RASGRF1 in CRF cells controls the early adolescent female response to repeated stress

in Journal of Endocrinology
View More View Less
  • 1 Department of Developmental, Molecular, and Chemical Biology, Boston, Massachusetts, USA
  • 2 Neuroscence Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, USA
  • 3 Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, USA

Correspondence should be addressed to L A Feig: larry.feig@tufts.edu

*(S Jin and D A Dickson contributed equally to this work)

Restricted access

RASGRF1 (GRF1) is a calcium-stimulated guanine-nucleotide exchange factor that activates RAS and RAC GTPases. In hippocampus neurons, it mediates the action of NMDA and calcium-permeable AMPA glutamate receptors on specific forms of synaptic plasticity, learning, and memory in both male and female mice. Recently, we showed GRF1 also regulates the HPA axis response to restraint stress, but only in female mice before puberty. In particular, we found that after 7 days of restraint stress (7DRS) (30 min/day) both elevated serum CORT levels and induction of an anxiolytic phenotype normally observed in early adolescent (EA) female mice are blocked in GRF1-knockout mice. In contrast, no effects were observed in EA male or adult females. Here, we show this phenotype is due, at least in part, to GRF1 loss in CRF cells of the paraventricular nucleus of the hypothalamus, as GRF1 knockout specifically in these cells suppressed 7DRS-induced elevation of serum CORT levels specifically in EA females, but only down to levels found in comparably stressed EA males. Nevertheless, it still completely blocked the 7DRS-induced anxiolytic phenotype observed in EA females. Interestingly, loss of GRF1 in CRF cells had no effect after only three restraint stress exposures, implying a role for GRF1 in 7DRS stress-induced plasticity of CRF cells that appears to be specific to EA female mice. Overall, these findings indicate that GRF1 in CRF cells makes a key contribution to the distinct response EA females display to repeated stress.

 

      Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 522 522 54
Full Text Views 47 47 2
PDF Downloads 26 26 0
  • Aguilera G & Liu Y 2012 The molecular physiology of CRH neurons. Frontiers in Neuroendocrinology 33 6784. (https://doi.org/10.1016/j.yfrne.2011.08.002)

    • Search Google Scholar
    • Export Citation
  • Andersen SL & Teicher MH 2008 Stress, sensitive periods and maturational events in adolescent depression. Trends in Neurosciences 31 183191. (https://doi.org/10.1016/j.tins.2008.01.004)

    • Search Google Scholar
    • Export Citation
  • Andersen SL, Tomada A, Vincow ES, Valente E, Polcari A & Teicher MH 2008 Preliminary evidence for sensitive periods in the effect of childhood sexual abuse on regional brain development. Journal of Neuropsychiatry and Clinical Neurosciences 20 292301. (https://doi.org/10.1176/jnp.2008.20.3.292)

    • Search Google Scholar
    • Export Citation
  • Arnold AP 2009 The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Hormones and Behavior 55 570578. (https://doi.org/10.1016/j.yhbeh.2009.03.011)

    • Search Google Scholar
    • Export Citation
  • Bains JS, Wamsteeker Cusulin JI & Inoue W 2015 Stress-related synaptic plasticity in the hypothalamus. Nature Reviews: Neuroscience 16 377388. (https://doi.org/10.1038/nrn3881)

    • Search Google Scholar
    • Export Citation
  • Bale TL & Epperson CN 2015 Sex differences and stress across the lifespan. Nature Neuroscience 18 14131420. (https://doi.org/10.1038/nn.4112)

    • Search Google Scholar
    • Export Citation
  • Bangasser DA & Valentino RJ 2014 Sex differences in stress-related psychiatric disorders: neurobiological perspectives. Frontiers in Neuroendocrinology 35 303319. (https://doi.org/10.1016/j.yfrne.2014.03.008)

    • Search Google Scholar
    • Export Citation
  • Blumenthal H, Leen-Feldner EW, Trainor CD, Babson KA & Bunaciu L 2009 Interactive roles of pubertal timing and peer relations in predicting social anxiety symptoms among youth. Journal of Adolescent Health 44 401403. (https://doi.org/10.1016/j.jadohealth.2008.08.023)

