Final Report Summary - FEAR AND TRAUMA (Neurobiology of the persistence of traumatic memories)
Although our brains are extremely well prepared to deal with danger, extreme traumatic events (military combat, motor vehicle accidents, physical or sexual assault) can lead to debilitating anxiety disorders, including posttraumatic stress disorder (PTSD), generalised anxiety and depression. Threatening or fearful experiences trigger the activation of the amygdala (a structure of the temporal lobe) that coordinates the automatic physiological (e.g. mobilisation of the energetic resources) and behavioural (e.g. immobilisation or freezing) responses necessary to face the origin of the threat. Normally, the stressful event should cause only transitory changes within the brain. However, under certain conditions, such as in PTSD, more than a third fails to recover even after many years. Imaging studies have reported that these patients exhibit hyperactivation of the amygdala. Anxiety disorders and PTSD affect millions of people worldwide, representing a major public health concern and, therefore, clinical interventions to reduce the long term consequences of psychological trauma are essential. In most persistent anxiety and PTSD cases, fear learning has been described to be resistant to extinction processes and exposure therapies. Recent studies in rats have reported that animals are unable to correctly extinguish fear when extinction processes occur shortly after fear conditioning, whereas fear extinction occurs when the same type of training is applied 24 h post-conditioning. We reasoned that this constitutes a strong model to understand the neurobiological mechanisms whereby traumatic memories are resistant to extinction, as well as to explore potential therapeutic treatments that could foster fear extinction processes.
In this project, we aimed at identifying key neural mechanisms whereby behavioural principles involved in the inefficiency of extinction processes when applied to recent fear memories. We hypothesised a critical involvement of the basolateral amygdala (BLA) under conditions of high emotional distress and studied the implication of the corticotropin releasing factor (CRF) system and glutamatergic receptors. More specifically, using rat as the model system, this project involved the following objectives:
1) Mapping the extinction-induced activation of brain circuits with FOS immunohistochemistry.
2) Study of the involvement of CRF receptor (CRFR1) system in resistance to extinction. This objective was formulated following the hypothesis that the deficit of immediate fear extinction learning results from a competition between fear consolidation and extinction acquisition, which both depend on the BLA. The release of CRF in the BLA triggered by the fear experience would thus render this amygdala nucleus over-activated and not susceptible to respond to immediate extinction learning. We also hypothesised that the action of CRF would be mediated through the CRFR1.
3) Study of the involvement of synaptic proteins in resistance to extinction. This objective was formulated following the hypothesis that consolidation of fear learning involves profound modifications in relevant synaptic networks.
4) To apply a developmental perspective to assess whether early life experiences can be effective, when reactivated in adulthood, to overcome inefficiency to fear extinction.
The project, initially designed for a period of two years, was finally circumscribed to only one year, with the completion of objectives 2 and 3. Objectives 1 and 4 will be pursued in future studies from the host laboratory.
The main results obtained included the establishment of a rat model of impaired fear extinction. First, we determined the experimental conditions to investigate the phenomenon of impaired fear extinction. Thus, we showed that extinction deficits depend on the post-training interval at which extinction is applied.
In this project, we aimed at identifying key neural mechanisms whereby behavioural principles involved in the inefficiency of extinction processes when applied to recent fear memories. We hypothesised a critical involvement of the basolateral amygdala (BLA) under conditions of high emotional distress and studied the implication of the corticotropin releasing factor (CRF) system and glutamatergic receptors. More specifically, using rat as the model system, this project involved the following objectives:
1) Mapping the extinction-induced activation of brain circuits with FOS immunohistochemistry.
2) Study of the involvement of CRF receptor (CRFR1) system in resistance to extinction. This objective was formulated following the hypothesis that the deficit of immediate fear extinction learning results from a competition between fear consolidation and extinction acquisition, which both depend on the BLA. The release of CRF in the BLA triggered by the fear experience would thus render this amygdala nucleus over-activated and not susceptible to respond to immediate extinction learning. We also hypothesised that the action of CRF would be mediated through the CRFR1.
3) Study of the involvement of synaptic proteins in resistance to extinction. This objective was formulated following the hypothesis that consolidation of fear learning involves profound modifications in relevant synaptic networks.
4) To apply a developmental perspective to assess whether early life experiences can be effective, when reactivated in adulthood, to overcome inefficiency to fear extinction.
The project, initially designed for a period of two years, was finally circumscribed to only one year, with the completion of objectives 2 and 3. Objectives 1 and 4 will be pursued in future studies from the host laboratory.
The main results obtained included the establishment of a rat model of impaired fear extinction. First, we determined the experimental conditions to investigate the phenomenon of impaired fear extinction. Thus, we showed that extinction deficits depend on the post-training interval at which extinction is applied.