Skip to main content

Advertisement

SpringerLink
Log in

The role of PKC signaling in CRF-induced modulation of startle

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Hypersignaling of corticotropin releasing factor (CRF) has been implicated in stress disorders; however, many of its downstream mechanisms of action remain unclear. In vitro, CRF1 receptor activation initiates multiple cell signaling cascades, including protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein kinase kinase MEK1/2 signaling. It is unclear, however, which of these signaling cascades mediate CRF-induced behaviors during stress.

Objectives

We examined the role of PKA, PKC, and MEK1/2 signaling pathways in CRF-induced anxiety as measured by startle hyperreactivity.

Methods

Mice treated with intracerbroventricular (ICV) ovine CRF (oCRF) were pretreated with the PKA inhibitor Rp-cAMPS, PKC inhibitor bisindolylmaleimide (BIM), or MEK1/2 inhibitor PD98059 (ICV) and assessed for acoustic startle reactivity.

Results

The PKC inhibitor BIM significantly attenuated CRF-induced increases in startle. BIM was also able to block startle increases induced by oCRF when both compounds were infused directly into the bed nucleus of stria terminalis (BNST). PKA and MEK1/2 inhibition had no significant effects on CRF-induced changes in startle at the dose ranges tested. CRF-induced disruption of prepulse inhibition was not significantly reversed by any of the three pretreatments at the dose ranges tested.

Conclusions

PKC signaling is required for CRF-induced increases in startle, and this effect is mediated at least in part at the BNST. These findings suggest that PKC signaling cascades (1) may be important for the acute effects of CRF to induce startle hyperreactivity and (2) support further research of the role of PKC signaling in startle abnormalities relevant to disorders such as posttraumatic stress disorder.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Adamec R, Fougere D, Risbrough V (2010) CRF receptor blockade prevents initiation and consolidation of stress effects on affect in the predator stress model of PTSD. Int J Neuropsychopharmacol 13(6):747–57

    Article  PubMed  CAS  Google Scholar 

  • Bajo M, Cruz MT, Siggins GR, Messing R, Roberto M (2008) Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala. Proc Natl Acad Sci U S A 105(24):8410–5

    Article  PubMed  CAS  Google Scholar 

  • Baker DG, West SA, Nicholson WE, Ekhator NN, Kasckow JW, Hill KK, Bruce AB, Orth DN, Geracioti TD Jr (1999) Serial CSF corticotropin-releasing hormone levels and adrenocortical activity in combat veterans with posttraumatic stress disorder. Am J Psychiatry 156(4):585–8

    PubMed  CAS  Google Scholar 

  • Bakshi VP, Alsene KM, Roseboom PH, Connors EE (2012) Enduring sensorimotor gating abnormalities following predator exposure or corticotropin-releasing factor in rats: a model for PTSD-like information-processing deficits? Neuropharmacology 62(2):737–48

    Article  PubMed  CAS  Google Scholar 

  • Bale TL, Contarino A, Smith GW, Chan R, Gold LH, Sawchenko PE, Koob GF, Vale WW, Lee KF (2000) Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat Genet 24(4):410–4

    Article  PubMed  CAS  Google Scholar 

  • Berger H, Heinrich N, Wietfeld D, Bienert M, Beyermann M (2006) Evidence that corticotropin-releasing factor receptor type 1 couples to Gs- and Gi-proteins through different conformations of its J-domain. Br J Pharmacol 149(7):942–7

    Article  PubMed  CAS  Google Scholar 

  • Beyermann M, Heinrich N, Fechner K, Furkert J, Zhang W, Kraetke O, Bienert M, Berger H (2007) Achieving signalling selectivity of ligands for the corticotropin-releasing factor type 1 receptor by modifying the agonist’s signalling domain. Br J Pharmacol 151(6):851–9

