Exercise-induced increases in Anandamide and BDNF during extinction consolidation contribute to reduced threat following reinstatement: Preliminary evidence from a randomized controlled trial

Kevin M. Crombie; Anneliis Sartin-Tarm; Kyrie Sellnow; Rachel Ahrenholtz; Sierra Lee; Megan Matalamaki; Neda E. Almassi; Cecilia J. Hillard; Kelli F. Koltyn; Tom G. Adams; Josh M. Cisler

doi:10.1016/j.psyneuen.2021.105355

Exercise-induced increases in Anandamide and BDNF during extinction consolidation contribute to reduced threat following reinstatement: Preliminary evidence from a randomized controlled trial

Kevin M. Crombie, Anneliis Sartin-Tarm, Kyrie Sellnow, Rachel Ahrenholtz, Sierra Lee, Megan Matalamaki, Neda E. Almassi, Cecilia J. Hillard, Kelli F. Koltyn, Tom G. Adams, Josh M. Cisler

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

Introduction: We recently demonstrated that moderate-intensity aerobic exercise delivered during the consolidation of fear extinction learning reduced threat expectancy during a test of extinction recall among women with posttraumatic stress disorder (PTSD). These findings suggest that exercise may be a potential candidate for improving the efficacy of exposure-based therapies, which are hypothesized to work via the mechanisms of fear extinction learning. The purpose of this secondary analysis was to examine whether exercise-induced increases in circulating concentrations of candidate biomarkers: endocannabinoids (anandamide [AEA]; 2-arachidonoylglycerol [2-AG], brain-derived neurotrophic factor (BDNF), and homovanillic acid (HVA), mediate the effects of exercise on extinction recall. Methods: Participants (N = 35) completed a 3-day fear acquisition (day 1), extinction (day 2), and extinction recall (day 3) protocol, in which participants were randomly assigned to complete either moderate-intensity aerobic exercise (EX) or a light-intensity control (CON) condition following extinction training (day 2). Blood was obtained prior to and following EX or CON. Threat expectancy ratings during tests of extinction recall (i.e., initial fear recall and fear recall following reinstatement) were obtained 24 h following EX or CON. Mediation was tested using linear-mixed effects models and bootstrapping of the indirect effect. Results: Circulating concentrations of AEA and BDNF (but not 2-AG and HVA) were found to mediate the relationship between moderate-intensity aerobic exercise and reduced threat expectancy ratings following reinstatement (AEA 95% CI: −0.623 to −0.005; BDNF 95% CI: −0.941 to −0.005). Conclusions: Exercise-induced increases in peripheral AEA and BDNF appear to play a role in enhancing consolidation of fear extinction learning, thereby leading to reduced threat expectancies following reinstatement among women with PTSD. Future mechanistic research examining these and other biomarkers (e.g., brain-based biomarkers) is warranted.

Original language	English
Article number	105355
Journal	Psychoneuroendocrinology
Volume	132
DOIs	https://doi.org/10.1016/j.psyneuen.2021.105355
State	Published - Oct 2021

Bibliographical note

Funding Information:
This study was supported by the Virginia Horne Henry Fund at the University of Wisconsin – Madison. The funding source had no role in the collection, analysis, and interpretation of data; in writing the report, or in the decision to submit the article for publication. Research reported in this publication (i.e., BDNF and HVA results) was also supported in part by the Office of the Director, National Institutes of Health under Award Number P51OD011106 to the Wisconsin National Primate Research Center, University of Wisconsin-Madison. TGA was supported by the National Institute of Health under award numbers K23MH111977 and L30MH111037 . The content is solely the responsibility of the authors. We would like to express many thanks to Delaney Dvorak for assisting with blood processing, Garrett Sauber for conducting the endocannabinoid assays, and all of the participants.

Funding Information:
This study was supported by the Virginia Horne Henry Fund at the University of Wisconsin ? Madison. The funding source had no role in the collection, analysis, and interpretation of data; in writing the report, or in the decision to submit the article for publication. Research reported in this publication (i.e. BDNF and HVA results) was also supported in part by the Office of the Director, National Institutes of Health under Award Number P51OD011106 to the Wisconsin National Primate Research Center, University of Wisconsin-Madison. TGA was supported by the National Institute of Health under award numbers K23MH111977 and L30MH111037. The content is solely the responsibility of the authors. We would like to express many thanks to Delaney Dvorak for assisting with blood processing, Garrett Sauber for conducting the endocannabinoid assays, and all of the participants. CJH is a member of the Scientific Advisory Board of Phytecs, Inc. and has an equity position in Formulate Biosciences. KMC, AS-T, KS, RA, SL, MM, NEA, KFK, TGA, and JMC have no conflicts of interest.

