Cargando…

SAT-362 Hypothalamic Pituitary Adrenal Axis Dysregulation Alters Central and Peripheral Adaptation to Repeated Stress Exposure in Mice

Aims: The hypothalamic pituitary adrenal (HPA) axis is the key neuroendocrine mediator of the stress response and controls many aspects of physiology and behavior. We previously showed that experimentally disrupting normal HPA function in mice led to altered neural and behavioral responses to acute...

Descripción completa

Detalles Bibliográficos
Autores principales: Kinlein, Scott, Wallace, Naomi, Blekkenk, Parker, Savenkova, Marina, Karatsoreos, Ilia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Endocrine Society 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551872/
http://dx.doi.org/10.1210/js.2019-SAT-362
_version_ 1783424473492357120
author Kinlein, Scott
Wallace, Naomi
Blekkenk, Parker
Savenkova, Marina
Karatsoreos, Ilia
author_facet Kinlein, Scott
Wallace, Naomi
Blekkenk, Parker
Savenkova, Marina
Karatsoreos, Ilia
author_sort Kinlein, Scott
collection PubMed
description Aims: The hypothalamic pituitary adrenal (HPA) axis is the key neuroendocrine mediator of the stress response and controls many aspects of physiology and behavior. We previously showed that experimentally disrupting normal HPA function in mice led to altered neural and behavioral responses to acute stress. When exposed to prolonged or repeated stress, organisms undergo adaptation in many processes of metabolism, endocrine function, and behavior. Further, many of these processes are thought to be driven by HPA secreted hormones. In this study, we aimed to test this hypothesis by disrupting normal HPA axis function and measuring metabolic, endocrine, and neural outcomes following repeated stress exposure. Methods: HPA axis function in male C57BL/6 mice was disrupted via noninvasive, oral corticosterone administration, which we have shown blunts hormonal and behavioral stress responses. Mice were then exposed to repeated immobilization stress (2h/d for 14d), during which time body weight was measured to assess metabolic adaptation to stress. Mice were euthanized and adipose tissue, adrenal glands, blood, and brain were collected for analysis. We evaluated the effects of HPA disruption on mass of white adipose tissue and adrenal glands, and determined plasma corticosterone concentrations as a measure of endocrine adaptation to stress. Using RTqPCR we investigated the effects of HPA disruption on the expression of genes related to synaptic excitability in the medial prefrontal cortex (mPFC), a brain region known to regulate behavioral and emotional responses to stress. Results: Repeated stress led to body weight loss in all mice, however body weight loss was exaggerated by HPA disruption, suggesting increased sensitivity to stress. Additionally, this decrease in body weight could not be accounted for by decreased white adipose mass alone, suggesting effects on other tissues caused by HPA disruption. Repeated stress increased adrenal weight similarly in all mice, but only elevated levels of plasma corticosterone in Control mice, demonstrating altered endocrine adaptation to stress after HPA disruption. Finally, we observed increased gene expression of the astrocytic glutamate exchanger xCT in the mPFC following repeated stress only in HPA disrupted mice, suggesting that HPA disruption affects processes of neural adaptation. Conclusions: HPA axis disruption increased sensitivity to metabolic outcomes of repeated stress exposure and altered endocrine stress adaptation. Additionally, effects on mPFC gene expression suggest altered neural adaptation to stress. These results support the hypothesis that an intact HPA axis is crucial in mediating adaptive responses to stress, and that dysfunction of this system may be linked to negative health outcomes of stress exposure. Sources of Research Support: NSF 1553067 and NIA R21AG050054 to INK.
format Online
Article
Text
id pubmed-6551872
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Endocrine Society
record_format MEDLINE/PubMed