    Article  PubMed  CAS  Google Scholar 

  • Bijlsma EY, van Leeuwen ML, Westphal KG, Olivier B, Groenink L (2011) Local repeated corticotropin-releasing factor infusion exacerbates anxiety- and fear-related behavior: differential involvement of the basolateral amygdala and medial prefrontal cortex. Neuroscience 173:82–92

    Article  PubMed  CAS  Google Scholar 

  • Blank T, Nijholt I, Eckart K, Spiess J (2002) Priming of long-term potentiation in mouse hippocampus by corticotropin-releasing factor and acute stress: implications for hippocampus-dependent learning. J Neurosci 22(9):3788–94

    PubMed  CAS  Google Scholar 

  • Blank T, Nijholt I, Grammatopoulos DK, Randeva HS, Hillhouse EW, Spiess J (2003) Corticotropin-releasing factor receptors couple to multiple G-proteins to activate diverse intracellular signaling pathways in mouse hippocampus: role in neuronal excitability and associative learning. J Neurosci 23(2):700–7

    PubMed  CAS  Google Scholar 

  • Boulis NM, Davis M (1990) Blockade of the spinal excitatory effect of cAMP on the startle reflex by intrathecal administration of the isoquinoline sulfonamide H-8: comparison to the protein kinase C inhibitor H-7. Brain Res 525(2):198–204

    Article  PubMed  CAS  Google Scholar 

  • Bourtchouladze R, Abel T, Berman N, Gordon R, Lapidus K, Kandel ER (1998) Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. Learn Mem 5(4–5):365–74

    PubMed  CAS  Google Scholar 

  • Bowers BJ, Collins AC, Tritto T, Wehner JM (2000) Mice lacking PKC gamma exhibit decreased anxiety. Behav Genet 30(2):111–21

    Article  PubMed  CAS  Google Scholar 

  • Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM, Nemeroff CB, Charney DS (1997) Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 154(5):624–9

    PubMed  CAS  Google Scholar 

  • Casabona G (1997) Intracellular signal modulation: a pivotal role for protein kinase C. Prog Neuropsychopharmacol Biol Psychiatry 21(3):407–25

    Article  PubMed  CAS  Google Scholar 

  • Cecchi M, Khoshbouei H, Javors M, Morilak DA (2002) Modulatory effects of norepinephrine in the lateral bed nucleus of the stria terminalis on behavioral and neuroendocrine responses to acute stress. Neuroscience 112(1):13–21

    Article  PubMed  CAS  Google Scholar 

  • Cohen H, Kozlovsky N, Matar MA, Kaplan Z, Zohar J (2010) Mapping the brain pathways of traumatic memory: inactivation of protein kinase M zeta in different brain regions disrupts traumatic memory processes and attenuates traumatic stress responses in rats. Eur Neuropsychopharmacol 20(4):253–71

    Article  PubMed  CAS  Google Scholar 

  • Conti LH, Murry JD, Ruiz MA, Printz MP (2002) Effects of corticotropin-releasing factor on prepulse inhibition of the acoustic startle response in two rat strains. Psychopharmacology (Berl) 161(3):296–303

    Article  CAS  Google Scholar 

  • Cooper MA, Huhman KL (2005) Corticotropin-releasing factor type II (CRF-sub-2) receptors in the bed nucleus of the stria terminalis modulate conditioned defeat in Syrian hamsters (Mesocricetus auratus). Behav Neurosci 119(4):1042–51

    Article  PubMed  Google Scholar 

  • Dautzenberg FM, Gutknecht E, Van der Linden I, Olivares-Reyes JA, Dürrenberger F, Hauger RL (2004) Cell-type specific calcium signaling by corticotropin-releasing factor type 1 (CRF1) and 2a (CRF2(a)) receptors: phospholipase C-mediated responses in human embryonic kidney 293 but not SK-N-MC neuroblastoma cells. Biochem Pharmacol 68(9):1833–44

    Article  PubMed  CAS  Google Scholar 

  • Davis M (1980) Neurochemical modulation of sensory-motor reactivity: acoustic and tactile startle reflexes. Neurosci Biobehav Rev 4(2):241–63

