Team 'Pathophysiology of declarative memory ', group leader: Aline Marighetto, MD, PhD.
Aline Desmedt in "Science": Post-traumatic stress and reorganization of the hippocampus-amygdala circuit.
Our research activity is aimed at identifying the psychobiological bases of memory degradation occurring in aging and in post-traumatic stress disorder (PTSD). To achieve our goal, we first needed to develop satisfactory animal models, as the memory form which preferentially degrades in aging and PTSD is declarative memory (DM), i.e. a typically human form of memory. In aging DM declines, whilst in PTSD there is a paradoxical memory profile in which DM degradation is coupled with enhanced non declarative expression of the core traumatic event. Therefore, we develop two main lines of research: one on DM decline in aging and the other on DM alterations in stress-related memories. Each research line is based on a specific behavioral model in mice. Regarding aging, we have established a model of the preferential DM degradation in aged mice based on the characteristic flexibility of DM expression (Etchamendy et al., 2003a; Marighetto et al., 1999; Mingaud et al., 2007; Touzani et al., 2003), and we have translated this model to human subjects (Etchamendy et al, in press) (Figure 1).
Using this mouse model, we have recently identified a specific psychological defect in the encoding phase of DM and a neurobiological correlate of this deficit in memory system activity. Namely, the deficit in DM flexibility seen in aged mice is secondary to a defect in the relational processing of learnt information by which temporally distant events are linked together during learning. This deficit is related to a defect in learning-induced hippocampal CA1 activation (as measured by Fos protein expression). We also have identified pharmacological and nutritional factors (including vitamin A and retinoic acid) that could restore and prevent these impairments(Etchamendy et al., 2003b; Etchamendy et al., 2001; Marighetto et al., 2000; Marighetto et al., 2008a; Marighetto et al., 2008b; Marighetto et al., 2008c; Mingaud et al., 2008). Our research activity has now two principal aims: 1) identifying the critical molecular and cellular mechanisms of the aging-related degradation in temporal binding in DM encoding, and studying the potential influence of estrogens on these mechanisms. 2) Pursuing the translational approach to assess the predictive value of our mouse model in understanding DM degradation in senescence. Regarding stress-related memories, we have established the first behavioral model which assesses qualitative features that permit to distinguish between normal/adaptive memory, and maladaptive fear memory characteristic of PTSD. Namely, adaptive fear memory is adequately related to the best predictor of the aversive event whereas PTSD-like memory is maladaptive in the sense that it is focalized on a simple trauma-related but irrelevant cue, and is not associated to the context of the traumatic event (Figure 2).
By using this model we found that the coordination of the hippocampus-based DM system and amygdala-based non DM system during fear learning could be involved in the appearance of PTSD-like memories (Calandreau et al., ; Calandreau et al., 2005; Calandreau et al., 2007; Desmedt et al., 1998; Desmedt et al., 1999; Trifilieff et al., 2006; Yaniv et al., 2004). On these bases we will now try to identify which factors are able to prompt the shift from adaptive to PTSD-like memories, in particular we will study the characteristics of the stressful conditions (i.e. stress intensity and controllability) and of individual vulnerabilities. Then, once the conditions that induce PTSD-like memories will be identified, we will study the underlying mechanisms by analyzing activities and interactions among memory systems. By continuing our integrative approach, linking intracellular markers of activity and plasticity to memory system function, we expect to help developing new therapeutics and prevention strategies of memory alterations in aging and PTSD.
Composition table of the team
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