PT  - JOURNAL ARTICLE
AU  - Charles Finsterwald
AU  - Adam B. Steinmetz
AU  - Alessio Travaglia
AU  - Cristina M. Alberini
TI  - From Memory Impairment to Posttraumatic Stress Disorder-Like Phenotypes: The Critical Role of an Unpredictable Second Traumatic Experience
AID  - 10.1523/JNEUROSCI.0771-15.2015
DP  - 2015 Dec 02
TA  - The Journal of Neuroscience
PG  - 15903--15915
VI  - 35
IP  - 48
4099  - http://www.jneurosci.org/content/35/48/15903.short
4100  - http://www.jneurosci.org/content/35/48/15903.full
SO  - J. Neurosci.2015 Dec 02; 35
AB  - Arousal and stress critically regulate memory formation and retention. Increasing levels of stress produce an inverted U-shaped effect on cognitive performance, including the retention of explicit memories, and experiencing a severe stress during a traumatic event may lead to posttraumatic stress disorder (PTSD). The molecular mechanisms underlying the impairing effect of a severe stress on memory and the key contribution of traumatic experiences toward the development of PTSD are still unknown. Here, using increasing footshock intensities in an inhibitory avoidance paradigm, we reproduced the inverted U-shaped curve of memory performance in rats. We then show that the inverted U profile of memory performance correlates with an inverted U profile of corticosterone level in the circulation and of brain-derived neurotrophic factor, phosphorylated tropomyosin-receptor kinase B, and methyl CpG binding protein in the dorsal hippocampus. Furthermore, training with the highest footshock intensity (traumatic experience) led to a significant elevation of hippocampal glucocorticoid receptors. Exposure to an unpredictable, but not to a predictable, highly stressful reminder shock after a first traumatic experience resulted in PTSD-like phenotypes, including increased memory of the trauma, high anxiety, threat generalization, and resistance to extinction. Systemic corticosterone injection immediately after the traumatic experience, but not 3 d later, was sufficient to produce PTSD-like phenotypes. We suggest that, although after a first traumatic experience a suppression of the corticosterone-dependent response protects against the development of an anxiety disorder, experiencing more than one trauma (multiple hits) is a critical contributor to the etiology of PTSD.SIGNIFICANCE STATEMENT Increasing levels of stress produce an inverted U-shaped effect on memory retention. Humans experiencing an acute trauma may develop posttraumatic stress disorder (PTSD), but the key contributions of trauma to PTSD formation are still unknown. This study in rats shows that a single traumatic experience leads to memory impairment, accompanied by blunted activations of circulating corticosterone and of plasticity molecular changes in the hippocampus. Experiencing a traumatic, unpredictable reminder, but not a repetition of the same trauma (predictable), leads to high anxiety, threat memory generalization, and extinction failure, typical responses of anxiety disorders and PTSD. Thus, although a first trauma elicits inhibiting responses, which may be protective, experiencing more than one unpredictable trauma is a critical contributor of PTSD etiology.