Biology subjects

Maheu, M.

Publications and source records attributed to Maheu, M..

10 recordsLinked to original sources

bioRxiv2026

Interplay of pupil-linked arousal and cortical decision computations in mice

Influential frameworks hold that brainstem neuromodulatory systems are rapidly recruited in a top-down manner during decision-making, adapting brain-wide activity and cognitive behavior in real time. Here, we examined the relationship between decision-related frontal cortical activity and pupil responses (a peripheral proxy of neuromodulatory activity) in mice accumulating fluctuating auditory evidence to choose among two options. We found two components of preparatory activity during decision formation, prior to motor action: a non-selective component shared between hemispheres and a choice-selective component that reflected decision uncertainty. Both components were mirrored in pupil responses during the task, which, in turn, scaled with decision uncertainty during decision formation and with uncertainty-modulated prediction errors after experiencing the outcome. Pupil responses also predicted an adjustment of choice behavior at the next trial. Our results point to a recurrent interplay between cortical decision computation and pupil-linked neuromodulation. HIGHLIGHTSO_LIMice switch between evidence integration and heuristic strategies during auditory-informed decisions C_LIO_LIPupil responses track decision uncertainty and uncertainty-modulated prediction errors C_LIO_LIDecision-related frontal cortical activity is coupled with pupil responses C_LIO_LIPupil responses predict an adjustment of future choice behavior C_LI IN SHORTMaheu et al. show that the phasic transitions in the arousal state mirror distinct components of cortical activity, including one directly involved in decision computations. In turn, these pupil-linked arousal responses predicted the strategy adopted at the next trial.

neuroscience↗

bioRxiv2025

Regulation of Decision Threshold by the Locus Coeruleus

A fundamental challenge for decision-making under uncertainty lies in regulating the balance between speed and accuracy. Humans and animals solve this problem by adjusting their decision thresholds -- the criterion that determines how much information is required before committing to a choice. While brain regions associated with this process have been identified, the neural circuits able to directly alter decision thresholds remain to be identified. Here we investigate the role of the locus coeruleus (LC) norepinephrine (NE) system in controlling the balance between speed and accuracy during decision making. Through cell-type specific chemogenetic manipulations, we discovered that LC-NE activation increased decision thresholds. We further demonstrated that this effect is replicated by systemic administration of the 2 adrenergic receptor (2 AR) agonist, clonidine. Notably, 2 AR activation drove changes in decision threshold specifically, without reproducing other LC-NE activation effects such as promoting task engagement. Together, these results suggest that LC-NE regulates decision thresholds via activation of downstream 2 ARs. HighlightsO_LILC-NE activation increases reaction time and accuracy of perceptual decisions C_LIO_LIBehavioral effects are consistent with an elevation of decision thresholds C_LIO_LIHeightened decision thresholds are replicated by selective activation of 2 ARs C_LIO_LIActivation of LC-NE and 2 ARs differently alter task engagement C_LI

animal behavior and cognition↗

bioRxiv2025

Haploinsufficiency of KPNA7 causes otosclerosis, likely due to the release of import inhibition of PTHrP and the reactivation of chondrogenesis in the globuli interossei

Otosclerosis is a genetic bone disorder restricted to the otic capsule and a common cause of conductive hearing loss with both familial and sporadic cases. To date, 14 genomic loci (OTSC) and four underlying OTSC genes (MEPE, SERPINF1, FOXL1, SMARCA4) have been identified in autosomal dominant families. A combined genetic/genomics approach on five affected siblings of Northern European ancestry from the island of Newfoundland, Canada identified a premature stop mutation in Karyopherin subunit 7 (KPNA7, c.49C>T, p.R17X). KPNA7 maps to OTSC2 (7q22.1) and encodes the newest of the seven-member importin- family of nuclear transporters and plays a critical role in early embryonic cleavage events and zygotic genome activation. Previous studies reveal that recessive KPNA7 variants cause skeletal abnormalities, including scoliosis and ocular hypertelorism in two sisters with Partial Corpus Callosum Agenesis-Cerebellar Vermis Hypoplasia With Posterior Fosa Cysts Syndrome and more recently, have been implicated in preimplantation embryo arrest (PREMBA) (OMIM 614107). Interestingly, KPNA7 is also a maternal factor with an exclusively embryonic role and likely inhibits non-classical NLS transport of PTHrP, a known activator of chondrogenesis. We propose that KPNA7 haploinsufficiency causes a failure in nuclear transport inhibition of PTHrP in the quiescent embryonic cells of the globuli interossei in the otic capsule and re-activates chondrogenesis. The KPNA7 discovery provides new insights into the pathogenesis of otosclerosis and potential for targeted therapies. Author SummaryOtosclerosis is a distinctly human genetic bone disorder of the otic capsule and a major cause of progressive hearing loss in young adults, particularly in females. Even though otosclerosis has been recognized as a distinct entity for a long time, both its pathogenesis and restriction to the otic capsule remains a mystery. Here, we use a combined genetic/genomics approach to identify a premature stop mutation in five affected siblings of Northern European ancestry from the island of Newfoundland, Canada. KPNA7 encodes the newest of the seven-member importin- family of nuclear transporters and plays a critical role in early embryonic cleavage events and zygotic genome activation. Based on the unique features of the otic capsule, we hypothesize that the premature stop mutation in KPNA7 leads to haploinsufficiency causing a failure in nuclear transport inhibition of PTHrP and reactivates chondrogenesis in the otherwise quiescent embryonic cells within the otic capsule. The KPNA7 discovery provides new insights into the pathogenesis of otosclerosis and potential for targeted therapies.

