Monari, S. | bioRxiv Science

bioRxiv2023

Blunted glucocorticoid responsiveness to stress causes behavioral and biological alterations that lead to posttraumatic stress disorder vulnerability

BACKGROUNDUnderstanding why only a subset of trauma-exposed individuals develop posttraumatic stress disorder (PTSD) is critical for advancing clinical strategies. A few behavioral (deficits in fear extinction) and biological (blunted glucocorticoid levels, small hippocampal size, and rapid-eye movement sleep (REMS) disturbances) traits have been identified as potential vulnerability factors. However, whether and to what extent these traits are interrelated and whether one of them could causally engender the others are not known. METHODSIn a genetically selected rat model of reduced corticosterone responsiveness to stress, we explored PTSD-related biobehavioral traits using ex vivo magnetic resonance imaging, cued fear conditioning, and polysomnographic recordings combined with in vivo photometric measurements. RESULTSWe showed that genetic selection for blunted glucocorticoid responsiveness leads to a correlated multitrait response, including impaired fear extinction, small hippocampal volume, and REMS disturbances, supporting their interrelatedness. Fear extinction deficits and concomitant disruptions in REMS could be normalized through postextinction corticosterone administration, causally implicating glucocorticoid deficiency in two core PTSD-related risk factors and manifestations. Furthermore, reduced REMS was accompanied by higher norepinephrine levels in the hippocampal dentate gyrus that were also reverted by postextinction corticosterone treatment. CONCLUSIONSOur results indicate a predominant role for glucocorticoid deficiency over the contribution of reduced hippocampal volume in engendering both REMS alterations and associated deficits in fear extinction consolidation, and causally implicate blunted glucocorticoids in sustaining neurophysiological disturbances leading to fear extinction deficits.

neuroscience↗

bioRxiv2019

Constitutive differences in glucocorticoid responsiveness are related to divergent spatial information processing abilities

The stress response facilitates survival through adaptation and is intimately related to cognitive processes. The Morris water maze task probes spatial learning and memory in rodents and glucocorticoids (i.e. corticosterone in rats) have been suggested to elicit a facilitating action on memory formation. Moreover, the early aging period (around 16-18 months of age) is susceptible to stress- and glucocorticoid-mediated acceleration of cognitive decline. In this study, we tested three lines of rats selectively bred according to their individual differences in corticosterone responsiveness to repeated stress exposure during juvenility. We investigated whether endogenous differences in glucocorticoid responses influenced spatial learning, long-term memory and reversal learning abilities in a Morris water maze task at early aging. Additionally, we assessed the quality of the different swimming strategies of the rats. Our results indicate that rats with differential corticosterone responsiveness exhibit similar spatial learning abilities but different long-term memory retention and reversal learning. Specifically, the high corticosterone responding line had a better long-term spatial memory, while the low corticosterone responding line was impaired for both long-term retention and reversal learning. Our modeling analysis of performance strategies revealed further important line-related differences. Therefore, our findings support the view that individuals with high corticosterone responsiveness would form stronger long-term memories to navigate in stressful environments. Conversely, individuals with low corticosterone responsiveness would be impaired at different phases of spatial learning and memory.

animal behavior and cognition↗