title: Cell type-specific modifications of corticotropin-releasing factor (CRF) and its type 1 receptor (CRF1) on startle behavior and sensorimotor gating.
abstract: The corticotropin-releasing factor (CRF) family of peptides and receptors coordinates the mammalian endocrine, autonomic, and behavioral responses to stress. Excessive CRF production has been implicated in the etiology of stress-sensitive psychiatric disorders such as posttraumatic stress disorder (PTSD), which is associated with alterations in startle plasticity. The CRF family of peptides and receptors mediate acute startle response changes during stress, and chronic CRF activation can induce startle abnormalities. To determine what neural circuits modulate startle in response to chronic CRF activation, transgenic mice overexpressing CRF throughout the central nervous system (CNS; CRF-COE(CNS)) or restricted to inhibitory GABAergic neurons (CRF-COE(GABA)) were compared across multiple domains of startle plasticity. CRF overexpression throughout the CNS increased startle magnitude and reduced ability to inhibit startle (decreased habituation and decreased prepulse inhibition (PPI)), similar to previous reports of exogenous effects of CRF. Conversely, CRF overexpression confined to inhibitory neurons decreased startle magnitude but had no effect on inhibitory measures. Acute CRF receptor 1 (CRF1) antagonist treatment attenuated only the effects on startle induced by CNS-specific CRF overexpression. Specific deletion of CRF1 receptors from forebrain principal neurons failed to alter the effects of exogenous CRF or stress on startle, suggesting that these CRF1 expressing neurons are not required for CRF-induced changes in startle behaviors. These data indicate that the effects of CRF activation on startle behavior utilize an extensive neural circuit that includes both forebrain and non-forebrain regions. Furthermore, these findings suggest that the neural source of increased CRF release determines the startle phenotype elicited. It is conceivable that this may explain why disorders characterized by increased CRF in cerebrospinal fluid (e.g. PTSD and major depressive disorder) have distinct symptom profiles in terms of startle reactivity.
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Flandreau
authors.affiliation: Veterans Administration Center of Excellence for Stress and Mental Health, 3350 La Jolla Village Drive San Diego, CA 92161, USA. Electronic address: vrisbrough@ucsd.edu.
authors.forename: Victoria
authors.initials: V
authors.lastname: Risbrough
authors.affiliation: Unit of Innate Immunity, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China.
authors.forename: Ailing
authors.initials: A
authors.lastname: Lu
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, D-80804, Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Ableitner
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA 92093-0804, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
authors.affiliation: Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, D-80804, Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Holsboer
authors.affiliation: Department Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, D-80804, Munich, Germany.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Deussing
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D059330:GABAergic Neurons / Q000378:metabolism*; D006185:Habituation, Psychophysiologic / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D065808:Prepulse Inhibition / Q000235:genetics; D016548:Prosencephalon / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D012021:Reflex, Abnormal / Q000235:genetics; D013216:Reflex, Startle / Q000235:genetics*; D055139:Sensory Gating / Q000235:genetics*; D013315:Stress, Psychological / Q000235:genetics* / Q000378:metabolism; D000099052:CRF Receptor, Type 1
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone
keywords: Acoustic startle; CRF; CRH; PTSD; Prepulse inhibition