Thèse Influence de l'Origine Temporelle sur la Plasticité et les Fonctions des Neurones Granulaires du Gyrus Denté H/F - 33

Établissement : Université de Bordeaux
École doctorale : Sciences de la Vie et de la Santé
Laboratoire de recherche : Neurocentre Magendie
Direction de la thèse : Emilie PACARY ORCID 0000000273164546
Début de la thèse : 2026-10-01
Date limite de candidature : 2026-05-20T23:59:59

Le gyrus denté (DG) constitue une porte d'entrée essentielle de l'hippocampe, impliquée dans le traitement de la mémoire et la régulation émotionnelle, et se distingue par une neurogenèse qui se poursuit tout au long de la vie. Plus précisément, les neurones granulaires du gyrus denté (DGNs), principal type cellulaire du DG, sont produits de la fin de l'embryogenèse jusqu'à l'âge adulte. Cette période prolongée de neurogenèse soulève des questions fondamentales concernant les rôles fonctionnels des DGNs générés à différents stades de la vie.
Bien que les DGNs nés à l'âge adulte aient été largement étudiés, les DGNs nés au cours du développement - qui constituent la majorité des DGNs dans le DG adulte - restent encore mal caractérisés. Ces populations temporellement distinctes ont généralement été considérées comme anatomiquement et fonctionnellement équivalentes une fois matures. Cependant, nos travaux récents remettent en cause cette hypothèse en montrant que les DGNs nés précocement présentent des architectures dendritiques et axonales distinctes.
S'appuyant sur ces résultats, ce projet vise à déterminer comment des populations temporellement distinctes de DGNs matures contribuent à la plasticité et aux fonctions hippocampiques. Dans un premier temps, nous évaluerons si les DGNs générés au cours de l'embryogenèse, de la période néonatale, de l'adolescence ou de l'âge adulte présentent une plasticité morphologique comparable en réponse à une activité physique volontaire, et s'ils sont différemment affectés par un stress induit par un isolement social pendant l'adolescence. Dans un second temps, nous étudierons la contribution de ces populations aux comportements dépendants du gyrus denté, notamment la détection de la nouveauté, le comportement social, l'anxiété, la flexibilité cognitive et la discrimination mnésique (séparation des patrons).
En s'appuyant sur des approches de pointe, ce travail fera progresser la compréhension de la fonction hippocampique en révélant comment la date de naissance des neurones dans le gyrus denté façonne les circuits neuronaux et le comportement.

The dentate gyrus (DG) serves as the main gateway to the hippocampus, a brain region essential for memory processing and emotional regulation. Unlike other hippocampal subfields (CA1-CA3), where neurogenesis is restricted to embryonic development, the DG generates dentate granule neurons (DGNs) from late embryonic stages through adulthood. This prolonged neurogenesis raises fundamental questions about the functional roles of DGNs born at different life stages.
In CA1 and CA3, the temporal origin of principal neurons critically determines their laminar position, connectivity, and function (Cavalieri et al., eLife 2021; Kveim et al., Science 2024). By contrast, the influence of temporal origin on DGN properties remains poorly understood. While adult-born DGNs (Adu-DGNs) have been extensively studied, developmentally born DGNs (Dev-DGNs)-which constitute the majority of DGNs in the adult DG-have received far less attention, particularly those generated during embryogenesis. Despite this limited characterization, it is generally assumed that Adu-DGNs, once mature, are functionally and morphologically indistinguishable from DGNs generated during earlier developmental stages (Laplagne et al., Plos Biol 2006; Laplagne et al., Eur J of Neuroscience 2007).
Challenging this view, we have recently demonstrated that early-born DGNs, particularly those generated during embryogenesis, exhibit distinct anatomical characteristics at both dendritic and axonal levels compared to adult-born DGNs (Kerloch et al., Cereb Cortex, 2019; Mortessagne et al., unpublished). These findings underscore the need to determine how DGNs generated within specific developmental windows differentially contribute to hippocampal function.
Building on these observations, we aim to use multiscale analyses to investigate how mature DGNs generated during embryonic, postnatal, adolescent, and adult stages contribute to hippocampal physiology, function, and dysfunction. This work will provide critical insights into the role of DGN subpopulations in normal hippocampal function and may serve as a foundation for understanding their involvement in various brain disorders.

The first objective is to determine whether temporally distinct populations of mature DGNs-including those generated during embryogenesis, the early postnatal period, adolescence, or adulthood-exhibit comparable levels of experience-dependent plasticity (e.g., in response to running) and are differentially affected by stress exposure (e.g., social deprivation during adolescence). The second objective is to determine how these different populations contribute to behaviours in which the dentate gyrus has been implicated, including memory-related processes and the regulation of emotion and social behaviour.

This study will be conducted in mice and we will combine multiple technical approaches.
To tag the different DGNs populations, we will use two main approaches depending on the number of cells to be targeted. For sparse labeling, we will use, as previously described (Kerloch et al., Cereb Cortex 2018), in vivo electroporation to label DGNs generated in mouse embryos (E14.5) or in neonates (P0) and a Moloney murine leukemia virus (MMuLV)-derived retroviral vector to label adolescent (P21) and adult-born (P84) DGNs. To tag larger cohorts of DGNs, we will use transgenic mouse lines: the Osteocalcin-Cre (Ocn-Cre) mouse line to tag DGNs born during embryogenesis and early postnatal life (Sun et al., Biological Psychiatry 2021), and the Ascl1CreERT2 line to label large cohorts of adolescent- and adult-born-DGNs (Yang et al., J Neurosci 2015).
Following tagging, the morphological plasticity of each DGN population will be assessed at 6 months of age, either after three weeks of voluntary wheel running prior to sacrifice or following two weeks of social deprivation during adolescence (P21-P35). Dendritic and axonal morphologies will be analyzed using Neurolucida software.
We will then investigate whether these distinct DGN populations are activated during dentate gyrus-dependent behaviors, including novelty detection, social behavior, anxiety, cognitive flexibility, simple contextual discrimination, and complex memory discrimination (pattern separation). Neuronal activity will be assessed using immediate early gene-based approaches and/or fiber photometry while animals perform specific behavioral tasks.
To determine whether activated populations causally contribute to these behaviors, we will employ a loss-of-function approach based on DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in combination with the transgenic mouse lines described above. Mice will receive bilateral injections of an AAV allowing Cre-dependent expression of an inhibitory DREADD together with mCherry, or a control virus expressing mCherry alone. As an initial screening, one behavioral test per functional dimension will be used: exposure to a novel environment (novelty detection), direct social interaction (social behavior), the elevated plus maze (anxiety), the Morris water maze (cognitive flexibility), and fear conditioning to assess contextual discrimination under low and high pattern separation demands. If inhibition of a specific DGN population alters a given behavior, additional behavioral assays will be implemented to further characterize its functional role.