    Article  PubMed  CAS  Google Scholar 

  • Davis M, Aghajanian GK (1976) Effects of apomorphine and haloperidol on the acoustic startle response in rats. Psychopharmacology (Berl) 47(3):217–23

    Article  CAS  Google Scholar 

  • Davis M, Commissaris RL, Cassella JV, Yang S, Dember L, Harty TP (1986) Differential effects of dopamine agonists on acoustically and electrically elicited startle responses: comparison to effects of strychnine. Brain Res 371(1):58–69

    Article  PubMed  CAS  Google Scholar 

  • Davis M, Falls WA, Campeau S, Kim M (1993) Fear-potentiated startle: a neural and pharmacological analysis. Behav Brain Res 58(1–2):175–98

    Article  PubMed  CAS  Google Scholar 

  • Davis M, Walker DL, Lee Y (1997) Amygdala and bed nucleus of the stria terminalis: differential roles in fear and anxiety measured with the acoustic startle reflex. Philos Trans R Soc Lond B Biol Sci 352(1362):1675–87

    Article  PubMed  CAS  Google Scholar 

  • de Lima TC, Davis M (1995) Involvement of cyclic AMP at the level of the nucleus reticularis pontis caudalis in the acoustic startle response. Brain Res 700(1–2):59–69

    Article  PubMed  Google Scholar 

  • Di Benedetto B, Kallnik M, Weisenhorn DM, Falls WA, Wurst W, Hölter SM (2009) Activation of ERK/MAPK in the lateral amygdala of the mouse is required for acquisition of a fear-potentiated startle response. Neuropsychopharmacology 34(2):356–66

    Article  PubMed  Google Scholar 

  • Glover EM, Phifer JE, Crain DF, Norrholm SD, Davis M, Bradley B, Ressler KJ, Jovanovic T (2011) Tools for translational neuroscience: PTSD is associated with heightened fear responses using acoustic startle but not skin conductance measures. Depress Anxiety 28(12):1058–66

    Article  PubMed  Google Scholar 

  • Greetfeld M, Schmidt MV, Ganea K, Sterlemann V, Liebl C, Müller MB (2009) A single episode of restraint stress regulates central corticotrophin- releasing hormone receptor expression and binding in specific areas of the mouse brain. J Neuroendocrinol 21(5):473–80

    Article  PubMed  CAS  Google Scholar 

  • Gresack JE, Risbrough VB (2011) Corticotropin-releasing factor and noradrenergic signalling exert reciprocal control over startle reactivity. Int J Neuropsychopharmacol 14(9):1179–94

    Article  PubMed  CAS  Google Scholar 

  • Grillon C, Ameli R, Foot M, Davis M (1993) Fear-potentiated startle: relationship to the level of state/trait anxiety in healthy subjects. Biol Psychiatry 33(8–9):566–74

    Article  PubMed  CAS  Google Scholar 

  • Grillon C, Baas J (2003) A review of the modulation of the startle reflex by affective states and its application in psychiatry. Clin Neurophysiol 114(9):1557–79

    Article  PubMed  Google Scholar 

  • Grillon C, Morgan CA, Southwick SM, Davis M, Charney DS (1996) Baseline startle amplitude and prepulse inhibition in Vietnam veterans with posttraumatic stress disorder. Psychiatry Res 64(3):169–78

    Article  PubMed  CAS  Google Scholar 

  • Grillon C, Pine DS, Lissek S, Rabin S, Bonne O, Vythilingam M (2009) Increased anxiety during anticipation of unpredictable aversive stimuli in posttraumatic stress disorder but not in generalized anxiety disorder. Biol Psychiatry 66(1):47–53

    Article  PubMed  Google Scholar 

  • Gutknecht E, Van der Linden I, Van Kolen K, Verhoeven KF, Vauquelin G, Dautzenberg FM (2009) Molecular mechanisms of corticotropin-releasing factor receptor-induced calcium signaling. Mol Pharmacol 75(3):648–57

