The goal of this project is to use murine models to elucidate the mechanisms underlying the effects of stress and the neuropeptide corticotropin releasing factor (CRF) on information processing and response inhibition. Across species, presentation of a neutral, non-startling """"""""prepulse"""""""" 30-300 ms before a startling stimulus reduces startle magnitude, termed prepulse inhibition (PPI), theoretically by requiring the organism to allocate attentional resources to process the prepulse and hence filter or """"""""gate"""""""" the subsequent startling stimulus. PPI is used clinically as an operational measure of sensorimotor gating that is deficient in a number of neuropsychiatric disorders. Certain anxiety disorders, post-traumatic stress disorder (PTSD) and panic disorder (PD), exhibit deficits in PPI. These disorders also appear to exhibit pathology in the CRF system, either CRF hypersecretion or increased receptor signaling. CRF is a neuropeptide that coordinates many behavioral and neuroendocrine responses to stress via activation of 2 known receptor subtypes, CRF-R1 and CRF-R2. Over-expression of CRF or exogenous administration of CRF in rodents reduces PPI, mimicking the PPI deficits observed in PTSD and PD patients. CRF-induced deficits in PPI in mice appear to be mediated via CRF-R1 receptors while CRF-R2 receptors have opposing effects. To guide future clinical studies of the roles of CRF systems in PTSD and PD, experiments in mice are proposed to elucidate the role of CRF receptors in stress-induced deficits in PPI, and to clarify how these receptors modulate PPI when chronically activated. This project tests hypotheses based on a novel model of relative CRF-R1 and CRF-R2 receptor signaling processes in response to normal and pathological CRF release.
Aim 1 identifies the respective contributions of CRF and dopamine receptors in CRF effects on PPI.
Aim 2 identifies the CRF receptor mechanisms underlying shock stress effects on startle and PPI.
Aim 3 assesses the contribution of CRF-R2 receptors and endogenous ligands to the maintenance of and recovery from CRF-induced deficits in PPI.
Aim 4 assesses the neuroanatomical substrates contributing to both acute CRF and chronic CRF effects on information processing. These studies are critical for our basic understanding of the mechanisms of stress effects on information processing and response inhibition, and will elucidate new receptor targets for pharmacotherapeutic intervention in anxiety disorder patients exhibiting information processing deficits. ? ? ?
|Toth, Mate; Flandreau, Elizabeth I; Deslauriers, Jessica et al. (2016) Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood. Neuropsychopharmacology 41:1681-90|
|Park, Hyo-Jin; Ran, Yong; Jung, Joo In et al. (2015) The stress response neuropeptide CRF increases amyloid-? production by regulating ?-secretase activity. EMBO J 34:1674-86|
|Flandreau, Elizabeth; Risbrough, Victoria; Lu, Ailing et al. (2015) Cell type-specific modifications of corticotropin-releasing factor (CRF) and its type 1 receptor (CRF1) on startle behavior and sensorimotor gating. Psychoneuroendocrinology 53:16-28|
|Inslicht, Sabra S; Richards, Anne; Madden, Erin et al. (2014) Sex differences in neurosteroid and hormonal responses to metyrapone in posttraumatic stress disorder. Psychopharmacology (Berl) 231:3581-95|
|Toth, Mate; Gresack, Jodi E; Bangasser, Debra A et al. (2014) Forebrain-specific CRF overproduction during development is sufficient to induce enduring anxiety and startle abnormalities in adult mice. Neuropsychopharmacology 39:1409-19|
|Toth, Mate; Ziegler, Michael; Sun, Ping et al. (2013) Impaired conditioned fear response and startle reactivity in epinephrine-deficient mice. Behav Pharmacol 24:1-9|
|Hauger, Richard L; Olivares-Reyes, J Alberto; Braun, Sandra et al. (2013) Desensitization of human CRF2(a) receptor signaling governed by agonist potency and ?arrestin2 recruitment. Regul Pept 186:62-76|
|Tatro, Erick T; Risbrough, Victoria; Soontornniyomkij, Benchawanna et al. (2013) Short-term recognition memory correlates with regional CNS expression of microRNA-138 in mice. Am J Geriatr Psychiatry 21:461-73|
|Li, Xia; Risbrough, Victoria B; Cates-Gatto, Chelsea et al. (2013) Comparison of the effects of the GABAB receptor positive modulator BHF177 and the GABAB receptor agonist baclofen on anxiety-like behavior, learning, and memory in mice. Neuropharmacology 70:156-67|
|Toth, M; Gresack, J E; Hauger, R L et al. (2013) The role of PKC signaling in CRF-induced modulation of startle. Psychopharmacology (Berl) 229:579-89|
Showing the most recent 10 out of 36 publications