title: Neuropeptide Y Impairs Retrieval of Extinguished Fear and Modulates Excitability of Neurons in the Infralimbic Prefrontal Cortex.
abstract: Neuropeptide Y (NPY), a 36 aa peptide, regulates stress and emotional behaviors. Preclinical and clinical studies support an association of NPY with trauma-evoked syndromes such as posttraumatic stress disorder (PTSD), although the exact contribution of NPY is not clear. In the current study, we examined functional attributes of NPY in the infralimbic (IL) cortex, an area that regulates fear memories and is reported to be hypoactive in PTSD. Carriers of NPY gene polymorphism rs16147 have been reported to have elevated prefrontal NPY expression. Infusion of NPY into the IL cortex in rats significantly impaired fear extinction memory without affecting conditioned fear expression or acquisition of extinction. Neuroendocrine stress response, depression-like behavior, and working memory performance were not affected by NPY infusion into the IL. The NPY Y1 receptor antagonist BIBO3304 completely abolished NPY effects on fear extinction retrieval. Y1 receptor expression was localized on CaMKII-positive pyramidal projection neurons and GAD67-positive interneurons in the IL. Patch-clamp recordings revealed increased inhibitory synaptic transmission onto IL projection neurons in the presence of NPY. Thus, NPY dampens excitability of IL projection neurons and impairs retrieval of extinction memory by inhibiting consolidation of extinction. Of relevance to PTSD, elevation of prefrontal NPY attributable to the genetic polymorphism rs16147 may contribute to IL hypoactivity, resulting in impaired extinction memory and susceptibility to the disorder.
  
  
  CONCLUSIONS
  Neuropeptide Y (NPY), a stress modulatory transmitter, is associated with posttraumatic stress disorder (PTSD). Contribution of NPY to PTSD symptomology is unclear. PTSD patients have reduced activity in the infralimbic (IL) subdivision of the medial prefrontal cortex (mPFC), associated with compromised extinction memory. No information exists on fear modulation by NPY in the IL cortex, although NPY and NPY receptors are abundant in these areas. This study shows that IL NPY inhibits consolidation of extinction, resulting in impaired retrieval of extinction memory and modulates excitability of IL projection neurons. In addition to providing a novel perspective on extinction memory modulation by NPY, our findings suggest that elevated mPFC NPY in gene polymorphism rs16147 carriers or after chronic stress could increase susceptibility to PTSD.
authors.affiliation: Departments of Psychiatry and Behavioral Neuroscience and Neuroscience Graduate Program, University of Cincinnati, Cincinnati, Ohio 45221, and.
authors.forename: Lauren L
authors.identifier: http://orcid.org/0000-0001-6496-7235
authors.initials: LL
authors.lastname: Vollmer
authors.affiliation: Neuroscience Graduate Program, University of Cincinnati, Cincinnati, Ohio 45221, and.
authors.forename: Sarah
authors.identifier: http://orcid.org/0000-0003-4333-1566
authors.initials: S
authors.lastname: Schmeltzer
authors.affiliation: Departments of Psychiatry and Behavioral Neuroscience and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Schurdak
authors.affiliation: Departments of Psychiatry and Behavioral Neuroscience and.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Ahlbrand
authors.affiliation: Departments of Psychiatry and Behavioral Neuroscience and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rush
authors.affiliation: Departments of Psychiatry and Behavioral Neuroscience and.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Dolgas
authors.affiliation: Anesthesiology and Neuroscience Graduate Program, University of Cincinnati, Cincinnati, Ohio 45221, and.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Baccei
authors.affiliation: Departments of Psychiatry and Behavioral Neuroscience and Neuroscience Graduate Program, University of Cincinnati, Cincinnati, Ohio 45221, and Veterans Administration Medical Center, Cincinnati, Ohio 45220 sahr@uc.edu.
authors.forename: Renu
authors.initials: R
authors.lastname: Sah
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000627:therapeutic use; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000187:drug effects*; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007859:Learning Disabilities / Q000139:chemically induced*; D008297:Male; D011939:Mental Recall / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D009478:Neuropeptide Y / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D055366:Synaptic Potentials / Q000187:drug effects
chemical_list: D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; D001120:Arginine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C117416:BIBO 3304; D003345:Corticosterone
keywords: Neuropeptide Y; Y1; extinction; fear; infralimbic; prefrontal
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