    Article  PubMed  CAS  Google Scholar 

  • Hains AB, Vu MA, Maciejewski PK, van Dyck CH, Gottron M, Arnsten AF (2009) Inhibition of protein kinase C signaling protects prefrontal cortex dendritic spines and cognition from the effects of chronic stress. Proc Natl Acad Sci U S A 106(42):17957–62

    Article  PubMed  CAS  Google Scholar 

  • Hauger RL, Olivares-Reyes JA, Braun S, Catt KJ, Dautzenberg FM (2003) Mediation of corticotropin releasing factor type 1 receptor phosphorylation and desensitization by protein kinase C: a possible role in stress adaptation. J Pharmacol Exp Ther 306(2):794–803

    Article  PubMed  CAS  Google Scholar 

  • Hauger RL, Olivares-Reyes JA, Dautzenberg FM, Lohr JB, Braun S, Oakley RH (2012) Molecular and cell signaling targets for PTSD pathophysiology and pharmacotherapy. Neuropharmacology 62(2):705–14

    Article  PubMed  CAS  Google Scholar 

  • Hauger RL, Risbrough V, Oakley RH, Olivares-Reyes JA, Dautzenberg FM (2009) Role of CRF receptor signaling in stress vulnerability, anxiety, and depression. Ann N Y Acad Sci 1179:120–43

    Article  PubMed  CAS  Google Scholar 

  • Hillhouse EW, Grammatopoulos DK (2006) The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev 27(3):260–86

    Article  PubMed  CAS  Google Scholar 

  • Jovanovic T, Norrholm SD, Fennell JE, Keyes M, Fiallos AM, Myers KM, Davis M, Duncan EJ (2009) Posttraumatic stress disorder may be associated with impaired fear inhibition: relation to symptom severity. Psychiatry Res 167(1–2):151–60

    Article  PubMed  Google Scholar 

  • Kash TL, Winder DG (2006) Neuropeptide Y and corticotropin-releasing factor bi-directionally modulate inhibitory synaptic transmission in the bed nucleus of the stria terminalis. Neuropharmacology 51(5):1013–22

    Article  PubMed  CAS  Google Scholar 

  • Kehne JH, Astrachan DI, Astrachan E, Tallman JF, Davis M (1986) The role of spinal cord cyclic AMP in the acoustic startle response in rats. J Neurosci 6(11):3250–7

    PubMed  CAS  Google Scholar 

  • Kelly MP, Isiegas C, Cheung YF, Tokarczyk J, Yang X, Esposito MF, Rapoport DA, Fabian SA, Siegel SJ, Wand G, Houslay MD, Kanes SJ, Abel T (2007) Constitutive activation of Galphas within forebrain neurons causes deficits in sensorimotor gating because of PKA-dependent decreases in cAMP. Neuropsychopharmacology 32(3):577–88

    Article  PubMed  CAS  Google Scholar 

  • Koob GF (1999) Corticotropin-releasing factor, norepinephrine, and stress. Biol Psychiatry 46(9):1167–80

    Article  PubMed  CAS  Google Scholar 

  • Lee Y, Davis M (1997) Role of the hippocampus, the bed nucleus of the stria terminalis, and the amygdala in the excitatory effect of corticotropin-releasing hormone on the acoustic startle reflex. J Neurosci 17(16):6434–46

    PubMed  CAS  Google Scholar 

  • Lee Y, Fitz S, Johnson PL, Shekhar A (2008) Repeated stimulation of CRF receptors in the BNST of rats selectively induces social but not panic-like anxiety. Neuropsychopharmacology 33(11):2586–94

    Article  PubMed  CAS  Google Scholar 

  • Lesscher HM, McMahon T, Lasek AW, Chou WH, Connolly J, Kharazia V, Messing RO (2008) Amygdala protein kinase C epsilon regulates corticotropin-releasing factor and anxiety-like behavior. Genes Brain Behav 7(3):323–33

