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

Monari, S.; Guillot de Suduiraut, I.; Grosse, J.; Zanoletti, O.; Walker, S. E.; Mesquita, M.; Wood, T.; Cash, D.; Astori, S.; Sandi, C.

doi:10.1101/2023.08.20.554001

bioRxiv · 10.1101/2023.08.20.554001

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

Monari, S.·Guillot de Suduiraut, I.·Grosse, J.·Zanoletti, O.·Walker, S. E.·Mesquita, M.·Wood, T.·Cash, D.·Astori, S.·Sandi, C.

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Abstract

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.

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Monari, S., Guillot de Suduiraut, I., Grosse, J., Zanoletti, O., Walker, S. E., Mesquita, M., Wood, T., Cash, D., Astori, S., Sandi, C.. 2023-08-21. Blunted glucocorticoid responsiveness to stress causes behavioral and biological alterations that lead to posttraumatic stress disorder vulnerability. https://doi.org/10.1101/2023.08.20.554001

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