spelling pubmed-65518722019-06-13 SAT-362 Hypothalamic Pituitary Adrenal Axis Dysregulation Alters Central and Peripheral Adaptation to Repeated Stress Exposure in Mice Kinlein, Scott Wallace, Naomi Blekkenk, Parker Savenkova, Marina Karatsoreos, Ilia J Endocr Soc Adrenal Aims: The hypothalamic pituitary adrenal (HPA) axis is the key neuroendocrine mediator of the stress response and controls many aspects of physiology and behavior. We previously showed that experimentally disrupting normal HPA function in mice led to altered neural and behavioral responses to acute stress. When exposed to prolonged or repeated stress, organisms undergo adaptation in many processes of metabolism, endocrine function, and behavior. Further, many of these processes are thought to be driven by HPA secreted hormones. In this study, we aimed to test this hypothesis by disrupting normal HPA axis function and measuring metabolic, endocrine, and neural outcomes following repeated stress exposure. Methods: HPA axis function in male C57BL/6 mice was disrupted via noninvasive, oral corticosterone administration, which we have shown blunts hormonal and behavioral stress responses. Mice were then exposed to repeated immobilization stress (2h/d for 14d), during which time body weight was measured to assess metabolic adaptation to stress. Mice were euthanized and adipose tissue, adrenal glands, blood, and brain were collected for analysis. We evaluated the effects of HPA disruption on mass of white adipose tissue and adrenal glands, and determined plasma corticosterone concentrations as a measure of endocrine adaptation to stress. Using RTqPCR we investigated the effects of HPA disruption on the expression of genes related to synaptic excitability in the medial prefrontal cortex (mPFC), a brain region known to regulate behavioral and emotional responses to stress. Results: Repeated stress led to body weight loss in all mice, however body weight loss was exaggerated by HPA disruption, suggesting increased sensitivity to stress. Additionally, this decrease in body weight could not be accounted for by decreased white adipose mass alone, suggesting effects on other tissues caused by HPA disruption. Repeated stress increased adrenal weight similarly in all mice, but only elevated levels of plasma corticosterone in Control mice, demonstrating altered endocrine adaptation to stress after HPA disruption. Finally, we observed increased gene expression of the astrocytic glutamate exchanger xCT in the mPFC following repeated stress only in HPA disrupted mice, suggesting that HPA disruption affects processes of neural adaptation. Conclusions: HPA axis disruption increased sensitivity to metabolic outcomes of repeated stress exposure and altered endocrine stress adaptation. Additionally, effects on mPFC gene expression suggest altered neural adaptation to stress. These results support the hypothesis that an intact HPA axis is crucial in mediating adaptive responses to stress, and that dysfunction of this system may be linked to negative health outcomes of stress exposure. Sources of Research Support: NSF 1553067 and NIA R21AG050054 to INK. Endocrine Society 2019-04-30 /pmc/articles/PMC6551872/ http://dx.doi.org/10.1210/js.2019-SAT-362 Text en Copyright © 2019 Endocrine Society https://creativecommons.org/licenses/by-nc-nd/4.0/ This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Adrenal
Kinlein, Scott
Wallace, Naomi
Blekkenk, Parker
Savenkova, Marina
Karatsoreos, Ilia
SAT-362 Hypothalamic Pituitary Adrenal Axis Dysregulation Alters Central and Peripheral Adaptation to Repeated Stress Exposure in Mice
title SAT-362 Hypothalamic Pituitary Adrenal Axis Dysregulation Alters Central and Peripheral Adaptation to Repeated Stress Exposure in Mice
title_full SAT-362 Hypothalamic Pituitary Adrenal Axis Dysregulation Alters Central and Peripheral Adaptation to Repeated Stress Exposure in Mice
title_fullStr SAT-362 Hypothalamic Pituitary Adrenal Axis Dysregulation Alters Central and Peripheral Adaptation to Repeated Stress Exposure in Mice
title_full_unstemmed SAT-362 Hypothalamic Pituitary Adrenal Axis Dysregulation Alters Central and Peripheral Adaptation to Repeated Stress Exposure in Mice
title_short SAT-362 Hypothalamic Pituitary Adrenal Axis Dysregulation Alters Central and Peripheral Adaptation to Repeated Stress Exposure in Mice
title_sort sat-362 hypothalamic pituitary adrenal axis dysregulation alters central and peripheral adaptation to repeated stress exposure in mice
topic Adrenal
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551872/
http://dx.doi.org/10.1210/js.2019-SAT-362
work_keys_str_mv AT kinleinscott sat362hypothalamicpituitaryadrenalaxisdysregulationalterscentralandperipheraladaptationtorepeatedstressexposureinmice
AT wallacenaomi sat362hypothalamicpituitaryadrenalaxisdysregulationalterscentralandperipheraladaptationtorepeatedstressexposureinmice
AT blekkenkparker sat362hypothalamicpituitaryadrenalaxisdysregulationalterscentralandperipheraladaptationtorepeatedstressexposureinmice
AT savenkovamarina sat362hypothalamicpituitaryadrenalaxisdysregulationalterscentralandperipheraladaptationtorepeatedstressexposureinmice
AT karatsoreosilia sat362hypothalamicpituitaryadrenalaxisdysregulationalterscentralandperipheraladaptationtorepeatedstressexposureinmice