genetics↗

bioRxiv2025

Serotonergic and noradrenergic interactions in pupil-linked arousal

Changes in central arousal state shape cortical computations underlying perception, thought, and action. Variations in arousal are accompanied by fluctuations in pupil size. In turn, pupil dynamics are often used as a marker of noradrenaline release from neurons of the locus coeruleus. The serotonergic system of the dorsal raphe also contributes to the brainstem control of waking states. However, little is known about its relationship to noradrenergic activity and arousal dynamics in awake animals. Here, we simultaneously accessed both systems in awake mice and unraveled their unique and joint contributions to pupil-linked arousal. Serotonergic and noradrenergic systems co-fluctuated, and serotonergic dorsal raphe neurons affected pupil size partly via noradrenergic populations in the locus coeruleus. Yet, part of the serotonergic control of pupil dynamics was independent of the locus coeruleus. Our findings challenge common assumptions about the neuromodulatory control of pupil dynamics and illuminate the interplay between distinct neurochemical systems within the arousal network of the brainstem.

neuroscience↗

bioRxiv2025

Schaffer commissural inputs regulate the stability of CA1 spatial representation

Neuronal representations of the world are dynamic. A striking example is the rapid remapping of the hippocampal spatial code, which occurs even when the environment and behavior remain unchanged. CA3 input to CA1 has been shown to exert a key role in triggering synaptic plasticity in place-encoding CA1 cells -- a phenomenon which could provide the cellular foundations for the remapping of the hippocampal code for space. However, how CA3 input directly contributes to place field formation and remapping of the place code in CA1 remains incompletely understood. By combining longitudinal two-photon calcium imaging of CA1 place cells with optogenetic stimulation of presynaptic CA3 neurons in mice running on a linear treadmill, we demonstrate that CA3 transiently modulates the code for allocentric space in CA1. Activation of CA3 cells both induced a small pool of new CA1 place cells and altered the pre-existing CA1 place code. The latter occurred through an unbiased shift of existing place fields specifically, and not through modifications of place field precision or a loss of place tuning in pre-existing place cells. All CA3-driven changes in the CA1 place code were transient and almost completely disappeared by the next day. Taken together, stimulation of CA3 input to CA1 cells alters CA1-encoded spatial representations, leading to a transient decrease in place field precision rather than an overrepresentation of the stimulation zone. HIGHLIGHTSO_LIOptogenetic CA3 stimulation with two-photon CA1 imaging in behaving mice C_LIO_LIStimulation of CA3 input induces a small pool of new CA1 place cells C_LIO_LIPre-existing CA1 place fields shift without loss of tuning or precision C_LIO_LICA3-driven remapping is unbiased in space and largely disappears by next day C_LI

neuroscience↗

bioRxiv2024

Disruption of consciousness depends on insight in OCD and on positive symptoms in schizophrenia

Disruption of conscious access contributes to the advent of psychotic symptoms in schizophrenia but could also explain lack of insight in other psychiatric disorders. In this study, we explored how insight and psychotic symptoms related to disruption of consciousness. We explored consciousness in patients with schizophrenia, patients with obsessive-compulsive disorder (OCD) with good vs. poor insight and matched controls. Participants underwent clinical assessments and performed a visual masking task allowing us to measure individual consciousness threshold. We used a principal component analysis to reduce symptom dimensionality and explored how consciousness measures related to symptomatology. We found that clinical dimensions could be well summarized by a restricted set of principal components which also correlated with the extent of consciousness disruption. More specifically, positive symptoms were associated with impaired conscious access in patients with schizophrenia whereas the level of insight delineated two subtypes of OCD patients, those with poor insight who had consciousness impairments similar to patients with schizophrenia, and those with good insight who resemble healthy controls. Our study provides new insights about consciousness disruption in psychiatric disorders, showing that it relates to positive symptoms in schizophrenia and with insight in OCD. In OCD, it revealed a distinct subgroup sharing neuropathological features with schizophrenia. Our findings refine the mapping between symptoms and cognition, paving the way for a better treatment selection.

neuroscience↗

bioRxiv2022

Impact of galvanic vestibular stimulation electrode current density on brain current flow patterns: Does electrode size matter?

