Response and recovery of endocrine, behavioral, and neuronal morphology outcomes after different traumatic stressor exposures in male rats.

Preclinical models of organismal response to traumatic stress (threat of death or serious injury) can be monitored using neuroendocrine, behavioral, and structural metrics. While many rodent models of traumatic stress have provided a glimpse into select components of the physiological response to acute and chronic stressors, few studies have directly examined the potential differences between stressors and their potential outcomes. To address this gap, we conducted a multi-level comparison of the immediate and longer-term effects of two types of acute traumatic stressors. Adult male rats were exposed to either underwater trauma (UWT), predator exposure (PE), or control procedural handling conditions. Over the next 7 days, yoked cohorts underwent either serial blood sampling for neuroendocrine evaluation across the circadian cycle, or repeated behavioral testing in the elevated plus maze. In addition, a subset of brains from the latter cohort were assessed for dendritic spine changes in the prefrontal cortex and basolateral amygdala. We observed stressor-dependent patterns of response and recovery across all measures, with divergence between endocrine responses despite similar behavioral outcomes. These results demonstrate that different stressors elicit unique behavioral, neuroendocrine, and neuro-structural response profiles and suggest that specific stress models can be used to model desired responses for specific preclinical applications, such as evaluations of underlying mechanisms or therapeutic candidates.

Adulthood stress responses in rats are variably altered as a factor of adolescent stress exposure.

Stress exposure during development may influence adulthood stress response severity. The present study investigates persisting effects of two adolescent stressors upon adulthood response to predator exposure (PE). Rats were exposed to underwater trauma (UWT) or PE during adolescence, then to PE after reaching adulthood. Rats were then exposed to predator odor (PO) to test responses to predator cues alone. Behavioral and neuroendocrine assessments were conducted to determine acute effects of each stress experience. Adolescent stress altered behavioral response to adulthood PE. Acoustic startle response was blunted. Bidirectional changes in plus maze exploration were revealed as a factor of adolescent stress type. Neuroendocrine response magnitude did not predict severity of adolescent or adult stress response, suggesting that different adolescent stress events may differentially alter developmental outcomes regardless of acute behavioral or neuroendocrine response. We report that exposure to two different stressors in adolescence may differentially affect stress response outcomes in adulthood. Acute response to an adolescent stressor may not be consistent across all stressors or all dependent measures, and may not predict alterations in developmental outcomes pertaining to adulthood stress exposure. Further studies are needed to characterize factors underlying long-term effects of a developmental stressor.

Multiple presentations reduce the behavioral impact of protected predator exposure in rats.

Exposure of rats to a predator species, such as a cat, or stimuli associated with a predator species has been used to model the effects of traumatic stress. We further investigated this procedure to determine if the behavioral effects from such exposure could be increased by multiple exposures. In rats (n=8 for each treatment group), we evaluated single (1×) and multiple (1×/day for 3 consecutive days [3×] and 2×/day for 3 consecutive days [6×]) exposures using cats and soiled cat litter. All exposures were 15min in duration and the rats were directly exposed to the cats but in a protected fashion that did not allow the predator to physically injure the rat. Sham exposures were conducted using similar conditions without the presence of the predator or litter. The effects of the exposures were evaluated using an elevated plus maze (EPM). Sessions on the EPM were conducted before the exposures and at various times after the exposure. Difference scores (post-pre) were calculated for dependent measures from the EPM, and statistical analyses compared the slopes and intercept values derived from regression functions from these scores over the post-exposure sessions. During the first 30 days after exposure, a significant reduction in activity on the EPM was observed for the 1× treatment and a smaller reduction was observed for the 3× treatment, but no reduction was observed for the 6× and sham control treatments. Thus, increasing the number of exposures did not increase the magnitude of the effect but, instead, resulted in a decrease. These results show that adaptation to the effects of the predator exposure occurred with repeated sessions.

Adolescent traumatic stress experience results in less robust conditioned fear and post-extinction fear cue responses in adult rats.

Early exposure to a traumatic event may produce lasting effects throughout the lifespan. Traumatic stress during adolescence may deliver a distinct developmental insult compared with more-often studied neonatal or juvenile traumatic stress paradigms. The present study describes the lasting effects of adolescent traumatic stress upon adulthood fear conditioning. Adolescent rats were exposed to a traumatic stressor (underwater trauma, UWT), then underwent fear conditioning during adulthood. Fear extinction was tested over five conditioned suppression extinction sessions three weeks later. The efficacies of two potential extinction-enhancing compounds, endocannabinoid reuptake inhibitor AM404 (10mg/kg) and M1 muscarinic positive allosteric modulator BQCA (10mg/kg), were also assessed. Finally, post-extinction fear responses were examined using a fear cue (light) as a prepulse stimulus. Rats traumatically stressed during adolescence showed blunted conditioned suppression on day 1 of extinction training, and AM404 reversed this effect. Post-extinction startle testing showed that fear conditioning eliminates prepulse inhibition to the light cue. Startle potentiation was observed only in rats without adolescent UWT exposure. AM404 and BQCA both ameliorated this startle potentiation, while BQCA increased startle in the UWT group. These results suggest that exposure to a traumatic stressor during adolescence alters developmental outcomes related to stress response and fear extinction compared to rats without adolescent traumatic stress exposure, blunting the adulthood fear response and reducing residual post-extinction fear expression. Efficacy of pharmacological interventions may also vary as a factor of developmental traumatic stress exposure.

Differential severity of anxiogenic effects resulting from a brief swim or underwater trauma in adolescent male rats.

Clinical studies have shown a link between early-life adversity and severity of adulthood responses to a traumatic stress event (post-traumatic stress disorder, PTSD). Despite a need for basic research, few rodent models are available to test the lasting impacts of early-life traumatic stressors. Underwater trauma (UWT) has been used previously to model traumatic stress; however, effects of this procedure have only been characterized in adulthood. Susceptibility of younger animals to physiological or psychological damage from a forced submersion procedure is unknown. A procedure involving swimming may be a stressful stimulus outside of the underwater component of the experience, as well. The acute effects of a 1-minute sham exposure (empty water tank), swim-only, and UWT (40s swim followed by 20s underwater) were compared in adolescent rats at postnatal day 37. No effects on blood oxygenation or lung tissue were observed. Stepwise decreases in open arm behavior were observed on the elevated plus maze (EPM) in swim-only rats, while UWT rats showed an immediate, lasting decrease in open arm behavior. UWT rats showed a significant decrease in basal corticosterone one week after trauma. These results show that while water immersion is a stressor, UWT causes a distinct syndrome of traumatic stress response in adolescent rats.