    • Search Google Scholar
    • Export Citation
  • Blumenthal H, Leen-Feldner EW, Badour CL, Trainor CD & Babson KA 2014 Pubertal maturation and cortisol level in response to a novel social environment among female adolescents. Journal of Adolescence 37 893900. (https://doi.org/10.1016/j.adolescence.2014.06.005)

    • Search Google Scholar
    • Export Citation
  • 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. American Journal of Psychiatry 154 624629. (https://doi.org/10.1176/ajp.154.5.624)

    • Search Google Scholar
    • Export Citation
  • Burke AR & Miczek KA 2014 Stress in adolescence and drugs of abuse in rodent models: role of dopamine, CRF, and HPA axis. Psychopharmacology 231 15571580. (https://doi.org/10.1007/s00213-013-3369-1)

    • Search Google Scholar
    • Export Citation
  • Cerovic M, Bagetta V, Pendolino V, Ghiglieri V, Fasano S, Morella I, Hardingham N, Heuer A, Papale A, Marchisella F, et al. 2015 Derangement of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and extracellular signal-regulated kinase (ERK) dependent striatal plasticity in L-DOPA-induced dyskinesia. Biological Psychiatry 77 106115. (https://doi.org/10.1016/j.biopsych.2014.04.002)

    • Search Google Scholar
    • Export Citation
  • Chi P, Greengard P & Ryan TA 2003 Synaptic vesicle mobilization is regulated by distinct synapsin I phosphorylation pathways at different frequencies. Neuron 38 6978. (https://doi.org/10.1016/s0896-6273(03)00151-x)

    • Search Google Scholar
    • Export Citation
  • Darcy MJ, Trouche S, Jin SX & Feig LA 2014 Age-dependent role for ras-GRF1 in the late stages of adult neurogenesis in the dentate gyrus. Hippocampus 24 315325. (https://doi.org/10.1002/hipo.22225)

    • Search Google Scholar
    • Export Citation
  • Doremus-Fitzwater TL & Spear LP 2016 Reward-centricity and attenuated aversions: an adolescent phenotype emerging from studies in laboratory animals. Neuroscience and Biobehavioral Reviews 70 121134. (https://doi.org/10.1016/j.neubiorev.2016.08.015)

    • Search Google Scholar
    • Export Citation
  • Feig LA 2011 Regulation of neuronal function by Ras-GRF exchange factors. Genes and Cancer 2 306319. (https://doi.org/10.1177/1947601911408077)

    • Search Google Scholar
    • Export Citation
  • Fuzesi T, Daviu N, Wamsteeker Cusulin JI, Bonin RP & Bains JS 2016 Hypothalamic CRH neurons orchestrate complex behaviours after stress. Nature Communications 7 11937. (https://doi.org/10.1038/ncomms11937)

    • Search Google Scholar
    • Export Citation
  • Gunnar MR, Talge NM & Herrera A 2009 Stressor paradigms in developmental studies: what does and does not work to produce mean increases in salivary cortisol. Psychoneuroendocrinology 34 953967. (https://doi.org/10.1016/j.psyneuen.2009.02.010)

    • Search Google Scholar
    • Export Citation
  • Handa RJ & Weiser MJ 2014 Gonadal steroid hormones and the hypothalamo-pituitary-adrenal axis. Frontiers in Neuroendocrinology 35 197220. (https://doi.org/10.1016/j.yfrne.2013.11.001)

    • Search Google Scholar
    • Export Citation
  • Hankin BL, Abramson LY, Moffitt TE, Silva PA, McGee R & Angell KE 1998 Development of depression from preadolescence to young adulthood: emerging gender differences in a 10-year longitudinal study. Journal of Abnormal Psychology 107 128140. (https://doi.org/10.1037//0021-843x.107.1.128)

