TY - JOUR
T1 - Corticotrophin releasing factor receptor 1 antagonists prevent chronic stress-induced behavioral changes and synapse loss in aged rats
AU - Dong, Hongxin
AU - Keegan, Jack M.
AU - Hong, Ellie
AU - Gallardo, Christopher
AU - Montalvo-Ortiz, Janitza
AU - Wang, Becky
AU - Rice, Kenner C.
AU - Csernansky, John
N1 - Funding Information:
Drs. Dong and Csernansky have received research grants from the NIMH, NIA, and Dr. John G. Csernansky has served as a Data Safety and Monitoring Board (DSMB) member for Eli Lilly and Sanofi-Aventis, and has received funding for his research from Genentech. The rest of the authors declare that they have no competing financial interests.
Funding Information:
This work was supported by the Alzheimer’s Drug Discovery Foundation (grant 20111208 , JGC) and NIH ( 1R56AG053491-01 and 1R01AG057884-01 , HXD). A portion of this research was supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute of Alcohol Abuse and Alcoholism , NIH, US Department of Health and Human Services (KCR) .
PY - 2018/4
Y1 - 2018/4
N2 - Mounting evidence suggests that chronic stress can alter brain structure and function and promote the development of neuropsychiatric disorders, such as depression and Alzheimer's disease. Although the results of several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown whether antagonists of a key stress regulator, the corticotrophin releasing factor receptor 1 (CRF1), can prevent stress-induced anxiety and memory deficits in animal models. In this study, we evaluated the potential benefits of two CRF1 antagonists, R121919 and antalarmin, for preventing stress-induced anxiety-related behavioral and memory deficits and neurodegeneration in aged rats. We stressed rats using isolation-restraint for 3 months starting from the 18 months of age. Subsets of animals were administrated either R121919 or antalarmin through food chow for 3 months, followed by a series of behavioral, biochemical and morphological analyses. We found that stressed aged rats displayed body weight losses and increased corticosterone levels, as well as anxiety-related behaviors and memory deficits. Additionally, chronic stress induced a loss of cortical dendritic spines and synapses. However, R121919 and antalarmin both prevented stress-induced behavioral changes including anxiety-related behaviors and memory deficits and prevented synapse loss, perhaps through reversing HPA axis dysfunction. These results suggest that CRF1 antagonists may hold promise as a potential therapy for preventing stress-induced anxiety and memory deficits in aged individuals.
AB - Mounting evidence suggests that chronic stress can alter brain structure and function and promote the development of neuropsychiatric disorders, such as depression and Alzheimer's disease. Although the results of several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown whether antagonists of a key stress regulator, the corticotrophin releasing factor receptor 1 (CRF1), can prevent stress-induced anxiety and memory deficits in animal models. In this study, we evaluated the potential benefits of two CRF1 antagonists, R121919 and antalarmin, for preventing stress-induced anxiety-related behavioral and memory deficits and neurodegeneration in aged rats. We stressed rats using isolation-restraint for 3 months starting from the 18 months of age. Subsets of animals were administrated either R121919 or antalarmin through food chow for 3 months, followed by a series of behavioral, biochemical and morphological analyses. We found that stressed aged rats displayed body weight losses and increased corticosterone levels, as well as anxiety-related behaviors and memory deficits. Additionally, chronic stress induced a loss of cortical dendritic spines and synapses. However, R121919 and antalarmin both prevented stress-induced behavioral changes including anxiety-related behaviors and memory deficits and prevented synapse loss, perhaps through reversing HPA axis dysfunction. These results suggest that CRF1 antagonists may hold promise as a potential therapy for preventing stress-induced anxiety and memory deficits in aged individuals.
KW - Aging
KW - Corticotrophin releasing factor receptor 1 antagonist
KW - Memory
KW - Neurodegeneration
KW - Rats
KW - Stress
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U2 - 10.1016/j.psyneuen.2018.02.013
DO - 10.1016/j.psyneuen.2018.02.013
M3 - Article
C2 - 29477954
AN - SCOPUS:85042369357
VL - 90
SP - 92
EP - 101
JO - Psychoneuroendocrinology
JF - Psychoneuroendocrinology
SN - 0306-4530
ER -