We address this question using whole-cell recordings and calcium imaging in rat pontine slices in combination with LC neuronal ensemble modelling to assess the influence of local noradrenaline release on cross-modular interactions. Electrophysiological recordings of LC neurons from rats transduced with the optogenetic actuator ChR2 showed auto-inhibition and lateral inhibition (of surrounding non-transduced neurons). This inhibition was strongly frequency dependent and was mediated by noradrenaline acting on alpha2-adrenceptors (2R). To allow calcium-imaging of LC neuronal ensembles a Canine-Adenoviral vector strategy was developed using the PRS promoter to drive selective expression GCaMP6s. Calcium imaging allowed resolution of both increases and decreases in LC activity (to TTX / clonidine or high potassium). Selective chemogenetic-activation of subsets of LC neurons (expressing the ionotropic actuator PSAM) revealed both a direct excitation (after application of PSEM308, 3-30{micro}M) and an 2R-mediated inhibition of neighbouring LC cells (non-transduced). Differential retrograde targeting of PSAM or GCaMP6s to specific LC modules showed the presence of strong, reciprocal cross-modular inhibition (shown for the LC-olfactory bulb vs LC bulbospinal modules) and a subsequent rebound activity inversion. This represents a preferential, targeted, cross-modular, lateral inhibition within the LC rather than a non-specific surround inhibition. Computational modelling showed the emergence of lateral inhibition and biphasic responses to modular activation when 2R signalling and noradrenergic reuptake saturation were included. This interaction may facilitate recruitment of neuronal ensembles by coherent inputs and represents a bottom-up differential contrast-enhancement mechanism within the LC to produce a modality specific focus.

neuroscience↗

bioRxiv2022

Noradrenergic signaling in the rodent orbitofrontal cortex is required to update goal-directed actions.

In a constantly changing environment, organisms must track the current relationship between actions and their specific consequences and use this information to guide decision-making. Such goal-directed behavior relies on circuits involving cortical and subcortical structures. Notably, a functional heterogeneity exists within the medial prefrontal, insular, and orbitofrontal cortices (OFC) in rodents. The role of the latter in goal-directed behavior has been debated, but recent data indicate that the ventral and lateral subregions of the OFC are needed to integrate changes in the relationships between actions and their outcomes. Neuromodulatory agents are also crucial components of prefrontal functions and behavioral flexibility might depend upon the noradrenergic modulation of prefrontal cortex. Therefore, we assessed whether noradrenergic innervation of the OFC plays a role in updating action-outcome relationships. We used an identity-based reversal task and found that depletion or chemogenetic silencing of noradrenergic inputs within the OFC rendered rats unable to associate new outcomes with previously acquired actions. Silencing of noradrenergic inputs in the medial prefrontal cortex or depletion of dopaminergic inputs in the OFC did not reproduce this deficit. Together, our results indicate that noradrenergic projections to the OFC are required to update goal-directed actions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/498245v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@afc586org.highwire.dtl.DTLVardef@1d10ff4org.highwire.dtl.DTLVardef@6e6863org.highwire.dtl.DTLVardef@874b30_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIRats learn initial action-outcome associations in an instrumental task C_LIO_LINoradrenergic depletion in the OFC prevents the encoding and expression of these associations following reversal learning C_LIO_LIDopaminergic depletion in the OFC does not result in behavioral deficits C_LIO_LILC:OFC noradrenergic projections are required to update action-outcome associations C_LI IN BRIEFCerpa et al. investigate whether noradrenergic projections from the locus coeruleus (LC) to the orbitofrontal cortex are involved in updating previously established goal-directed actions following environmental change. They find that these LC projections are required to both encode and express reversed action-outcome associations in rats.

neuroscience↗

bioRxiv2022

eIf2α-regulated translation modulates the early adhesion of mesenchymal-like cells

Cellular invasion is a complex process that requires several interdependent biological mechanisms, which are initiated by changes in adhesion that establish a morphology favorable for migration. Hence, the regulation of adhesion potential is a rate-limiting step in metastasis. Our previous work revealed that de novo translation is necessary to regulate the adhesion of mesenchymal-like cells; however, the underlying translational regulatory mechanism and the identity of newly synthesized proteins needed for the adhesion process remain unidentified. Here, we identify a mechanotransduction pathway linking force-mediated protein unfolding to translational reprogramming via the activation of the integrated stress response (ISR). Specifically, we demonstrate that phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2) during early adhesion events leads to selective translation of mRNAs encoding proteins critical for adhesion complex formation, mechanosensing, and contractility. These findings uncover a mechanosensitive translational control axis that links intracellular force generation to cell adhesion and stress adaptation, with implications for understanding mesenchymal cell adhesion and morphological behavior

cell biology↗

bioRxiv2019

Locus-coeruleus norepinephrine activity gates sensory-evoked awakenings from sleep

A defining feature of sleep is reduced responsiveness to external stimuli, but the mechanisms gating sensory-evoked arousal remain unclear. We hypothesized that reduced locus-coeruleus norepinephrine (LC-NE) activity during sleep mediates unresponsiveness, and its action promotes sensory-evoked awakenings. We tested this using electrophysiological, behavioral, pharmacological, and optogenetic techniques alongside auditory stimulation in freely behaving rats. We found that systemic reduction of NE signaling lowered probability of sound-evoked awakenings (SEAs). The level of tonic LC activity during sleep anticipated SEAs. Optogenetic LC activation promoted arousal as evident in sleep-wake transitions, EEG desynchronization, and pupil dilation. Importantly, liminal LC excitation before sound presentation increased SEA probability. Optogenetic LC silencing using a soma-targeted anion-conducting channelrhodopsin (stGtACR2) suppressed LC spiking and constricted pupils. Brief periods of LC opto-silencing reduced the probability of SEAs. Thus, LC-NE activity determines the likelihood of sensory-evoked awakenings and its reduction during sleep constitutes a key factor mediating behavioral unresponsiveness.

neuroscience↗