    Article  PubMed  CAS  Google Scholar 

  • Liang KC, Chen HC, Chen DY (2001) Posttraining infusion of norepinephrine and corticotropin releasing factor into the bed nucleus of the stria terminalis enhanced retention in an inhibitory avoidance task. Chin J Physiol 44(1):33–43

    PubMed  CAS  Google Scholar 

  • Lu KT, Walker DL, Davis M (2001) Mitogen-activated protein kinase cascade in the basolateral nucleus of amygdala is involved in extinction of fear-potentiated startle. J Neurosci 21(16):RC162

    PubMed  CAS  Google Scholar 

  • McElligott ZA, Klug JR, Nobis WP, Patel S, Grueter BA, Kash TL, Winder DG (2010) Distinct forms of Gq-receptor-dependent plasticity of excitatory transmission in the BNST are differentially affected by stress. Proc Natl Acad Sci U S A 107(5):2271–6

    Article  PubMed  CAS  Google Scholar 

  • Meloni EG, Gerety LP, Knoll AT, Cohen BM, Carlezon WA Jr (2006) Behavioral and anatomical interactions between dopamine and corticotropin-releasing factor in the rat. J Neurosci 26(14):3855–63

    Article  PubMed  CAS  Google Scholar 

  • Morgan CA 3rd, Grillon C, Southwick SM, Davis M, Charney DS (1995) Fear-potentiated startle in posttraumatic stress disorder. Biol Psychiatry 38(6):378–85

    Article  PubMed  Google Scholar 

  • Müller MB, Zimmermann S, Sillaber I, Hagemeyer TP, Deussing JM, Timpl P, Kormann MS, Droste SK, Kühn R, Reul JM, Holsboer F, Wurst W (2003) Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci 6(10):1100–7

    Article  PubMed  Google Scholar 

  • Oberlander JG, Henderson LP (2012) Corticotropin-releasing factor modulation of forebrain GABAergic transmission has a pivotal role in the expression of anabolic steroid-induced anxiety in the female mouse. Neuropsychopharmacology 37(6):1483–99. doi:10.1038/npp.2011.334

    Article  PubMed  CAS  Google Scholar 

  • Nobis WP, Kash TL, Silberman Y, Winder DG (2011) β-Adrenergic receptors enhance excitatory transmission in the bed nucleus of the stria terminalis through a corticotrophin-releasing factor receptor-dependent and cocaine-regulated mechanism. Biol Psychiatry 69(11):1083–90

    Article  PubMed  CAS  Google Scholar 

  • Parsons RG, Davis M (2011) Temporary disruption of fear-potentiated startle following PKMζ inhibition in the amygdala. Nat Neurosci 14(3):295–6

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates. Academic, San Diego

    Google Scholar 

  • Pollandt S, Liu J, Orozco-Cabal L, Grigoriadis DE, Vale WW, Gallagher JP, Shinnick-Gallagher P (2006) Cocaine withdrawal enhances long-term potentiation induced by corticotropin-releasing factor at central amygdala glutamatergic synapses via CRF, NMDA receptors and PKA. Eur J Neurosci 24(6):1733–43

    Article  PubMed  Google Scholar 

  • Price ML, Kirby LG, Valentino RJ, Lucki I (2002) Evidence for corticotropin-releasing factor regulation of serotonin in the lateral septum during acute swim stress: adaptation produced by repeated swimming. Psychopharmacology (Berl) 162(4):406–14

    Article  CAS  Google Scholar 

  • Punn A, Levine MA, Grammatopoulos DK (2006) Identification of signaling molecules mediating corticotropin-releasing hormone-R1alpha-mitogen-activated protein kinase (MAPK) interactions: the critical role of phosphatidylinositol 3-kinase in regulating ERK1/2 but not p38 MAPK activation. Mol Endocrinol 20(12):3179–95