    • Search Google Scholar
    • Export Citation
  • Heck AL & Handa RJ 2019 Sex differences in the hypothalamic-pituitary-adrenal axis’ response to stress: an important role for gonadal hormones. Neuropsychopharmacology 44 4558. (https://doi.org/10.1038/s41386-018-0167-9)

    • Search Google Scholar
    • Export Citation
  • Herman JP & Tasker JG 2016 Paraventricular hypothalamic mechanisms of chronic stress adaptation. Frontiers in Endocrinology 7 137. (https://doi.org/10.3389/fendo.2016.00137)

    • Search Google Scholar
    • Export Citation
  • Jin SX, Arai J, Tian X, Kumar-Singh R & Feig LA 2013 Acquisition of contextual discrimination involves the appearance of a RAS-GRF1/p38 mitogen-activated protein (MAP) kinase-mediated signaling pathway that promotes long term potentiation (LTP). Journal of Biological Chemistry 288 2170321713. (https://doi.org/10.1074/jbc.M113.471904)

    • Search Google Scholar
    • Export Citation
  • Juraska JM & Willing J 2017 Pubertal onset as a critical transition for neural development and cognition. Brain Research 1654 8794. (https://doi.org/10.1016/j.brainres.2016.04.012)

    • Search Google Scholar
    • Export Citation
  • Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, Gelenberg AJ, Davis SM, Harrison WM & Keller MB 2000 Gender differences in treatment response to sertraline versus imipramine in chronic depression. American Journal of Psychiatry 157 14451452. (https://doi.org/10.1176/appi.ajp.157.9.1445)

    • Search Google Scholar
    • Export Citation
  • Krapivinsky G, Krapivinsky L, Manasian Y, Ivanov A, Tyzio R, Pellegrino C, Ben-Ari Y, Clapham DE & Medina I 2003 The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1. Neuron 40 775784. (https://doi.org/10.1016/s0896-6273(03)00645-7)

    • Search Google Scholar
    • Export Citation
  • Li S, Tian X, Hartley DM & Feig LA 2006 Distinct roles for Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 in the induction of long-term potentiation and long-term depression. Journal of Neuroscience 26 17211729. (https://doi.org/10.1523/JNEUROSCI.3990-05.2006)

    • Search Google Scholar
    • Export Citation
  • Maguire J 2014 Stress-induced plasticity of GABAergic inhibition. Frontiers in Cellular Neuroscience 8 157. (https://doi.org/10.3389/fncel.2014.00157)

    • Search Google Scholar
    • Export Citation
  • McEwen BS 2007 Physiology and neurobiology of stress and adaptation: central role of the brain. Physiological Reviews 87 873904. (https://doi.org/10.1152/physrev.00041.2006)

    • Search Google Scholar
    • Export Citation
  • McLaughlin KA & King K 2015 Developmental trajectories of anxiety and depression in early adolescence. Journal of Abnormal Child Psychology 43 311323. (https://doi.org/10.1007/s10802-014-9898-1)

    • Search Google Scholar
    • Export Citation
  • Melon LC, Hooper A, Yang X, Moss SJ & Maguire J 2018 Inability to suppress the stress-induced activation of the HPA axis during the peripartum period engenders deficits in postpartum behaviors in mice. Psychoneuroendocrinology 90 182193. (https://doi.org/10.1016/j.psyneuen.2017.12.003)

    • Search Google Scholar
    • Export Citation
  • Nectow AR, Moya MV, Ekstrand MI, Mousa A, McGuire KL, Sferrazza CE, Field BC, Rabinowitz GS, Sawicka K, Liang Y, et al. 2017 Rapid molecular profiling of defined cell types using viral TRAP. Cell Reports 19 655667. (https://doi.org/10.1016/j.celrep.2017.03.048)

    • Search Google Scholar
    • Export Citation
  • Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K, Kilts CD, Loosen PT & Vale W 1984 Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science 226 13421344. (https://doi.org/10.1126/science.6334362)

    • Search Google Scholar
    • Export Citation
  • Romanov RA, Zeisel A, Bakker J, Girach F, Hellysaz A, Tomer R, Alpar A, Mulder J, Clotman F, Keimpema E, et al. 2017 Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes. Nature Neuroscience 20 176188. (https://doi.org/10.1038/nn.4462)