BackgroundGalvanic vestibular stimulation (GVS) uses at least one electrode placed on the mastoid process with one or multiple placed over other head areas to stimulate the vestibular system. The exact electrode size used is not given much importance in the literature and has not been reported in several studies. In a previous study, we compared the clinical effects of using different electrode sizes (3 cm2 and 35 cm2) with placebo but with the same injected current, on postural control. We observed significant improvement using the smaller size electrode but not with the bigger size electrode. The goal of this study was to simulate the current flow patterns with the intent to shed light and potentially explain the experimental outcome. MethodsWe used an ultra-high-resolution structural dataset and developed a model to simulate the application of different electrode sizes. We considered current flow in the brain and in the vestibular labyrinth. ResultsOur simulation results verified the focality increase using smaller electrodes that we postulated as the main reason for our clinical effect. The use of smaller size electrodes in combination with the montage employed also result in higher induced electric field (E-field) in the brain. ConclusionsElectrode size and related current density is a critical parameter to characterize any GVS administration as the choice impacts the induced E-field. It is evident that the higher induced E-field likely contributed to the clinical outcome reported in our prior study.

bioengineering↗

bioRxiv2022

Targeting Noradrenergic Neurons of the Locus Coeruleus: A Comparison of Model Systems and Strategies

The locus coeruleus (LC) norepinephrine (NE) system is involved in a variety of physiological and pathophysiological processes. Refining our understanding of LC function largely relies on selective transgene expression in LC-NE neurons, allowing targeted manipulation and readout of noradrenergic neurons. Here, we performed a side-by-side comparison of the most commonly used strategies to genetically target the LC, including different cre driver lines and promoter-mediated transgene expression. We report differences between these strategies in terms of transgene expression efficacy and specificity. Parallelly, we found no behavioral alterations in cre-expressing mice of any mouse line compared to wild-type littermates. Finally, to further facilitate the investigation of LC-NE function, we created a suite of constructs, including a reporter protein, a calcium indicator, and a light-driven cation channel, whose expression is mediated by the previously described PRSx8 promoter. These constructs allow identification, monitoring, and manipulation of LC-NE activity either in wild-type mice, or in combination with tissue-specific manipulations of different cre driver lines. The results of our study are crucial for the interpretation of previous experiments using the respective targeting strategies, as well as for the design of future studies. BlurbThis study reports substantial heterogeneity in transgene expression patterns when using different strategies to virally transduce noradrenergic neurons of the locus coeruleus, highlighting the need to carefully validate each experimental approach in order to avoid misinterpretations when studying locus coeruleus function. Highlights- Heterogeneous expression patterns with different targeting strategies for LC-NE neurons - Substantial ectopic transgene expression observed in some approaches - No behavioral alterations in heterozygous cre mice as compared to wild-types - PRSx8-driven reporters, indicators and actuators as a resource to investigate LC function

neuroscience↗

bioRxiv2020

Rational arbitration between statistics and rules in human sequence learning

Detecting and learning temporal regularities is essential to accurately predict the future. A long-standing debate in cognitive science concerns the existence of a dissociation, in humans, between two systems, one for handling statistical regularities governing the probabilities of individual items and their transitions, and another for handling deterministic rules. Here, to address this issue, we used finger tracking to continuously monitor the online build-up of evidence, confidence, false alarms and changes-of-mind during sequence processing. All these aspects of behaviour conformed tightly to a hierarchical Bayesian inference model with distinct hypothesis spaces for statistics and rules, yet linked by a single probabilistic currency. Alternative models based either on a single statistical mechanism or on two non-commensurable systems were rejected. Our results indicate that a hierarchical Bayesian inference mechanism, capable of operating over distinct hypothesis spaces for statistics and rules, underlies the human capability for sequence processing.

neuroscience↗

bioRxiv2017

Impaired conscious access and abnormal attentional amplification in schizophrenia

Previous research suggests that the conscious perception of a masked stimulus is impaired in schizophrenia, while unconscious bottom-up processing of the same stimulus, as assessed by subliminal priming, can be preserved. Here, we test this postulated dissociation between intact bottom-up and impaired top-down processing and evaluate its brain mechanisms using high-density recordings of event-related potentials. Sixteen patients with schizophrenia and sixteen controls were exposed to peripheral digits with various degrees of visibility, under conditions of either focused attention or distraction by another task. In the distraction condition, the brain activity evoked by masked digits was drastically reduced in both groups, but early bottom-up visual activation could still be detected and did not differ between patients and controls. By contrast, under focused top-down attention, a major impairment was observed: in patients, contrary to controls, the late non-linear ignition associated with the P3 component was reduced. Interestingly, the patients showed an essentially normal attentional amplification of the PI and N2 components. These results suggest that some but not all top-down attentional amplification processes are impaired in schizophrenia, while bottom-up processing seems to be preserved.

neuroscience↗