    Article  PubMed  CAS  Google Scholar 

  • Radulovic J, Rühmann A, Liepold T, Spiess J (1999) Modulation of learning and anxiety by corticotropin-releasing factor (CRF) and stress: differential roles of CRF receptors 1 and 2. J Neurosci 19(12):5016–25

    PubMed  CAS  Google Scholar 

  • Regev L, Neufeld-Cohen A, Tsoory M, Kuperman Y, Getselter D, Gil S, Chen A (2011) Prolonged and site-specific over-expression of corticotropin-releasing factor reveals differential roles for extended amygdala nuclei in emotional regulation. Mol Psychiatry 16(7):714–28. doi:10.1038/mp.2010.64

    Article  PubMed  CAS  Google Scholar 

  • Risbrough VB, Geyer MA (2005) Anxiogenic treatments do not increase fear-potentiated startle in mice. Biol Psychiatry 57(1):33–43

    Article  PubMed  CAS  Google Scholar 

  • Risbrough VB, Geyer MA, Hauger RL, Coste S, Stenzel-Poore M, Wurst W, Holsboer F (2009) CRF1 and CRF2 receptors are required for potentiated startle to contextual but not discrete cues. Neuropsychopharmacology 34(6):1494–503

    Article  PubMed  CAS  Google Scholar 

  • Risbrough VB, Hauger RL, Pelleymounter MA, Geyer MA (2003) Role of corticotropin releasing factor (CRF) receptors 1 and 2 in CRF-potentiated acoustic startle in mice. Psychopharmacology (Berl) 170(2):178–87

    Article  CAS  Google Scholar 

  • Risbrough VB, Hauger RL, Roberts AL, Vale WW, Geyer MA (2004) Corticotropin-releasing factor receptors CRF1 and CRF2 exert both additive and opposing influences on defensive startle behavior. J Neurosci 24(29):6545–52

    Article  PubMed  CAS  Google Scholar 

  • Risbrough VB, Stein MB (2006) Role of corticotropin releasing factor in anxiety disorders: a translational research perspective. Horm Behav 50(4):550–61

    Article  PubMed  CAS  Google Scholar 

  • Sahuque LL, Kullberg EF, Mcgeehan AJ, Kinder JR, Hicks MP, Blanton MG, Janak PH, Olive MF (2006) Anxiogenic and aversive effects of corticotropin-releasing factor (CRF) in the bed nucleus of the stria terminalis in the rat: role of CRF receptor subtypes. Psychopharmacology (Berl) 186(1):122–32

    Article  CAS  Google Scholar 

  • Sananbenesi F, Fischer A, Schrick C, Spiess J, Radulovic J (2003) Mitogen-activated protein kinase signaling in the hippocampus and its modulation by corticotropin-releasing factor receptor 2: a possible link between stress and fear memory. J Neurosci 23(36):11436–43

    PubMed  CAS  Google Scholar 

  • Sautter FJ, Bissette G, Wiley J, Manguno-Mire G, Schoenbachler B, Myers L, Johnson JE, Cerbone A, Malaspina D (2003) Corticotropin-releasing factor in posttraumatic stress disorder (PTSD) with secondary psychotic symptoms, nonpsychotic PTSD, and healthy control subjects. Biol Psychiatry 54(12):1382–8

    Article  PubMed  CAS  Google Scholar 

  • Schafe GE, Atkins CM, Swank MW, Bauer EP, Sweatt JD, LeDoux JE (2000) Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning. J Neurosci 20(21):8177–87

    PubMed  CAS  Google Scholar 

  • Schafe GE, Nadel NV, Sullivan GM, Harris A, LeDoux JE (1999) Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. Learn Mem 6(2):97–110

    PubMed  CAS  Google Scholar 

  • Selvamani A, Lincoln C, Uphouse L (2007) The PKC inhibitor, bisindolymaleimide, blocks DOI’s attenuation of the effects of 8-OH-DPAT on female rat lordosis behavior. Behav Brain Res 179(1):99–106

