Interactions hippocampo-corticales sous-tendant la mémoire épisodique

À la fin des années 50, les premières descriptions d’amnésie antérograde chez le patient H.M. ont mis en évidence le rôle crucial de l’hippocampe dans la mémoire, et plus précisément dans la mémoire déclarative, regroupant la mémoire épisodique (souvenirs personnels : ce qui s’est passé [’quoi’], son contexte spatial [’où’] et son contexte temporel [’quand’]), et la mémoire sémantique (connaissances générales). Afin d’étudier les bases neurales sous-tendant la mémoire, des études pionnières ont été menées sur des modèles de rongeurs. Ces études ont établi que l’hippocampe forme la base neurale d’une carte cognitive de l’environnement. Des travaux ultérieurs ont progressivement décortiqué l’organisation et la dynamique du réseau hippocampique. Lorsqu’un rat explore son environnement, des séquences rapides de cellules de lieu (d’une durée de #100 ms) représentant la trajectoire en cours et anticipant les choix futurs déchargent dans l’hippocampe. Ces séquences se forment au sein d’un unique cycle du rythme thêta (oscillation caractéristique de 8 Hz), d’où leur appellation «séquences thêta». Pendant les périodes de pause et le sommeil survenant immédiatement après l’exploration, des séquences similaires rejouent spontanément les mêmes trajectoires au cours de ripples (oscillations transitoires 200 Hz), comme si le rat «rêvait» de son expérience passée. Ces séquences rapides permettent aux neurones de décharger successivement dans des fenêtres de temps très courtes, optimales pour modifier les connexions synaptiques entre eux et former une trace mnésique persistante. En effet, la perturbation expérimentale de ces séquences thêta ou des ripples entraîne des déficits dans l’encodage, la consolidation de la mémoire ainsi que la planification. C’est donc cette fine organisation temporelle qui sous-tend les processus mnésiques, plutôt que l’activation lente des neurones à l’échelle de temps comportementale. L’hippocampe code donc à la fois l’espace et le temps, deux des trois composantes de la mémoire épisodique (’où’ et ’quand’). Qu’en est-il de la troisième composante (’quoi’) ? La preuve que certaines informations non spatiales sont encodées dans l’hippocampe est bien étayée par des décennies de travaux. Il a été rapporté que les neurones hippocampiques s’activent en réponse à des stimuli visuels, tactiles, olfactifs et auditifs dans un large éventail de conditions expérimentales et peuvent également représenter le temps, la récompense et les interactions sociales. L’activation successive des neurones hippocampiques codant ces informations non spatiales permet la formation de séquences ordonnées à une échelle de temps relativement longue correspondant à l’activité comportementale de l’animal. Elle ne permet donc pas la mise en place des mécanismes de plasticité nécessaires à la formation d’un souvenir persistant, lequel requiert au contraire une échelle de temps plus rapide (de l’ordre de dizaines de millisecondes) correspondant aux séquences thêta et aux ripples. Le but de mon projet est de mieux comprendre l’intégration des informations non spatiales dans les séquences hippocampiques à une échelle de temps rapide, pendant les ondulations de l’éveil et du sommeil, ainsi que pendant le rythme thêta. Nous avons enregistré des neurones dans l’hippocampe CA1 dorsal de rats effectuant une tâche comportementale comprenant des stimuli séquentiels spatiaux et non spatiaux. Les rats devaient apprendre à dissocier deux séquences composées de trois textures, ABC vs CBA, afin de faire un choix (tourner à droite ou à gauche) sur un labyrinthe en forme de huit numérique.In the late 50’s, the first descriptions of anterograde amnesia in patient H.M. have highlighted the crucial role of the hippocampus in memory, and more specifically in declarative memory, i.e. episodic memory (personal memories: what happened [‘what’], its spatial context [‘where’] and its temporal context [‘when’]), and semantic memory (general knowledge). To investigate the neural bases of hippocampal function, pioneering studies have been carried out in rodent models. These studies have established that the hippocampus forms the neural basis of a cognitive map of the environment. Subsequent work has progressively revealed a much more dynamic organization of hippocampal activity. As a rat explores its environment, the hippocampus continuously emits fast sequences of place cells (lasting 100 ms) that represent the ongoing trajectory and anticipate future choices. These sequences occur during single cycles of the ongoing theta rhythm (a prominent 8 Hz oscillation) and are thus called ‘theta sequences’. During subsequent pauses and sleep, similar sequences spontaneously replay the same trajectories during ripples (transient 200 Hz oscillations), as if the rat were ‘dreaming’ of its previous experience. Critical function of fast sequences is to ensure that neurons fire within the very short time windows that are optimal to modify synaptic connections and store memory traces. Indeed, experimental perturbation of theta and ripple sequences results in deficits in memory encoding, consolidation, and planning. Thus, it is this fine timescale organization that underlies memory processes, rather than the slow activation of neurons at the behavioural timescale. It has thus become clear that hippocampal activity encodes both space and time, two of the three components of episodic memory (‘where’ and ‘when’). How about the third (‘what’) component? The evidence that some non-spatial information is encoded within hippocampal firing patterns is well supported by decades of works. Hippocampal neurons have been reported to fire associated with visual, tactile, olfactory, and auditory cues in a broad range of learning and memory paradigms and to encode time, goal and even social interaction. The successive activation of hippocampal neurons allow the formation of ordered sequences, but on a relatively long time scale which corresponds to the behavioural activity of the animal and do not permit the plasticity mechanisms allowing the formation of a persistent memory trace, which instead require the much faster time scales (dozens of milliseconds) of theta and ripple sequences. The aim of my project is to better understand the integration of non-spatial information in hippocampal sequences at fast timescale, during the ripples of wakefulness and sleep, as well as during the theta rhythm. We recorded neurons in dorsal CA1 while rats performed a behavioural task including spatial as well as non spatial sequential stimuli. Rats have to dissociate two sequences of three textures, ABC vs CBA, to make a choice (turn right or left) on a eight-shaped maze. We found an great proportion of place cells with place fields near textures, as well as a significant number of cells with several place fields located at the location of different textures. We now want to study these cells more specifically in order to confirm that their activity is modulated by a non-spatial component (the textures) and then to see how these integrate into the spatial representation carried by classical place cells

