title: Grin1 receptor deletion within CRF neurons enhances fear memory.
abstract: Corticotropin releasing factor (CRF) dysregulation is implicated in mood and anxiety disorders such as posttraumatic stress disorder (PTSD). CRF is expressed in areas engaged in fear and anxiety processing including the central amygdala (CeA). Complicating our ability to study the contribution of CRF-containing neurons to fear and anxiety behavior is the wide variety of cell types in which CRF is expressed. To manipulate specific subpopulations of CRF containing neurons, our lab has developed a mouse with a Cre recombinase gene driven by a CRF promoter (CRFp3.0Cre) (Martin et al., 2010). In these studies, mice that have the gene that encodes NR1 (Grin1) flanked by loxP sites (floxed) were crossed with our previously developed CRFp3.0Cre mouse to selectively disrupt Grin1 within CRF containing neurons (Cre+/fGrin1+). We find that disruption of Grin1 in CRF neurons did not affect baseline levels of anxiety, locomotion, pain sensitivity or exploration of a novel object. However, baseline expression of Grin1 was decreased in Cre+/fGrin1+ mice as measured by RTPCR. Cre+/fGrin1+ mice showed enhanced auditory fear acquisition and retention without showing any significant effect on fear extinction. We measured Gria1, the gene that encodes AMPAR1 and the CREB activator Creb1 in the amygdala of Cre+/fGrin1+ mice after fear conditioning. Both Gria1 and Creb1 were enhanced in the amygdala after training. To determine if the Grin1-expressing CRF neurons within the CeA are responsible for the enhancement of fear memory in adults, we infused a lentivirus with Cre driven by a CRF promoter (LV pCRF-Cre/fGrin1+) into the CeA of floxed Grin1 mice. Cre driven deletion of Grin1 specifically within CRF expressing cells in the CeA also resulted in enhanced fear memory acquisition and retention. Altogether, these findings suggest that selective disruption of Grin1 within CeA CRF neurons strongly enhances fear memory.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Georgette
authors.initials: G
authors.lastname: Gafford
authors.affiliation: Department of Psychological Sciences, Kent State University, Kent, Ohio, United States of America.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Jasnow
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Kerry J
authors.initials: KJ
authors.lastname: Ressler
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D001007:Anxiety; D001522:Behavior, Animal; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D003433:Crosses, Genetic; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005239:Fear; D017353:Gene Deletion; D017404:In Situ Hybridization, Fluorescence; D019426:Integrases / Q000378:metabolism; D016086:Lentivirus / Q000378:metabolism; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D009474:Neurons / Q000378:metabolism; D011401:Promoter Regions, Genetic; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000502:physiology
chemical_list: D003346:Corticotropin-Releasing Hormone; D017362:Cyclic AMP Response Element-Binding Protein; D019426:Integrases; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C492004:Creb1 protein, mouse; C121673:Gprin1 protein, mouse; C045073:Cre recombinase