    Article  PubMed  CAS  Google Scholar 

  • Sheng H, Zhang Y, Sun J, Gao L, Ma B, Lu J, Ni X (2008) Corticotropin-releasing hormone (CRH) depresses n-methyl-D-aspartate receptor-mediated current in cultured rat hippocampal neurons via CRH receptor type 1. Endocrinology 149(3):1389–98

    Article  PubMed  CAS  Google Scholar 

  • Sink KS, Walker DL, Freeman SM, Flandreau EI, Ressler KJ, Davis M (2013) Effects of continuously enhanced corticotropin releasing factor expression within the bed nucleus of the stria terminalis on conditioned and unconditioned anxiety. Mol Psychiatry 18(3):308–319. doi:10.1038/mp.2011.188

    Article  PubMed  CAS  Google Scholar 

  • Siuciak JA, McCarthy SA, Chapin DS, Martin AN (2008) Behavioral and neurochemical characterization of mice deficient in the phosphodiesterase-4B (PDE4B) enzyme. Psychopharmacology (Berl) 197(1):115–26

    Article  CAS  Google Scholar 

  • Sztainberg Y, Kuperman Y, Justice N, Chen A (2011) An anxiolytic role for CRF receptor type 1 in the globus pallidus. J Neurosci 31:17416–24

    Article  PubMed  CAS  Google Scholar 

  • Steckler T, Risbrough V (2012) Pharmacological treatment of PTSD—established and new approaches. Neuropharmacology 62(2):617–27

    Article  PubMed  CAS  Google Scholar 

  • Sweatt JD (2001) The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76(1):1–10

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, Britton KT, Koob GF (1989) Potentiation of acoustic startle by corticotropin-releasing factor (CRF) and by fear are both reversed by alpha-helical CRF (9–41). Neuropsychopharmacology 2(4):285–92

    Article  PubMed  CAS  Google Scholar 

  • Takahashi LK (2001) Role of CRF(1) and CRF(2) receptors in fear and anxiety. Neurosci Biobehav Rev 25(7–8):627–36

    Article  PubMed  CAS  Google Scholar 

  • Tan H, Zhong P, Yan Z (2004) Corticotropin-releasing factor and acute stress prolongs serotonergic regulation of GABA transmission in prefrontal cortical pyramidal neurons. J Neurosci 24(21):5000–8

    Article  PubMed  CAS  Google Scholar 

  • Todorovic C, Sherrin T, Pitts M, Hippel C, Rayner M, Spiess J (2009) Suppression of the MEK/ERK signaling pathway reverses depression-like behaviors of CRF2-deficient mice. Neuropsychopharmacology 34(6):1416–26

    Article  PubMed  CAS  Google Scholar 

  • Ugolini A, Sokal DM, Arban R, Large CH (2008) CRF1 receptor activation increases the response of neurons in the basolateral nucleus of the amygdala to afferent stimulation. Front Behav Neurosci 2:2

    Article  PubMed  Google Scholar 

  • Ungless MA, Singh V, Crowder TL, Yaka R, Ron D, Bonci A (2003) Corticotropin-releasing factor requires CRF binding protein to potentiate NMDA receptors via CRF receptor 2 in dopamine neurons. Neuron 39(3):401–7

    Article  PubMed  CAS  Google Scholar 

  • Van Pett K, Viau V, Bittencourt JC, Chan RK, Li HY, Arias C, Prins GS, Perrin M, Vale W, Sawchenko PE (2000) Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse. J Comp Neurol 428:191–212

    Google Scholar 

  • Vinkers CH, Risbrough VB, Geyer MA, Caldwell S, Low MJ, Hauger RL (2007) Role of dopamine D1 and D2 receptors in CRF-induced disruption of sensorimotor gating. Pharmacol Biochem Behav 86(3):550–8