Publisher Copyright:
© 2021 Elsevier Ltd

Keywords

Aerobic exercise
Brain-derived neurotrophic factor
Endocannabinoids
Exposure-therapy
Fear extinction
Posttraumatic stress disorder

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Endocrinology
Endocrine and Autonomic Systems
Psychiatry and Mental health
Biological Psychiatry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.psyneuen.2021.105355

Cite this

Crombie, K. M., Sartin-Tarm, A., Sellnow, K., Ahrenholtz, R., Lee, S., Matalamaki, M., Almassi, N. E., Hillard, C. J., Koltyn, K. F., Adams, T. G., & Cisler, J. M. (2021). Exercise-induced increases in Anandamide and BDNF during extinction consolidation contribute to reduced threat following reinstatement: Preliminary evidence from a randomized controlled trial. Psychoneuroendocrinology, 132, Article 105355. https://doi.org/10.1016/j.psyneuen.2021.105355

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title = "Exercise-induced increases in Anandamide and BDNF during extinction consolidation contribute to reduced threat following reinstatement: Preliminary evidence from a randomized controlled trial",

abstract = "Introduction: We recently demonstrated that moderate-intensity aerobic exercise delivered during the consolidation of fear extinction learning reduced threat expectancy during a test of extinction recall among women with posttraumatic stress disorder (PTSD). These findings suggest that exercise may be a potential candidate for improving the efficacy of exposure-based therapies, which are hypothesized to work via the mechanisms of fear extinction learning. The purpose of this secondary analysis was to examine whether exercise-induced increases in circulating concentrations of candidate biomarkers: endocannabinoids (anandamide [AEA]; 2-arachidonoylglycerol [2-AG], brain-derived neurotrophic factor (BDNF), and homovanillic acid (HVA), mediate the effects of exercise on extinction recall. Methods: Participants (N = 35) completed a 3-day fear acquisition (day 1), extinction (day 2), and extinction recall (day 3) protocol, in which participants were randomly assigned to complete either moderate-intensity aerobic exercise (EX) or a light-intensity control (CON) condition following extinction training (day 2). Blood was obtained prior to and following EX or CON. Threat expectancy ratings during tests of extinction recall (i.e., initial fear recall and fear recall following reinstatement) were obtained 24 h following EX or CON. Mediation was tested using linear-mixed effects models and bootstrapping of the indirect effect. Results: Circulating concentrations of AEA and BDNF (but not 2-AG and HVA) were found to mediate the relationship between moderate-intensity aerobic exercise and reduced threat expectancy ratings following reinstatement (AEA 95% CI: −0.623 to −0.005; BDNF 95% CI: −0.941 to −0.005). Conclusions: Exercise-induced increases in peripheral AEA and BDNF appear to play a role in enhancing consolidation of fear extinction learning, thereby leading to reduced threat expectancies following reinstatement among women with PTSD. Future mechanistic research examining these and other biomarkers (e.g., brain-based biomarkers) is warranted.",

keywords = "Aerobic exercise, Brain-derived neurotrophic factor, Endocannabinoids, Exposure-therapy, Fear extinction, Posttraumatic stress disorder",

author = "Crombie, {Kevin M.} and Anneliis Sartin-Tarm and Kyrie Sellnow and Rachel Ahrenholtz and Sierra Lee and Megan Matalamaki and Almassi, {Neda E.} and Hillard, {Cecilia J.} and Koltyn, {Kelli F.} and Adams, {Tom G.} and Cisler, {Josh M.}",

