Equipe Marighetto

Pathophysiology of declarative memory

Principal investigator: Aline Marighetto, MD, PhD.


The objective of our research is to identify the psychobiological bases of memory degradation related to aging or post-traumatic stress. For this purpose, we first needed to develop satisfactory animal models because the memory affected by aging or post-traumatic stress is called declarative memory (MD), i.e. a typically human form of memory. As we age, MD declines, whereas in post-traumatic stress disorder we observe a paradoxical memory alteration profile in which the degradation of declarative memory goes hand in hand with a reinforcement of the non-reporting expression of the traumatic event. As a result, we are developing two main areas of research: one on the decline of declarative memory during aging, and the other on the alterations of memories associated with stress. Each of our research axes is based on a specific behavioural model in mice.



With regard to aging, we established a model of preferential degradation of MD in elderly mice based on the flexibility characteristic of this form of memory (Etchamendy et al., 2003a; Marighetto et al., 1999; Mingaud et al., 2007; Touzani et al., 2003), then tested this model in humans (Etchamendy et al, in press) (Figure 1).


Using this mouse model, we have recently identified a specific psychological deficit in the encoding phase of MD, and a neurobiological correlate of this deficit in the activity of memory systems. Specifically, the MD deficit is secondary to a deterioration in the relational processing of information whereby temporally distant events are linked to each other at the time of learning. This degradation is associated with decreased activation of the CA1 field of the hippocampus through learning, with activation measured by expression of the Fos protein (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). We have also identified pharmacological and nutritional factors (including retinoic acid and vitamin A) that can restore and prevent these deteriorations (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 now has two main objectives: 1) to identify the molecular and cellular mechanisms that, during aging, are responsible for the temporal binding deficit in the encoding of MD, and to study the potential influence of estrogens on these mechanisms. 2) Continue the translational approach to assess the predictive value of our mouse model to understand the degradation of human declarative memory in aging. Regarding the memory of a stressful event, we have established the first behavioural model that evaluates qualitative traits that distinguish between a normal/adapted fear memory, and a pathological/inadequate fear memory, characteristic of post-traumatic stress disorder. Precisely, an adapted fear memory is preferentially oriented towards the most predictive stimulus of the traumatic event, whereas in post-traumatic stress disorder, memory is inadequate in the sense that it is focused on an elementary and irrelevant aspect of the trauma, and that it is "decontextualized", i.e. very little associated with the specific context of the traumatic event (Figure 2).



Using this model we have shown that, during the acquisition of fear conditioning, the functional coordination of declarative and non-declarative memory systems, based respectively on the hippocampus and the amygdala, is essential for the formation of normal fear memory. An alteration in this coordination could therefore be involved in the formation of pathological memory such as that observed in post-traumatic stress disorder (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 this basis, we will now try to identify the factors likely to induce the formation of a memory of fear characteristic of post-traumatic stress. In particular, we will study the characteristics of stress (i.e. its intensity and degree of "uncontrollability" by the subject undergoing it) and factors of individual vulnerability. Once the conditions that induce traumatic memories are identified, we will study the underlying mechanisms by analyzing the activities of memory systems and their interactions. By continuing our integrative approach, linking intracellular markers of activity and plasticity to the functioning of memory systems, we hope to help develop new therapeutic and preventive strategies for memory impairment caused by aging and post-traumatic stress.



Team members



Aline MARIGHETTO
Team leader
Catherine BENNETAU
Teacher-Researcher
Aline DESMEDT
Teacher-Researcher
Nicole ETCHAMENDY
Teacher-Researcher
Valérie LAMOTHE
ITA
Mylène POTIER
ITA
Christopher STEVENS
PhD