TY - JOUR
T1 - Severe, multimodal stress exposure induces PTSD-like characteristics in a mouse model of single prolonged stress
AU - Perrine, Shane A.
AU - Eagle, Andrew L.
AU - George, Sophie A.
AU - Mulo, Kostika
AU - Kohler, Robert J.
AU - Gerard, Justin
AU - Harutyunyan, Arman
AU - Hool, Steven M.
AU - Susick, Laura L.
AU - Schneider, Brandy L.
AU - Ghoddoussi, Farhad
AU - Galloway, Matthew P.
AU - Liberzon, Israel
AU - Conti, Alana C.
N1 - Funding Information:
This material is the result of work supported with resources and the use of facilities at the John D. Dingell VA Medical Center, Detroit, MI (ACC). The majority of support for these studies was provided by Wayne State University—Office of Vice President for Research (SAP, ALE), Department of Psychiatry and Behavioral Neurosciences (SAP, RJK, KM, MPG), Department of Neurosurgery (ACC, LSS), Department of Anesthesiology (MPG, FG), Translational Neuroscience Program Graduate Research Assistantship (BLS), Medical Student Summer Research Fellowship (SAP, JG), and Summer Research Experience Program (KM). Partial support was provided by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) grants F32 AA020435 (LLS) and K01 AA017683 (ACC) and by the Department of Defense grant W81XWH-13-1-0377 (IL, SAG). A portion of these findings were presented at the 2013 Society for Neuroscience annual scientific meeting (ALE).
Funding Information:
This material is the result of work supported with resources and the use of facilities at the John D. Dingell VA Medical Center, Detroit, MI (ACC). The majority of support for these studies was provided by Wayne State University—Office of Vice President for Research (SAP, ALE), Department of Psychiatry and Behavioral Neurosciences (SAP, RJK, KM, MPG), Department of Neurosurgery (ACC, LSS), Department of Anesthesiology (MPG, FG), Translational Neuroscience Program Graduate Research Assistantship (BLS), Medical Student Summer Research Fellowship (SAP, JG), and Summer Research Experience Program (KM). Partial support was provided by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) grants F32 AA020435 (LLS) and K01 AA017683 (ACC) and by the Department of Defense grant W81XWH-13-1-0377 (IL, SAG). A portion of these findings were presented at the 2013 Society for Neuroscience annual scientific meeting (ALE).
Publisher Copyright:
© 2016 Published by Elsevier B.V..
PY - 2016/4/15
Y1 - 2016/4/15
N2 - Appropriate animal models of posttraumatic stress disorder (PTSD) are needed because human studies remain limited in their ability to probe the underlying neurobiology of PTSD. Although the single prolonged stress (SPS) model is an established rat model of PTSD, the development of a similarly-validated mouse model emphasizes the benefits and cross-species utility of rodent PTSD models and offers unique methodological advantages to that of the rat. Therefore, the aims of this study were to develop and describe a SPS model for mice and to provide data that support current mechanisms relevant to PTSD. The mouse single prolonged stress (mSPS) paradigm, involves exposing C57Bl/6 mice to a series of severe, multimodal stressors, including 2 h restraint, 10 min group forced swim, exposure to soiled rat bedding scent, and exposure to ether until unconsciousness. Following a 7-day undisturbed period, mice were tested for cue-induced fear behavior, effects of paroxetine on cue-induced fear behavior, extinction retention of a previously extinguished fear memory, dexamethasone suppression of corticosterone (CORT) response, dorsal hippocampal glucocorticoid receptor protein and mRNA expression, and prefrontal cortex glutamate levels. Exposure to mSPS enhanced cue-induced fear, which was attenuated by oral paroxetine treatment. mSPS also disrupted extinction retention, enhanced suppression of stress-induced CORT response, increased mRNA expression of dorsal hippocampal glucocorticoid receptors and decreased prefrontal cortex glutamate levels. These data suggest that the mSPS model is a translationally-relevant model for future PTSD research with strong face, construct, and predictive validity. In summary, mSPS models characteristics relevant to PTSD and this severe, multimodal stress modifies fear learning in mice that coincides with changes in the hypothalamo-pituitary-adrenal (HPA) axis, brain glucocorticoid systems, and glutamatergic signaling in the prefrontal cortex.
AB - Appropriate animal models of posttraumatic stress disorder (PTSD) are needed because human studies remain limited in their ability to probe the underlying neurobiology of PTSD. Although the single prolonged stress (SPS) model is an established rat model of PTSD, the development of a similarly-validated mouse model emphasizes the benefits and cross-species utility of rodent PTSD models and offers unique methodological advantages to that of the rat. Therefore, the aims of this study were to develop and describe a SPS model for mice and to provide data that support current mechanisms relevant to PTSD. The mouse single prolonged stress (mSPS) paradigm, involves exposing C57Bl/6 mice to a series of severe, multimodal stressors, including 2 h restraint, 10 min group forced swim, exposure to soiled rat bedding scent, and exposure to ether until unconsciousness. Following a 7-day undisturbed period, mice were tested for cue-induced fear behavior, effects of paroxetine on cue-induced fear behavior, extinction retention of a previously extinguished fear memory, dexamethasone suppression of corticosterone (CORT) response, dorsal hippocampal glucocorticoid receptor protein and mRNA expression, and prefrontal cortex glutamate levels. Exposure to mSPS enhanced cue-induced fear, which was attenuated by oral paroxetine treatment. mSPS also disrupted extinction retention, enhanced suppression of stress-induced CORT response, increased mRNA expression of dorsal hippocampal glucocorticoid receptors and decreased prefrontal cortex glutamate levels. These data suggest that the mSPS model is a translationally-relevant model for future PTSD research with strong face, construct, and predictive validity. In summary, mSPS models characteristics relevant to PTSD and this severe, multimodal stress modifies fear learning in mice that coincides with changes in the hypothalamo-pituitary-adrenal (HPA) axis, brain glucocorticoid systems, and glutamatergic signaling in the prefrontal cortex.
KW - Fear conditioning
KW - Glucocorticoid
KW - Glutamate
KW - Mice
KW - Posttraumatic stress disorder
KW - Single prolonged stress
UR - http://www.scopus.com/inward/record.url?scp=84958280061&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84958280061&partnerID=8YFLogxK
U2 - 10.1016/j.bbr.2016.01.056
DO - 10.1016/j.bbr.2016.01.056
M3 - Article
C2 - 26821287
AN - SCOPUS:84958280061
VL - 303
SP - 228
EP - 237
JO - Behavioural Brain Research
JF - Behavioural Brain Research
SN - 0166-4328
ER -