title: Voluntary exercise during extinction of auditory fear conditioning reduces the relapse of fear associated with potentiated activity of striatal direct pathway neurons.
abstract: Relapse of previously extinguished fear presents a significant, pervasive obstacle to the successful long-term treatment of anxiety and trauma-related disorders. Thus, identification of a novel means to enhance fear extinction to stand the passage of time and generalize across contexts is of the utmost importance. Acute bouts of exercise can be used as inexpensive, noninvasive treatment strategies to reduce anxiety, and have been shown to enhance memory for extinction when performed in close temporal proximity to the extinction session. However, it is unclear whether acute exercise can be used to prevent relapse of fear, and the neural mechanisms underlying this potential effect are unknown. The current study therefore examined whether acute exercise during extinction of auditory fear can protect against the later relapse of fear. Male F344 rats lacking an extended history of wheel running were conditioned to fear a tone CS and subsequently extinguished within either a freely mobile running wheel, a locked wheel, or a control context lacking a wheel. Rats exposed to fear extinction within a freely mobile wheel ran during fear extinction, and demonstrated reduced fear as well as attenuated corticosterone levels during re-exposure to the extinguished CS during the relapse test in a novel context 1week later. Examination of cfos mRNA patterns elicited by re-exposure to the extinguished CS during the relapse test revealed that acute exercise during extinction decreased activation of brain circuits classically involved in driving fear expression and interestingly, increased activity within neurons of the direct striatal pathway involved in reward signaling. These data suggest that exercise during extinction reduces relapse through a mechanism involving the direct pathway of the striatum. It is suggested that a positive affective state could become associated with the CS during exercise during extinction, thus resulting in a relapse-resistant extinction memory.
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, 354 UCB, Boulder, CO 80309, United States; Center for Neuroscience, University of Colorado Boulder, UCB Boulder 80309, United States.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Mika
authors.affiliation: Department of Integrative Biology, University of Colorado Denver, Denver, CO 80217, United States.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Bouchet
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, 354 UCB, Boulder, CO 80309, United States.
authors.forename: Preston
authors.initials: P
authors.lastname: Bunker
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, 354 UCB, Boulder, CO 80309, United States.
authors.forename: Justin E
authors.initials: JE
authors.lastname: Hellwinkel
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, 354 UCB, Boulder, CO 80309, United States.
authors.forename: Katie G
authors.initials: KG
authors.lastname: Spence
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, 345 UCB Boulder CO 80309, United States; Center for Neuroscience, University of Colorado Boulder, UCB Boulder 80309, United States.
authors.forename: Heidi E W
authors.initials: HE
authors.lastname: Day
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, 345 UCB Boulder CO 80309, United States; Center for Neuroscience, University of Colorado Boulder, UCB Boulder 80309, United States.
authors.forename: Serge
authors.initials: S
authors.lastname: Campeau
authors.affiliation: Department of Integrative Physiology, University of Colorado Boulder, 354 UCB, Boulder, CO 80309, United States; Center for Neuroscience, University of Colorado Boulder, UCB Boulder 80309, United States.
authors.forename: Monika
authors.initials: M
authors.lastname: Fleshner
authors.affiliation: Department of Psychology, University of Colorado Denver, CO 80217, United States. Electronic address: Benjamin.Greenwood@ucdenver.edu.
authors.forename: Benjamin N
authors.initials: BN
authors.lastname: Greenwood
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D003214:Conditioning, Classical / Q000502:physiology*; D003342:Corpus Striatum / Q000502:physiology*; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology* / Q000523:psychology; D008297:Male; D009043:Motor Activity / Q000502:physiology*; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000502:physiology; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344
keywords: Anxiety; Direct pathway; Fear extinction; Fear renewal; Spontaneous recovery; Striatum; Wheel running