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Fortoul, A.

Publications and source records attributed to Fortoul, A..

5 recordsLinked to original sources

The Towers Foraging Park: A Flexible Naturalistic Framework to Study Learning, Decision-Making, and Motor Control in Freely Moving Mice

Adaptive behavior depends on a variety of brain functions, such as learning, decision-making, spatial navigation and motor control, which have been studied using two main strategies. Trial-based tasks allow their mechanistic dissection but tend to generate highly stereotypical behavior, whereas open-field investigations capture naturalistic dynamics with less experimental control. To leverage the strengths of both approaches, we developed a behavioral framework which recreates dilemmas faced by animals during patch foraging. In the Tower Foraging Park (TFP), mice harvest rewards along square towers (patches) by making quarter-turns around them in a single direction (exploit) and alternating between towers (explore) as patches eventually deplete. Within a couple of sessions, naive mice performed quarter-turns in the rewarded direction with increasing vigor and reduced variability, and switched towers after short exploitation bouts. When the harvest direction was reversed, mice rapidly adapted their turning direction, with quarter-turn trajectory variability and speed becoming decoupled. Mice subjected to daily reversals adapted progressively faster, revealing meta-learning. When the next rewarding tower became harder to locate, all trained mice increased exploitation duration, although metalearners outperformed animals trained under stable contingencies. Altogether, the TFP produced behavior consistent with foraging theory and revealed new processes facilitating flexible foraging: meta-learning and the decoupling of movement variability and speed. Moreover, because the TFP accommodates diverse protocol variants, adheres to FAIR principles, and is fully compatible with modern neurophysiological techniques, it provides a promising platform for mechanistic investigations of brain functions underlying adaptive behavior while maintaining ethological validity.

animal behavior and cognition↗

Emergence of neocortical function in heterotopic neurons

Brains come in various sizes and shapes, yet how neuronal position constrains the type of circuits that they can form remains largely unknown. The spatial layout of anatomical structures with corresponding functions varies widely across species (J-4). Also, during evolution, anatomical structures have duplicated and then diverged to generate new circuits and functions (5, 6). Thus, it is critical to understand how the position of neurons constrains their integration into circuits and, ultimately, their function. To address this question, we studied EmlJ knockout mice in which subsets of neocortical neurons form a new structure below the neocortex termed heterotopia (Ht). We examined how this new location affects the molecular identity, topography, input-output circuit connectivity, electrophysiology, and functional properties of these neurons. Our results reveal a striking conservation of the cellular features and circuit properties of Ht neurons, despite their abnormal location and misorientation. Supporting this observation, these neurons were able to functionally substitute for overlying neocortical neurons in a behaviorally relevant task when the latter were optogenetically silenced. Hence, specific neuronal identities and associated function can be reproduced in altered anatomical settings, revealing a remarkable level of self-organization and adaptability of neocortical circuits.

neuroscience↗

Distinct subtypes of grey matter heterotopia show subtype-specific morpho-electric neuronal properties and dynamics of epileptiform activity in mice

Grey matter heterotopia (GMH) are neurodevelopmental disorders associated with abnormal cortical function and epilepsy. Subcortical band heterotopia (SBH) and periventricular nodular heterotopia (PVNH) are two well-recognized GMH subtypes in which neurons are misplaced, either forming nodules lining the ventricles in PVNH, or forming bands in the white matter in SBH. Although both PVNH and SBH are commonly associated with epilepsy, it is unclear whether these two GMH subtypes differ in terms of pathological consequences or, on the contrary, share common altered mechanisms. Here, we studied two robust preclinical models of SBH and PVNH, and performed a systematic comparative assessment of the physiological and morphological diversity of heterotopia neurons, as well as the dynamics of epileptiform activity and input connectivity. We uncovered a complex set of altered properties, including both common and distinct physiological and morphological features across heterotopia subtypes, and associated with specific dynamics of epileptiform activity. Taken together, these results suggest that pro-epileptic circuits in GMH are, at least in part, composed of neurons with distinct, subtype-specific, physiological and morphological properties depending on the heterotopia subtype. Our work supports the notion that GMH represent a complex set of disorders, associating both shared and diverging pathological consequences, and contributing to forming epileptogenic networks with specific properties. A deeper understanding of these properties may help to refine current GMH classification schemes by identifying morpho-electric signatures of GMH subtypes, to potentially inform new treatment strategies.

neuroscience↗

Early suppression of excitability in subcortical band heterotopia modifies epileptogenesis in rats

Malformations of cortical development represent a major cause of epilepsy in childhood. However, the pathological substrate and dynamic changes leading to the development and progression of epilepsy remain unclear. Here, we characterized an etiology-relevant rat model of subcortical band heterotopia (SBH), a diffuse type of cortical malformation associated with drug-resistant seizures in humans. We used longitudinal electrographic recordings to monitor the age-dependent evolution of epileptiform discharges during the course of epileptogenesis in this model. We found both quantitative and qualitative age-related changes in seizures properties and patterns, accompanying a gradual progression towards a fully developed seizure pattern seen in adulthood. We also dissected the relative contribution of the band heterotopia and the overlying cortex to the development and age-dependent progression of epilepsy using timed and spatially targeted manipulation of neuronal excitability. We found that an early suppression of neuronal excitability in SBH slows down epileptogenesis in juvenile rats, whereas epileptogenesis is paradoxically exacerbated when excitability is suppressed in the overlying cortex. However, in rats with active epilepsy, similar manipulations of excitability have no effect on chronic spontaneous seizures. Together, our data support the notion that complex developmental alterations occurring in both the SBH and the overlying cortex concur to creating pathogenic circuits prone to generate seizures. Our study also suggests that early and targeted interventions could potentially influence the course of these altered developmental trajectories, and favorably modify epileptogenesis in malformations of cortical development. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/506850v2_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@32b0deorg.highwire.dtl.DTLVardef@1f9c40dorg.highwire.dtl.DTLVardef@b6348borg.highwire.dtl.DTLVardef@33bb12_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Dynamics of centriole amplification in centrosome-depleted brain multiciliated progenitors

Centrioles are essential microtubule-based organelles organizing cilia and centrosomes. Their mode of biogenesis is semi-conservative: each pre-existing centriole scaffolds the formation of a new one, a process coordinated with the cell cycle. By contrast, multiciliated progenitors with two centrosomal centrioles massively amplify centrioles to support the nucleation of hundred of motile cilia and transport vital fluids. This occurs through cell type-specific organelles called deuterosomes, composed of centrosome-related elements, and is regulated by the cell cycle machinery. Deuterosome-dependent centriole amplification was proposed for decades to occur de novo, i.e. independently from pre-existing centrioles. Challenging this hypothesis, we recently reported an accumulation of procentriole and deuterosome precursors at the centrosomal daughter centriole during centriole amplification in brain multiciliated cells. Here we further investigate the relationship between the centrosome and the dynamic of centriole amplification by (i) characterizing the centrosome behavior during the centriole amplification dynamics and (ii) assessing the dynamics of amplification in centrosome-depleted cells. Surprisingly, although our data strengthen the centrosomal origin of amplified centrioles, we show limited consequences in deuterosome/centriole number when we deplete centrosomal centrioles. Interestingly, in absence of centrosomal centrioles, procentrioles are still amplified sequentially from a single focal region, characterized by microtubule convergence and pericentriolar material (PCM) self-assembly. The relevance of deuterosome association with the daughter centriole as well as the role of the PCM in the focal and sequential genesis of centrioles in absence of centrosomal centrioles are discussed.

cell biology↗