Antidepressive effects of targeting ELK-1 signal transduction

Depression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement1. In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted2,3,4. The extracellular signal–regulated kinase (ERK) pathway is implicated in mood regulation5,6,7, but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner8, as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1.Medicin

Antidepressive effects of targeting ELK-1 signal transduction

International audienceDepression, a devastating psychiatric disorder, is a leading cause of disability worldwide. Current antidepressants address specific symptoms of the disease, but there is vast room for improvement 1 . In this respect, new compounds that act beyond classical antidepressants to target signal transduction pathways governing synaptic plasticity and cellular resilience are highly warranted2-4. The extracellular signal-regulated kinase (ERK) pathway is implicated in mood regulation5-7, but its pleiotropic functions and lack of target specificity prohibit optimal drug development. Here, we identified the transcription factor ELK-1, an ERK downstream partner 8 , as a specific signaling module in the pathophysiology and treatment of depression that can be targeted independently of ERK. ELK1 mRNA was upregulated in postmortem hippocampal tissues from depressed suicides; in blood samples from depressed individuals, failure to reduce ELK1 expression was associated with resistance to treatment. In mice, hippocampal ELK-1 overexpression per se produced depressive behaviors; conversely, the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states induced by stress. Our work stresses the importance of target selectivity for a successful approach for signal-transduction-based antidepressants, singles out ELK-1 as a depression-relevant transducer downstream of ERK and brings proof-of-concept evidence for the druggability of ELK-1

Antidepressive effects of targeting ELK-1 signal transduction

International audienceDepression, a devastating psychiatric disorder, is a leadingcause of disability worldwide. Current antidepressants addressspecific symptoms of the disease, but there is vast roomfor improvement1. In this respect, new compounds that actbeyond classical antidepressants to target signal transductionpathways governing synaptic plasticity and cellular resilienceare highly warranted2–4. The extracellular signal–regulatedkinase (ERK) pathway is implicated in mood regulation5–7, butits pleiotropic functions and lack of target specificity prohibitoptimal drug development. Here, we identified the transcriptionfactor ELK-1, an ERK downstream partner8, as a specificsignaling module in the pathophysiology and treatment ofdepression that can be targeted independently of ERK. ELK1mRNA was upregulated in postmortem hippocampal tissuesfrom depressed suicides; in blood samples from depressedindividuals, failure to reduce ELK1 expression was associatedwith resistance to treatment. In mice, hippocampal ELK-1 overexpressionper se produced depressive behaviors; conversely,the selective inhibition of ELK-1 activation prevented depression-like molecular, plasticity and behavioral states inducedby stress. Our work stresses the importance of target selectivityfor a successful approach for signal-transduction-basedantidepressants, singles out ELK-1 as a depression-relevanttransducer downstream of ERK and brings proof-of-conceptevidence for the druggability of ELK-1