    Article  PubMed  CAS  Google Scholar 

  • Waddell J, Bouton ME, Falls WA (2008) Central CRF receptor antagonist a-helical CRF9-41 blocks reinstatement of extinguished fear: the role of the bed nucleus of the stria terminalis. Behav Neurosci 122(5):1061–9

    Article  PubMed  Google Scholar 

  • Walker DL, Gold PE (1994) Intra-amygdala kinase inhibitors disrupt retention of a learned avoidance response in rats. Neurosci Lett 176(2):255–8

    Article  PubMed  CAS  Google Scholar 

  • Walker DL, Miles LA, Davis M (2009a) Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like responses. Prog Neuropsychopharmacol Biol Psychiatry 33(8):1291–308

    Article  PubMed  CAS  Google Scholar 

  • Walker D, Yang Y, Ratti E, Corsi M, Trist D, Davis M (2009b) Differential effects of the CRF-R1 antagonist GSK876008 on fear-potentiated, light- and CRF-enhanced startle suggest preferential involvement in sustained vs phasic threat responses. Neuropsychopharmacology 34(6):1533–42

    Article  PubMed  CAS  Google Scholar 

  • Walz R, Roesler R, Quevedo J, Sant'Anna MK, Madruga M, Rodrigues C, Gottfried C, Medina JH, Izquierdo I (2000) Time-dependent impairment of inhibitory avoidance retention in rats by posttraining infusion of a mitogen-activated protein kinase kinase inhibitor into cortical and limbic structures. Neurobiol Learn Mem 73(1):11–20

    Article  PubMed  CAS  Google Scholar 

  • Wanat MJ, Hopf FW, Stuber GD, Phillips PE, Bonci A (2008) Corticotropin-releasing factor increases mouse ventral tegmental area dopamine neuron firing through a protein kinase C-dependent enhancement of Ih. J Physiol 586(8):2157–70

    Article  PubMed  CAS  Google Scholar 

  • Waselus M, Nazzaro C, Valentino RJ, Van Bockstaele EJ (2009) Stress-induced redistribution of corticotropin-releasing factor receptor subtypes in the dorsal raphe nucleus. Biol Psychiatry 66(1):76–83

    Article  PubMed  CAS  Google Scholar 

  • Wehner JM, Sleight S, Upchurch M (1990) Hippocampal protein kinase C activity is reduced in poor spatial learners. Brain Res 523(2):181–7

    Article  PubMed  CAS  Google Scholar 

  • Yasoshima Y, Yamamoto T (1997) Rat gustatory memory requires protein kinase C activity in the amygdala and cortical gustatory area. Neuroreport 8(6):1363–7

    Article  PubMed  CAS  Google Scholar 

  • Zorrilla EP, Koob GF (2010) Progress in corticotropin-releasing factor-1 antagonist development. Drug Discov Today 15(9–10):371–83

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was funded by a Veterans Affairs Merit Grant to RLH, Veterans Affairs Center of Excellence for Stress and Mental Health to VBR and RLH, and NIMH 074697 to VBR.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Center of Excellence for Stress and Mental Health, Veterans Affairs Hospital, La Jolla, CA, USA

    M. Toth, R. L. Hauger & V. B. Risbrough

  2. Department of Psychiatry, University of California San Diego, 9500 Gilman Dr. MC0804, La Jolla, CA, 92093-0804, USA

    M. Toth, J. E. Gresack, R. L. Hauger, A. L. Halberstadt & V. B. Risbrough

  3. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA

    J. E. Gresack

Authors
  1. M. Toth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. E. Gresack
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. L. Hauger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. L. Halberstadt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. V. B. Risbrough
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V. B. Risbrough.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Toth, M., Gresack, J.E., Hauger, R.L. et al. The role of PKC signaling in CRF-induced modulation of startle. Psychopharmacology 229, 579–589 (2013). https://doi.org/10.1007/s00213-013-3114-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-013-3114-9

Keywords

Search

Navigation