note = "Funding Information: This study was supported by the Virginia Horne Henry Fund at the University of Wisconsin – Madison. The funding source had no role in the collection, analysis, and interpretation of data; in writing the report, or in the decision to submit the article for publication. Research reported in this publication (i.e., BDNF and HVA results) was also supported in part by the Office of the Director, National Institutes of Health under Award Number P51OD011106 to the Wisconsin National Primate Research Center, University of Wisconsin-Madison. TGA was supported by the National Institute of Health under award numbers K23MH111977 and L30MH111037 . The content is solely the responsibility of the authors. We would like to express many thanks to Delaney Dvorak for assisting with blood processing, Garrett Sauber for conducting the endocannabinoid assays, and all of the participants. Funding Information: This study was supported by the Virginia Horne Henry Fund at the University of Wisconsin ? Madison. The funding source had no role in the collection, analysis, and interpretation of data; in writing the report, or in the decision to submit the article for publication. Research reported in this publication (i.e. BDNF and HVA results) was also supported in part by the Office of the Director, National Institutes of Health under Award Number P51OD011106 to the Wisconsin National Primate Research Center, University of Wisconsin-Madison. TGA was supported by the National Institute of Health under award numbers K23MH111977 and L30MH111037. The content is solely the responsibility of the authors. We would like to express many thanks to Delaney Dvorak for assisting with blood processing, Garrett Sauber for conducting the endocannabinoid assays, and all of the participants. CJH is a member of the Scientific Advisory Board of Phytecs, Inc. and has an equity position in Formulate Biosciences. KMC, AS-T, KS, RA, SL, MM, NEA, KFK, TGA, and JMC have no conflicts of interest. Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",

year = "2021",

month = oct,

doi = "10.1016/j.psyneuen.2021.105355",

language = "English",

volume = "132",

}

Crombie, KM, Sartin-Tarm, A, Sellnow, K, Ahrenholtz, R, Lee, S, Matalamaki, M, Almassi, NE, Hillard, CJ, Koltyn, KF, Adams, TG & Cisler, JM 2021, 'Exercise-induced increases in Anandamide and BDNF during extinction consolidation contribute to reduced threat following reinstatement: Preliminary evidence from a randomized controlled trial', Psychoneuroendocrinology, vol. 132, 105355. https://doi.org/10.1016/j.psyneuen.2021.105355

Exercise-induced increases in Anandamide and BDNF during extinction consolidation contribute to reduced threat following reinstatement: Preliminary evidence from a randomized controlled trial. / Crombie, Kevin M.; Sartin-Tarm, Anneliis; Sellnow, Kyrie et al.
In: Psychoneuroendocrinology, Vol. 132, 105355, 10.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Exercise-induced increases in Anandamide and BDNF during extinction consolidation contribute to reduced threat following reinstatement

T2 - Preliminary evidence from a randomized controlled trial

AU - Crombie, Kevin M.

AU - Sartin-Tarm, Anneliis

AU - Sellnow, Kyrie

AU - Ahrenholtz, Rachel

AU - Lee, Sierra

AU - Matalamaki, Megan

AU - Almassi, Neda E.

AU - Hillard, Cecilia J.

AU - Koltyn, Kelli F.

AU - Adams, Tom G.

AU - Cisler, Josh M.

N1 - Funding Information: This study was supported by the Virginia Horne Henry Fund at the University of Wisconsin – Madison. The funding source had no role in the collection, analysis, and interpretation of data; in writing the report, or in the decision to submit the article for publication. Research reported in this publication (i.e., BDNF and HVA results) was also supported in part by the Office of the Director, National Institutes of Health under Award Number P51OD011106 to the Wisconsin National Primate Research Center, University of Wisconsin-Madison. TGA was supported by the National Institute of Health under award numbers K23MH111977 and L30MH111037 . The content is solely the responsibility of the authors. We would like to express many thanks to Delaney Dvorak for assisting with blood processing, Garrett Sauber for conducting the endocannabinoid assays, and all of the participants. Funding Information: This study was supported by the Virginia Horne Henry Fund at the University of Wisconsin ? Madison. The funding source had no role in the collection, analysis, and interpretation of data; in writing the report, or in the decision to submit the article for publication. Research reported in this publication (i.e. BDNF and HVA results) was also supported in part by the Office of the Director, National Institutes of Health under Award Number P51OD011106 to the Wisconsin National Primate Research Center, University of Wisconsin-Madison. TGA was supported by the National Institute of Health under award numbers K23MH111977 and L30MH111037. The content is solely the responsibility of the authors. We would like to express many thanks to Delaney Dvorak for assisting with blood processing, Garrett Sauber for conducting the endocannabinoid assays, and all of the participants. CJH is a member of the Scientific Advisory Board of Phytecs, Inc. and has an equity position in Formulate Biosciences. KMC, AS-T, KS, RA, SL, MM, NEA, KFK, TGA, and JMC have no conflicts of interest. Publisher Copyright: © 2021 Elsevier Ltd

