title: Fibroblast growth factor 8 deficiency compromises the functional response of the serotonergic system to stress.
abstract: Functionally heterogeneous populations of serotonergic neurons, located within the dorsal raphe nucleus (DR), play a role in stress-related behaviors and neuropsychiatric illnesses such as anxiety and depression. Abnormal development of these neurons may permanently alter their structure and connections, making the organism more susceptible to anxiety-related disorders. A factor that critically regulates the development of serotonergic neurons is fibroblast growth factor 8 (Fgf8). In this study, we used acute restraint stress followed by behavioral testing to examine whether Fgf8 signaling during development is important for establishing functional stress- and anxiety-related DR neurocircuits in adulthood. Wild-type and heterozygous male mice globally hypomorphic for Fgf8 were exposed to acute restraint stress and then tested for anxiety-like behavior on the elevated plus-maze. Further, we measured c-Fos immunostaining as a marker of serotonergic neuronal activation and tissue 5-hydroxyindoleacetic acid concentrations as a marker of serotonin functional output. Results showed that Fgf8 hypomorphs exhibited 1) an exaggerated response of DR anxiety-promoting circuits and 2) a blunted response of a DR panic-inhibiting circuit to stress, effects that together were associated with increased baseline anxiety-like behavior. Overall, our results provide a neural substrate upon which Fgf8 deficiency could affect stress response and support the hypothesis that developmental disruptions of serotonergic neurons affect their postnatal functional integrity.
authors.affiliation: Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado, United States of America.
authors.forename: Leah R
authors.initials: LR
authors.lastname: Brooks
authors.affiliation: Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado, United States of America.
authors.forename: Heide L
authors.initials: HL
authors.lastname: Pals
authors.affiliation: Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado, United States of America.
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Enix
authors.affiliation: Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado, United States of America.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Woolaver
authors.affiliation: Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado, United States of America.
authors.forename: Evan D
authors.initials: ED
authors.lastname: Paul
authors.affiliation: Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado, United States of America.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Lowry
authors.affiliation: Integrative Physiology and Center for Neuroscience, University of Colorado Boulder, Boulder, Colorado, United States of America.
authors.forename: Pei-San
authors.initials: PS
authors.lastname: Tsai
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D055664:Electrochemical Techniques; D051524:Fibroblast Growth Factor 8 / Q000235:genetics* / Q000378:metabolism; D006579:Heterozygote; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D059326:Serotonergic Neurons / Q000378:metabolism* / Q000473:pathology; D012701:Serotonin / Q000032:analysis; D013312:Stress, Physiological
chemical_list: D051524:Fibroblast Growth Factor 8; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid