title: Corticotropin-releasing factor in ventromedial prefrontal cortex mediates avoidance of a traumatic stress-paired context.
abstract: Post-traumatic stress disorder (PTSD) affects 7.7 million Americans. One diagnostic criterion for PTSD is avoidance of stimuli that are related to the traumatic stress. Using a predator odor stress conditioned place aversion (CPA) model, rats can be divided into groups based on stress reactivity, as measured by avoidance of the odor-paired context. Avoider rats, which show high stress reactivity, exhibit persistent avoidance of stress-paired context and escalated alcohol drinking. Here, we examined the potential role of corticotropin-releasing factor (CRF), a neuropeptide that promotes anxiety-like behavior in mediating avoidance and escalated alcohol drinking after stress. CRF is expressed in the medial prefrontal cortex (mPFC). The dorsal and ventral sub-regions of the mPFC (dmPFC and vmPFC) have opposing roles in stress reactivity and alcohol drinking. We hypothesized that vmPFC CRF-CRFR1 signaling contributes functionally to stress-induced avoidance and escalated alcohol self-administration. In Experiment 1, adult male Wistar rats were exposed to predator odor stress in a CPA paradigm, indexed for avoidance of odor-paired context, and brains processed for CRF-immunoreactive cell density in vmPFC and dmPFC. Post-stress, Avoiders exhibited higher CRF cell density in vmPFC, but not the dmPFC. In Experiment 2, rats were tested for avoidance of a context repeatedly paired with intra-vmPFC CRF infusions. In Experiment 3, rats were stressed and indexed, then tested for the effects of intra-vmPFC CRFR1 antagonism on avoidance and alcohol self-administration. Intra-vmPFC CRF infusion produced avoidance of a paired context, and intra-vmPFC CRFR1 antagonism reversed avoidance of a stress-paired context, but did not alter post-stress alcohol self-administration. These findings suggest that vmPFC CRF-CRFR1 signaling mediates avoidance of stimuli paired with traumatic stress.
authors.affiliation: Department of Physiology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.
authors.forename: Allyson L
authors.initials: AL
authors.lastname: Schreiber
authors.affiliation: Neuroscience and Behavior Program, University of Massachusetts, Amherst, MA, 01003, USA.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Lu
authors.affiliation: Department of Physiology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA.
authors.forename: Brittni B
authors.initials: BB
authors.lastname: Baynes
authors.affiliation: Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, MA, 01003, USA.
authors.forename: Heather N
authors.initials: HN
authors.lastname: Richardson
authors.affiliation: Department of Physiology, Louisiana State University Health Science Center, New Orleans, LA 70112, USA; Neuroscience Center of Excellence, Louisiana State University Health Science Center, New Orleans, LA, 70112, USA. Electronic address: ngilpi@lsuhsc.edu.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Gilpin
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000008:administration & dosage*; D057967:Infusions, Intraventricular; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology; D000099052:CRF Receptor, Type 1
chemical_list: D011743:Pyrimidines; C412383:R 121919; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone
keywords: Alcohol self-administration; Anxiety; Avoidance; Corticotropin-releasing factor (CRF); Medial prefrontal cortex (mPFC); Post-traumatic stress disorder (PTSD)