    • Search Google Scholar
    • Export Citation
  • Romeo RD 2018 The metamorphosis of adolescent hormonal stress reactivity: a focus on animal models. Frontiers in Neuroendocrinology 49 4351. (https://doi.org/10.1016/j.yfrne.2017.12.003)

    • Search Google Scholar
    • Export Citation
  • Romeo RD, Bellani R, Karatsoreos IN, Chhua N, Vernov M, Conrad CD & McEwen BS 2006 Stress history and pubertal development interact to shape hypothalamic-pituitary-adrenal axis plasticity. Endocrinology 147 16641674. (https://doi.org/10.1210/en.2005-1432)

    • Search Google Scholar
    • Export Citation
  • Senst L, Baimoukhametova D, Sterley TL & Bains JS 2016 Sexually dimorphic neuronal responses to social isolation. eLife 5 e18726. (https://doi.org/10.7554/eLife.18726)

    • Search Google Scholar
    • Export Citation
  • Skogli EW, Teicher MH, Andersen PN, Hovik KT & Oie M 2013 ADHD in girls and boys – gender differences in co-existing symptoms and executive function measures. BMC Psychiatry 13 298. (https://doi.org/10.1186/1471-244X-13-298)

    • Search Google Scholar
    • Export Citation
  • Sorge RE, Martin LJ, Isbester KA, Sotocinal SG, Rosen S, Tuttle AH, Wieskopf JS, Acland EL, Dokova A, Kadoura B, et al. 2014 Olfactory exposure to males, including men, causes stress and related analgesia in rodents. Nature Methods 11 629632. (https://doi.org/10.1038/nmeth.2935)

    • Search Google Scholar
    • Export Citation
  • Spear LP 2000 The adolescent brain and age-related behavioral manifestations. Neuroscience and Biobehavioral Reviews 24 417463. (https://doi.org/10.1016/s0149-7634(00)00014-2)

    • Search Google Scholar
    • Export Citation
  • Stern JE & Filosa JA 2013 Bidirectional neuro-glial signaling modalities in the hypothalamus: role in neurohumoral regulation. Autonomic Neuroscience: Basic and Clinical 175 5160. (https://doi.org/10.1016/j.autneu.2012.12.009)

    • Search Google Scholar
    • Export Citation
  • Taniguchi H, He M, Wu P, Kim S, Paik R, Sugino K, Kvitsiani D, Fu Y, Lu J, Lin Y, et al. 2011 A resource of Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex. Neuron 71 9951013. (https://doi.org/10.1016/j.neuron.2011.07.026)

    • Search Google Scholar
    • Export Citation
  • Toledo-Rodriguez M & Sandi C 2011 Stress during adolescence increases novelty seeking and risk-taking behavior in male and female rats. Frontiers in Behavioral Neuroscience 5 17. (https://doi.org/10.3389/fnbeh.2011.00017)

    • Search Google Scholar
    • Export Citation
  • Uzturk BG, Jin SX, Rubin B, Bartolome C & Feig LA 2015 RasGRF1 regulates the hypothalamic-pituitary-adrenal axis specifically in early-adolescent female mice. Journal of Endocrinology 227 112. (https://doi.org/10.1530/JOE-15-0304)

    • Search Google Scholar
    • Export Citation
  • Valentino RJ, Van Bockstaele E & Bangasser D 2013 Sex-specific cell signaling: the corticotropin-releasing factor receptor model. Trends in Pharmacological Sciences 34 437–444.

    • Search Google Scholar
    • Export Citation
  • Wille-Bille A, Ferreyra A, Sciangula M, Chiner F, Nizhnikov ME & Pautassi RM 2017 Restraint stress enhances alcohol intake in adolescent female rats but reduces alcohol intake in adolescent male and adult female rats. Behavioural Brain Research 332 269279. (https://doi.org/10.1016/j.bbr.2017.06.004)

    • Search Google Scholar
    • Export Citation