Célia BAK – PhD defense

Defense in french

Team : REMEMBeR (Revealing Memory Mechanisms of the Brain) – CRCA-CBI

Supervisors : Cédrick FLORIAN (CRCA-CBI) et Claire RAMPON (CRCA-CBI)

Committee members :

• Anne-Laurence BOUTILLIER – Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA), Strasbourg
• Cyrille VAILLEND – Institut des Neurosciences Paris-Saclay (NeuroPsi), Paris
• Jean-Louis GUILLOU – Institut de Neurosciences Cognitives et Intégratives d’Aquitaine (INCIA), Bordeaux
• Shauna PARKES – Institut de Neurosciences Cognitives et Intégratives d’Aquitaine (INCIA), Bordeaux
• Guillaume ISABEL – Centre de Recherches sur le Cognition Animale (CRCA-CBI), Toulouse

Abstract :

The long term memory is formed through a consolidation process requiring de novo gene transcription, regulated by epigenetic mechanisms. Epigenetic modifications, including histone acetylations that structure chromatin, are added or removed respectively by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The latter are recruited to targeted genes by transcriptional repressor complexes. Although still understudied, the literature shows the involvement of these repressor complexes in the formation of different types of memory, thus highlighting the question of their significant implication in mnemonic processes. Therefore, we chose to study one of these complexes, SIN3A- HDACs, in the context of hippocampus-dependent memory consolidation. Furthermore, numerous studies have investigated the function of HDACs, especially HDACs 1 and 2, in memory processes using genetically modified mice models for these enzymes. However, their role in the memory consolidation phase can only be demonstrated by their punctual inhibition, such as through acute administration of pharmacological HDAC inhibitors. Thus, to test our hypothesis that the SIN3A-HDAC complex participates in long term memory formation, we specifically targeted the two entities of this complex by attempting to establish a SIN3A-depleted mouse model or by specifically inhibiting HDACs 1 and 2 through the administration of Compound 60 (Cpd-60) in the dorsal hippocampus. The first results of this thesis work showed a role for SIN3A, but no effect of the Cpd-60 on the consolidation of contextual memory generated by subjecting adult mice to fear conditioning. The first part of this manuscript therefore presents the different approaches we used to target SIN3A and the effects of Cpd-60 injection at the molecular and behavioral levels. The second part of this thesis work addresses the effect of age on the behavioral and brain response of mice to a looming stimulus, mimicking the rapid approach of a flying predator. Adaptive defensive behaviors are essential for species survival. While these behaviors begin to develop early in an individual’s life, there is still little knowledge about how they evolve in older individuals. Considering that aging is accompanied by a decline in cognitive and physical functions, we hypothesize that innate fear behaviors and underlying brain mechanisms may undergo modifications with age. This work thus examines this hypothesis by observing the reaction of old mice to a threatening visual stimulus compared to young ones. Our results show that aged mice exhibit a different fear response than younger mice when confronted with the looming stimulus. Unlike young mice, old mice tend to adopt a freezing behavior without seeking for a refuge. Interestingly, this altered behavioral response in aged mice is associated with a distinct pattern of brain functional connectivity compared to young mice, with a deficit in cellular activation in key brain structures that regulate innate fear behaviors.