PTSD-like memory: neural system dysfunction and underlying molecular alteration – PTSDMEMO
Neurobiological bases of traumatic memory: risk and prevention factors
An intense stress can lead to the development of a normal fear memory or traumatic memory. Consequently, the challenge of this project is the identification of the psycho-neurobiological factors that will promote, or on the contrary prevent, the development of traumatic memory after a stressful situation.
Identification of neurobiological markers of PTSD-related memory
While for 50 years neuro-psychological studies have significantly contributed to the definition of a precise clinical picture of this disorder, the neurobiological bases of PTSD are poorly understood challenging the development of innovative treatments. A main reason for such situation is the lack, so far, of relevant animal models for PTSD-related memory: most current models do not distinguish between “normal”-adaptive and “traumatic”-maladaptive fear memory. Our team has recently developed a model for PTSD-related memory in mice that precisely allows the direct comparison between “normal” and traumatic (i.e. “PTSD-like”) memory (Kaouane et al., Science, 2012). Using this model, a major issue can now be solved: within a stressful situation which brain alterations contribute to, or on the contrary prevent, the development of traumatic memory? Combining the behavioural, system, cellular and molecular levels of analysis, our multidisciplinary project will identify the neurobiological markers of PTSD-related memory. By distinguishing these specific alterations from those underlying the development of a normal fear memory, this project should open new and especially relevant therapeutic avenues.
-Our behavioural model is based on classical fear conditioning: while a normal fear memory is formed by the association of a stressful episode with a context, the development of a PTSD-like memory is induced by the combination of the same stressful episode and a corticosterone injection (main stress hormone) that mimics a traumatic stress. Consequently, while a «normal« subject displays a fear reaction when re-exposed to the aversive context, a «PTSD« subject displays a amnesia for that context associated with a fear reaction to a salient but irrelevant stimulus.
-Our immunohistochemical approaches allow us the evaluation of both the levels of activation within the brain structures known to be involved in PTSD (ex: amygdala, hippocampus), and some altered epigenetic mechanisms which are suspected to be specifically associated with PTSD.
-Our neuropharmacological approaches allow the manipulation of some protein levels which are suspected to be involved in PTSD. These approaches thus allow the assessment of causal relationship between changes in these proteins levels and the development of normal vs. PTSD-like fear memory.
-Our (i) cellular and (ii) molecular analyses allow the identification of (i) putative neuromorphological alterations associated with PTSD-like memory and (ii) some possible dysfunction in signaling pathways involved in neuronal plasticity.
-At the systemic level, our studies have already shown that the switch from normal to PTSD-like memory in mice is associated with amygdalar hyperactivation and hippocampal hypoactivation. We are currently testing the hypothesis that dysfunction in the hippocampo-amygdalar interaction would contribute to the development of such pathological memory as well.
-At the cellular level, we showed that compared to normal fear memory, PTSD-like memory is associated with an impaired dendritic complexity in certain hippocampal neurons. Such altered neuromorphology could contribute to the contextual amnesia observed in PTSD. Current studies will tell us whether PTSD-like memory may be associated with altered neuromorphology in the amygdala.
-At the molecular level, our work has shown that (i) compared to normal fear memory, PTSD-like memory is associated with a downregulation of certain signaling pathways involved in neuronal plasticity in the hippocampus. we are currently assessing whether blocking and stimulating this molecular signaling pathway may promote and prevent, respectively, the development of PTSD-like memory in stressful conditions. Finally, compared to normal fear memory, PTSD-like memory is associated with altered epigenetic changes which might underlie the hippocampal hypoactivation and amygdalar hyperactivation observed in PTSD patients. We are now assessing to what extent the pharmacological manipulation of these epigenetic mechanisms may constrain the expression of plasticity-related genes and thereby promote, or on the contrary prevent, the development of the PTSD-like memory.
The identification of neurobiological alterations specific to PTSD-like memory, which are by definition different from those underlying the formation of normal fear memory, allow the identification of specific brain targets opening new and relevant therapeutic avenues. In a more general view, the systematic comparison between stressful situations leading to either normal or PTSD-like fear memory will allow the identification of the key mechanisms underlying the switch from stress-induced normal to pathological states. The neurobiological bases of such contrasted effects of stress are so far largely unknown.
So far, the different research axes of the project (systemic, cellular and molecular) initiated in parallel have been the object of 8 communications as posters in national (2) and international (3) neuroscience meetings, as well as 6 oral communications including 5 invited communications in national (2) and international (4) meetings.
In addition, the key ideas developed in the project have been the object of 4 publications in 2015 including 2 reviews and 2 papers for general public: Desmedt et al., Biological Psychiatry, 2015 ; Stress, 2015 ; Desmedt, La recherche, N°497 ; The conversation (France), 17 novembre 2015.
Post-traumatic stress disorder (PTSD) is developed by 25 to 50 % of subjects exposed to extreme stressful situations. A cardinal feature of PTSD is a paradoxical pattern of memory with hypermnesia for salient traumatic cues not predicting the trauma and amnesia for peritraumatic contextual cues. The neurobiological bases of this memory impairment are poorly understood due to the lack, so far, of relevant animal models for PTSD-related memory.
Recently, we precisely developed a model for this paradoxical memory in mice. The combination of a high stressful situation and corticosterone injections produces a memory deficit for traumatic contextual cues associated with the induction of a maladaptive fear response (hypermnesia) to a salient trauma-related cue but not predicting the trauma (e.g. a tone). On this basis, the main objective of the present project is the identification of the neurobiological bases of this traumatic memory and, in particular, the risk and prevention factors of this pathology at the system, cellular and molecular levels.
First, at the system level (i), as dysfunction in the hippocampal-amygdalar network is suspected to be a crucial etiologic factor of PTSD, we will characterize the functional hippocampal-amygdalar interactions in stressed animals with and without PTSD-like memory impairment. In addition, as hippocampal impairment is associated with PTSD, we will determine to what extent an impaired hippocampal function may constitute a risk factor for the development of PTSD-like memory. Second, at the cellular level (ii), on the basis of data indicating functional/structural hippocampal alterations after intense stress, we will determine to what extent alterations in the hippocampal neo-neurogenesis, neuromorphology and synaptic plasticity may be specifically associated with, and contribute to, PTSD-like memory. Third, at the molecular level (iii), as the MAPK and BDNF/TrkB signaling pathways are critically involved in the formation of normal fear memory, we will determine to what extent these molecular devices may play key roles in the development, prevention and/or treatment of PTSD-like memory. Finally, as normal fear memory involves epigenetic changes, partly mediated by histone post-translational modifications within the hippocampus-amygdalar network, we will test the hypothesis that a switch from normal to PTSD-like memory might involve a deregulated balance of histone acetylation/methylation, underlying the PTSD-related impaired neuronal plasticity in the hippocampal-amygdalar network. Hence, identifying cellular and molecular biomarkers of PTSD-related memory, this project should unveil relevant therapeutic targets promoting the treatment of this psychiatric stress-related disorder.
Madame Aline Desmedt (Physiopathology of declarative memory, INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
INSERM U862 Neurogénèse et physiopathologie, Neurocentre Magendie, INSERM U862
INSERM U862 Physiopathologie de l'addiction, Neurocentre Magendie, INSERM U862
INSERM U862 Physiopathology of declarative memory, INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
WIS, Israel Weizmann Institute of Science, Israel
INCIA, CNRS UMR 5287 Institut des neurosciences cognitives et intégratives d'Aquitaine, CNRS UMR 5287
Help of the ANR 355,992 euros
Beginning and duration of the scientific project: September 2014 - 48 Months