Many animals, including zebrafish (Danio rerio), form social hierarchies as a result of competition for limited resources. Socially subordinate fish experience chronic activation of the hypothalamic-pituitary-interrenal (HPI) axis, leading to prolonged elevation of plasma cortisol, the glucocorticoid end-product of HPI axis activation. Elevated cortisol levels can reduce cellular proliferation and neurogenesis in the brain. Thus, the present study tested the hypothesis that social stress suppresses cellular proliferation in the brain of subordinate zebrafish via a cortisol-mediated mechanism. Cellular proliferation was assessed using the incorporation of 5-bromo-2'-deoxyuridine (BrdU), a thymidine analogue, as a marker. After 48 and 96 h of social interaction, significantly lower numbers of BrdU-positive cells were present in the forebrain of subordinate male zebrafish compared to dominant or control fish, suggesting a suppression of cellular proliferation in fish experiencing chronic social stress. Treatment of interacting male zebrafish with metyrapone, a cortisol synthesis inhibitor, attenuated the suppression of cellular proliferation in subordinate fish. Subordinate female zebrafish did not experience elevation of plasma cortisol or suppression of cellular proliferation in the forebrain. Collectively, these data provide evidence that cortisol plays a role in regulating cellular proliferation in the forebrain of male zebrafish during social interactions.

People who endure horrific, life-threatening experiences are at risk for developing post-traumatic stress disorder (PTSD). However, only about 25% of all individuals who experience trauma develop PTSD. Recent research indicates that the presence of certain physiological conditions, such as reduced cortisol and parasympathetic inhibition, during trauma may increase one's susceptibility to developing PTSD. Thus, I attempted to develop a novel animal model of PTSD and test the hypothesis that reduced adrenal and parasympathetic activity during stress would exacerbate its long-term effects on behavior.In Experiment One, adult male rats were exposed to two stress sessions, each involving one hour of immobilization plus cat exposure. Before each session, rats were injected with vehicle, metyrapone, AF-DX 116, or both drugs. The second session occurred 10 days after the first and served to model a traumatic flashback. Stressed rats endured unstable housing conditions throughout t he experiment to add an element of daily anxiety. Three weeks after the second session, all rats underwent a battery of tests to examine the lasting effects of stress on physiology and behavior. The results indicated that stressed rats exhibited heightened anxiety on the elevated plus maze, an exaggerated startle response, and greater blood pressure, relative to controls. Moreover, metyrapone, when combined with stress, led to significant short- and long-term spatial memory impairments. Experiment Two assessed the effects of the same stress paradigm on rats' sensitivity to yohimbine, an alpha-2 adrenergic receptor antagonist. Yohimbine induces flashbacks and panic attacks in patients with PTSD; thus, I hypothesized that stressed rats would react abnormally to this agent. Stressed and unstressed rats were administered vehicle or yohimbine (1 mg/kg) 30 min prior to behavioral testing. The results indicated that stressed rats were hyperresponsive to yohimbine, as evidenced by a greater su ppression of rearing, greater avoidance of the center of the open field, and a greater suppression of activity on the elevated plus maze, relative to controls. Collectively, the findings of these studies indicate that uncontrollable and unpredictable psychological stress produces lasting changes in the physiology and behavior of rats that resemble symptoms commonly observed in people with PTSD.

Le syndrome de stress post-traumatique est une pathologie caractérisée par des symptômes de réexpérimentation, d’évitement et d’hypervigilance. L’apparition d’un syndrome de stress posttraumatique après un événement traumatisant peut être prédit par un déficit de sécrétion en glucocorticoïdes. Le rôle de ce déficit dans la vulnérabilité individuelle face au stress a été analysé par deux approches différentes chez le rat. Dans une première approche, une déplétion pharmacologique a été induite par la métyrapone puis les réactions physiologiques et comportementales pendant le stress ont été caractérisées. Dans une seconde approche, les différences interindividuelles d’une population soumise à un stresseur intense ont été caractérisées en termes de réponse physiologique, comportementale et d’expression génique dans l’hippocampe. Ces études n’ont pas mis en évidence de vulnérabilité accrue induite par un déficit en glucocorticoïde. Au contraire, la métyrapone a montré des propriétés anxiolytiques indépendamment de son effet sur les glucocorticoïdes. La métyrapone a également modifié le métabolisme central et périphérique d’une façon qui pourrait expliquer ses propriétés neuroprotectrices. Enfin, l’approche naturaliste a mis en évidence l’importance de la plasticité synaptique dans la résilience face au stress / Post-traumatic stress disorder is a pathology characterized by reexperience, avoidance and hyper-arousal symptoms. Emergence of post-traumatic stress disorder after a traumatic event can be predicted, to a certain extent, by a glucocorticoid secretion deficiency. The role of this deficiency in stress vulnerability has been analysed by two different approaches in the rat. In a first approach, a pharmacological depletion has been induced by metyrapone, then, physiological and behavioural reactions during stress have been characterized. In a second approach, inter-individual differences of a population submitted to an intense stressor has been characterized in terms of physiological, behavioural and hippocampal gene expression responses. These studies failed to evidence an increased vulnerability induced by a glucocorticoid deficiency. On the contrary, metyrapone exhibited anxiolytic-like properties independently of its effects on glucocorticoids. Metyrapone has also modified central and peripheral metabolism in a way that could explain its neuroprotective properties. Finally, the naturalistic approach has evidenced the emphasis of synaptic plasticity in the resilience to stress