title: From Memory Impairment to Posttraumatic Stress Disorder-Like Phenotypes: The Critical Role of an Unpredictable Second Traumatic Experience.
abstract: 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.
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003.
authors.forename: Charles
authors.initials: C
authors.lastname: Finsterwald
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Steinmetz
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003.
authors.forename: Alessio
authors.initials: A
authors.lastname: Travaglia
authors.affiliation: Center for Neural Science, New York University, New York, New York 10003 ca60@nyu.edu.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Alberini
mesh_terms: D000386:AIDS-Related Complex / Q000378:metabolism; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D050882:CREB-Binding Protein / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects; D005106:Exploratory Behavior / Q000502:physiology; D005793:Generalization, Psychological; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000209:etiology*; D051783:Methyl-CpG-Binding Protein 2; D010641:Phenotype; D051381:Rats; D020318:Rats, Long-Evans; D020813:Receptor, trkB / Q000378:metabolism; D013313:Stress Disorders, Post-Traumatic / Q000150:complications*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C497394:Mecp2 protein, rat; D051783:Methyl-CpG-Binding Protein 2; D050882:CREB-Binding Protein; D020813:Receptor, trkB; D003345:Corticosterone
keywords: PTSD; hippocampus; memory; molecular mechanisms; stress; trauma