title: Noradrenergic signaling in infralimbic cortex increases cell excitability and strengthens memory for fear extinction.
abstract: Emotional arousal strengthens memory. This is most apparent in aversive conditioning, in which the stress-related neurotransmitter norepinephrine (NE) enhances associations between sensory stimuli and fear-inducing events. In contrast to conditioning, extinction decreases fear responses, and is thought to form a new memory. It is not known, however, whether NE is necessary for extinction learning. Previous work has shown that the infralimbic prefrontal cortex (IL) is a site of extinction consolidation. Here, we show that blocking noradrenergic beta-receptors in IL before extinction training impaired retrieval of extinction the following day, consistent with a weakened extinction memory. We further found that the sequelae of beta-receptor activation, including protein kinase A (PKA), gene transcription and translation in IL, are necessary for extinction. To determine whether activation of this cascade modulates IL excitability, we measured the response of IL pyramidal neurons to injected current. NE increased the excitability of IL neurons in a beta-receptor- and PKA-dependent manner. We suggest that NE released in IL during fear extinction activates a PKA-mediated molecular cascade that strengthens extinction memory. Thus, emotional arousal evoked by conditioned fear paradoxically promotes the subsequent extinction of that fear, thereby ensuring behavioral flexibility.
authors.affiliation: Department of Psychiatry, University of Puerto Rico School of Medicine, San Juan, Puerto Rico. devin.mueller@gmail.com
authors.forename: Devin
authors.initials: D
authors.lastname: Mueller
authors.forename: James T
authors.initials: JT
authors.lastname: Porter
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Quirk
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000528:radiation effects; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000166:cytology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004347:Drug Interactions; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D005239:Fear; D066298:In Vitro Techniques; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology*; D011433:Propranolol / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000319:Adrenergic beta-Antagonists; D047428:Protein Kinase Inhibitors; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D011433:Propranolol; D000242:Cyclic AMP; D009638:Norepinephrine