title: A Transgenic Rat for Investigating the Anatomy and Function of Corticotrophin Releasing Factor Circuits.
abstract: Corticotrophin-releasing factor (CRF) is a 41 amino acid neuropeptide that coordinates adaptive responses to stress. CRF projections from neurons in the central nucleus of the amygdala (CeA) to the brainstem are of particular interest for their role in motivated behavior. To directly examine the anatomy and function of CRF neurons, we generated a BAC transgenic Crh-Cre rat in which bacterial Cre recombinase is expressed from the Crh promoter. Using Cre-dependent reporters, we found that Cre expressing neurons in these rats are immunoreactive for CRF and are clustered in the lateral CeA (CeL) and the oval nucleus of the BNST. We detected major projections from CeA CRF neurons to parabrachial nuclei and the locus coeruleus, dorsal and ventral BNST, and more minor projections to lateral portions of the substantia nigra, ventral tegmental area, and lateral hypothalamus. Optogenetic stimulation of CeA CRF neurons evoked GABA-ergic responses in 11% of non-CRF neurons in the medial CeA (CeM) and 44% of non-CRF neurons in the CeL. Chemogenetic stimulation of CeA CRF neurons induced Fos in a similar proportion of non-CRF CeM neurons but a smaller proportion of non-CRF CeL neurons. The CRF1 receptor antagonist R121919 reduced this Fos induction by two-thirds in these regions. These results indicate that CeL CRF neurons provide both local inhibitory GABA and excitatory CRF signals to other CeA neurons, and demonstrate the value of the Crh-Cre rat as a tool for studying circuit function and physiology of CRF neurons.
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin Austin, TX, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Pomrenze
authors.affiliation: Department of Neurology, University of California, San Francisco San Francisco, CA, USA.
authors.forename: E Zayra
authors.initials: EZ
authors.lastname: Millan
authors.affiliation: Department of Neurology, University of California, San Francisco San Francisco, CA, USA.
authors.forename: F Woodward
authors.initials: FW
authors.lastname: Hopf
authors.affiliation: Department of Neurology, University of California, San Francisco San Francisco, CA, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Keiflin
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin Austin, TX, USA.
authors.forename: Rajani
authors.initials: R
authors.lastname: Maiya
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin Austin, TX, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: Blasio
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at AustinAustin, TX, USA; Department of Neurology, University of California, San FranciscoSan Francisco, CA, USA.
authors.forename: Jahan
authors.initials: J
authors.lastname: Dadgar
authors.affiliation: Department of Neurology, University of California, San Francisco San Francisco, CA, USA.
authors.forename: Viktor
authors.initials: V
authors.lastname: Kharazia
authors.affiliation: Committee on The Neurobiology of Addictive Disorders, The Scripps Research Institute La Jolla, CA, USA.
authors.forename: Giordano
authors.initials: G
authors.lastname: De Guglielmo
authors.affiliation: Committee on The Neurobiology of Addictive Disorders, The Scripps Research Institute La Jolla, CA, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Crawford
authors.affiliation: Department of Neurology, University of California, San Francisco San Francisco, CA, USA.
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Janak
authors.affiliation: Committee on The Neurobiology of Addictive Disorders, The Scripps Research Institute La Jolla, CA, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: George
authors.affiliation: Chemical Biology Research Branch, Drug Design and Synthesis Section, National Institute on Drug Abuse, National Institute on Alcohol Abuse and Alcoholism Rockville, MD, USA.
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at AustinAustin, TX, USA; Department of Neurology, University of California, San FranciscoSan Francisco, CA, USA.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Messing
keywords: CRF; Cre recombinase; Fos; R121919; central amygdala; channelrhodopsin-2; designer receptors exclusively activated by designer drugs; transgenic rat models