PY - 2021/10

Y1 - 2021/10

N2 - Introduction: We recently demonstrated that moderate-intensity aerobic exercise delivered during the consolidation of fear extinction learning reduced threat expectancy during a test of extinction recall among women with posttraumatic stress disorder (PTSD). These findings suggest that exercise may be a potential candidate for improving the efficacy of exposure-based therapies, which are hypothesized to work via the mechanisms of fear extinction learning. The purpose of this secondary analysis was to examine whether exercise-induced increases in circulating concentrations of candidate biomarkers: endocannabinoids (anandamide [AEA]; 2-arachidonoylglycerol [2-AG], brain-derived neurotrophic factor (BDNF), and homovanillic acid (HVA), mediate the effects of exercise on extinction recall. Methods: Participants (N = 35) completed a 3-day fear acquisition (day 1), extinction (day 2), and extinction recall (day 3) protocol, in which participants were randomly assigned to complete either moderate-intensity aerobic exercise (EX) or a light-intensity control (CON) condition following extinction training (day 2). Blood was obtained prior to and following EX or CON. Threat expectancy ratings during tests of extinction recall (i.e., initial fear recall and fear recall following reinstatement) were obtained 24 h following EX or CON. Mediation was tested using linear-mixed effects models and bootstrapping of the indirect effect. Results: Circulating concentrations of AEA and BDNF (but not 2-AG and HVA) were found to mediate the relationship between moderate-intensity aerobic exercise and reduced threat expectancy ratings following reinstatement (AEA 95% CI: −0.623 to −0.005; BDNF 95% CI: −0.941 to −0.005). Conclusions: Exercise-induced increases in peripheral AEA and BDNF appear to play a role in enhancing consolidation of fear extinction learning, thereby leading to reduced threat expectancies following reinstatement among women with PTSD. Future mechanistic research examining these and other biomarkers (e.g., brain-based biomarkers) is warranted.

AB - Introduction: We recently demonstrated that moderate-intensity aerobic exercise delivered during the consolidation of fear extinction learning reduced threat expectancy during a test of extinction recall among women with posttraumatic stress disorder (PTSD). These findings suggest that exercise may be a potential candidate for improving the efficacy of exposure-based therapies, which are hypothesized to work via the mechanisms of fear extinction learning. The purpose of this secondary analysis was to examine whether exercise-induced increases in circulating concentrations of candidate biomarkers: endocannabinoids (anandamide [AEA]; 2-arachidonoylglycerol [2-AG], brain-derived neurotrophic factor (BDNF), and homovanillic acid (HVA), mediate the effects of exercise on extinction recall. Methods: Participants (N = 35) completed a 3-day fear acquisition (day 1), extinction (day 2), and extinction recall (day 3) protocol, in which participants were randomly assigned to complete either moderate-intensity aerobic exercise (EX) or a light-intensity control (CON) condition following extinction training (day 2). Blood was obtained prior to and following EX or CON. Threat expectancy ratings during tests of extinction recall (i.e., initial fear recall and fear recall following reinstatement) were obtained 24 h following EX or CON. Mediation was tested using linear-mixed effects models and bootstrapping of the indirect effect. Results: Circulating concentrations of AEA and BDNF (but not 2-AG and HVA) were found to mediate the relationship between moderate-intensity aerobic exercise and reduced threat expectancy ratings following reinstatement (AEA 95% CI: −0.623 to −0.005; BDNF 95% CI: −0.941 to −0.005). Conclusions: Exercise-induced increases in peripheral AEA and BDNF appear to play a role in enhancing consolidation of fear extinction learning, thereby leading to reduced threat expectancies following reinstatement among women with PTSD. Future mechanistic research examining these and other biomarkers (e.g., brain-based biomarkers) is warranted.

KW - Aerobic exercise

KW - Brain-derived neurotrophic factor

KW - Endocannabinoids

KW - Exposure-therapy

KW - Fear extinction

KW - Posttraumatic stress disorder

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Exercise-induced increases in Anandamide and BDNF during extinction consolidation contribute to reduced threat following reinstatement: Preliminary evidence from a randomized controlled trial

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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