Post-traumatic stress models in rodentspharmacological activation of trkb receptors reverses learning and memory deficits

Résumé

The present work focuses on the development of putative animal models of post-traumatic stress disorder (PTSD) and the effects of a recently characterized agonist of the high affinity BNDF receptor TrkB: 7,8-dyhidroxiflavone (DHF). DHF is a natural flavonoid compound that may prevent some of the long-lasting consequences of stress. PTSD develops in a percent of people exposed to traumatic situations. Only a single exposure can result in development of PTSD. Therefore, appropriate animal models of PTSD should be stressors of high intensity. In this regard, exposure of rats to immobilization on boards (IMO) has been found to be one of the most severe stressor on the basis of all well-characterized biological markers of stress intensity. It was then decided to study how a single exposure to IMO can affect spatial memory in the Morris water maze (MWM). This type of task was chosen because PTSD is characterized by alterations in declarative memory and hippocampal dysfunctions. Spatial memory is an equivalent in rats of declarative memory in humans. A single 2 h exposure to IMO caused impairment of spatial memory in the MWM when the task was started 4 or 10 days after IMO. Interestingly, this impairment was observed in long-term memory (assessed 24 h after the last training session), whereas neither learning nor short-term memory were affected by IMO. Once demonstrated that IMO caused spatial memory impairment, it was studied the effects of DHF given prior to IMO or 8 h after termination of IMO. The latter procedure was chosen to demonstrate that the drug may have therapeutic effects when given shortly after exposure to the stressor. Again IMO rats given vehicle showed impaired long-term memory in the MWM, but drug administration given either before or after IMO blocked the long-lasting negative consequences of IMO. These data not only demonstrate that BDNF-TrkB pathways are important to protect from the negative consequences of a traumatic stressor, but also that potentiation of this pathway after the traumatic situation may block the negative consequences of stress. BND-Trk B pathways is also present in the amygdala, a structure critical for emotional behaviour and particularly for fear conditioning. Exposure to severe stressors has been found to potentiate fear conditioning and, therefore, it was studied how DHF could alter fear conditioning in stress naive and IMO exposed animals. Mice instead of rats were used because of the opportunity they offer to genetic manipulation and characterization of neurobiological processes. It was found that DHF enhanced footshock-induced cue (tone) fear conditioning, but also enhanced extinction. As impaired extinction appears to be a critical feature of PTSD, the role of IMO and DHF on fear extinction was studied. As expected, prior exposure to IMO impaired fear extinction and administration of DHF prior to an extinction session improved extinction in both stress naive and IMO mice. It can be concluded that in mice, a single exposure to IMO also induces long-lasting effects on fear conditioning (delayed extinction), and that DHF improves extinction. Taken together, the present results demonstrate: (a) long-lasting detrimental effects of a single exposure to IMO on spatial memory and cue fear conditioning, which is in accordance with its severity; (b) the critical involvement of BDNF-TrkB pathways in the long-lasting consequences of IMO on spatial memory; and (c) that the recently characterized natural agonist of TrkB, DHF, can have important therapeutic effects in PTSD and other pathologies associated to stress and dysregulation of emotional memory. The present data represent an important contribution to the neurobiology of PTSD and open the way to therapeutic approaches.