Hostname: page-component-586b7cd67f-rcrh6 Total loading time: 0 Render date: 2024-12-04T09:24:39.344Z Has data issue: false hasContentIssue false
  • English
  • Français

Early life adversity and serotonin transporter gene variation interact to affect DNA methylation of the corticotropin-releasing factor gene promoter region in the adult rat brain

Published online by Cambridge University Press:  02 February 2015

Rick H. A. van der Doelen ,
Ilse A. Arnoldussen ,
Hussein Ghareh ,
Liselot van Och ,
Judith R. Homberg  and
Tamás Kozicz
Rick H. A. van der Doelen*
Affiliation:
Radboud University Nijmegen Medical Centre
Ilse A. Arnoldussen
Affiliation:
Radboud University Nijmegen Medical Centre
Hussein Ghareh
Affiliation:
Radboud University Nijmegen Medical Centre
Liselot van Och
Affiliation:
Radboud University Nijmegen Medical Centre
Judith R. Homberg
Affiliation:
Radboud University Nijmegen Medical Centre
Tamás Kozicz
Affiliation:
Radboud University Nijmegen Medical Centre
*
Address correspondence and reprint requests to: Rick H.A. van der Doelen, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21 (route 126), 6525 EZ Nijmegen, The Netherlands; E-mail: [email protected].
Get access Rights & Permissions [Opens in a new window]

Abstract

The interaction between childhood maltreatment and the serotonin transporter (5-HTT) gene linked polymorphic region has been associated with increased risk to develop major depression. This Gene × Environment interaction has furthermore been linked with increased levels of anxiety and glucocorticoid release upon exposure to stress. Both endophenotypes are regulated by the neuropeptide corticotropin-releasing factor (CRF) or hormone, which is expressed by the paraventricular nucleus of the hypothalamus, the bed nucleus of the stria terminalis, and the central amygdala (CeA). Therefore, we hypothesized that altered regulation of the expression of CRF in these areas represents a major neurobiological mechanism underlying the interaction of early life stress and 5-HTT gene variation. The programming of gene transcription by Gene × Environment interactions has been proposed to involve epigenetic mechanisms such as DNA methylation. In this study, we report that early life stress and 5-HTT genotype interact to affect DNA methylation of the Crf gene promoter in the CeA of adult male rats. Furthermore, we found that DNA methylation of a specific site in the Crf promoter significantly correlated with CRF mRNA levels in the CeA. Moreover, CeA CRF mRNA levels correlated with stress coping behavior in a learned helplessness paradigm. Together, our findings warrant further investigation of the link of Crf promoter methylation and CRF expression in the CeA with behavioral changes that are relevant for psychopathology.

Type
Special Section Articles
Information
Development and Psychopathology , Volume 27 , Issue 1: What Works for Whom? Genetic Moderation of Intervention Efficacy , February 2015 , pp. 123 - 135
Copyright
Copyright © Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Aisa, B., Tordera, R., Lasheras, B., Del Río, J., & Ramírez, M. J. (2007). Cognitive impairment associated to HPA axis hyperactivity after maternal separation in rats. Psychoneuroendocrinology, 32, 256–266.CrossRefGoogle ScholarPubMed
Alexander, N., Kuepper, Y., Schmitz, A., Osinsky, R., Kozyra, E., & Hennig, J. (2009). Gene–environment interactions predict cortisol responses after acute stress: Implications for the etiology of depression. Psychoneuroendocrinology, 34, 1294–1303.Google Scholar
Arborelius, L., Owens, M. J., Plotsky, P. M., & Nemeroff, C. B. (1999). The role of corticotropin-releasing factor in depression and anxiety disorders. Journal of Endocrinology, 160, 1–12.Google Scholar
Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2011). Differential susceptibility to rearing environment depending on dopamine-related genes: New evidence and a meta-analysis. Development and Psychopathology, 23, 39–52.Google Scholar
Bale, T. L., Baram, T. Z., Brown, A. S., Goldstein, J. M., Insel, T. R., McCarthy, M. M., et al. (2010). Early life programming and neurodevelopmental disorders. Biological Psychiatry, 68, 314–319.CrossRefGoogle ScholarPubMed
Bale, T. L., & Vale, W. W. (2004). CRF and CRF receptors: Role in stress responsivity and other behaviors. Annual Review of Pharmacology and Toxicology, 44, 525–557.Google Scholar
Belsky, J., Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2007). For better and for worse: Differential susceptibility to environmental influences. Psychological Science, 16, 300–305.Google Scholar
Belsky, J., Jonassaint, C., Pluess, M., Stanton, M., Brummett, B., & Williams, R. (2009). Vulnerability genes or plasticity genes? Molecular Psychiatry, 14, 746–754.CrossRefGoogle ScholarPubMed
Binder, E. B., & Nemeroff, C. B. (2010). The CRF system, stress, depression and anxiety—Insights from human genetic studies. Molecular Psychiatry, 15, 574–588.Google Scholar
Bogdan, R., Hyde, L. W., & Hariri, A. R. (2013). A neurogenetics approach to understanding individual differences in brain, behavior, and risk for psychopathology. Molecular Psychiatry, 18, 288–299.Google Scholar
Bravo, J. A., Dinan, T. G., & Cryan, J. F. (2011). Alterations in the central CRF system of two different rat models of comorbid depression and functional gastrointestinal disorders. International Journal of Neuropsychopharmacology, 14, 666–683.CrossRefGoogle ScholarPubMed
Callahan, L. B., Tschetter, K. E., & Ronan, P. J. (2013). Inhibition of corticotropin releasing factor expression in the central nucleus of the amygdala attenuates stress-induced behavioral and endocrine responses. Frontiers in Neuroscience, 7, Article 195.CrossRefGoogle ScholarPubMed
Caspi, A., Sugden, K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H., et al. (2003). Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science, 301, 386–389.CrossRefGoogle ScholarPubMed
Champagne, D. L., De Kloet, E. R., & Joëls, M. (2009). Fundamental aspects of the impact of glucocorticoids on the (immature) brain. Seminars in Fetal and Neonatal Medicine, 14, 136–142.Google Scholar
Chen, J., Evans, A. N., Liu, Y., Honda, M., Saavedra, J. M., & Aguilera, G. (2012). Maternal deprivation in rats is associated with corticotrophin-releasing hormone (CRH) promoter hypomethylation and enhances CRH transcriptional responses to stress in adulthood. Journal of Neuroendocrinology, 24, 1055–1064.CrossRefGoogle ScholarPubMed
Cicchetti, D., Rogosch, F. A., & Oshri, A. (2011). Interactive effects of corticotropin releasing hormone receptor 1, serotonin transporter linked polymorphic region, and child maltreatment on diurnal cortisol regulation and internalizing symptomatology. Development and Psychopathology, 23, 1125–1138.Google Scholar
Desbonnet, L., Garrett, L., Daly, E., McDermott, K. W., & Dinan, T. G. (2008). Sexually dimorphic effects of maternal separation stress on corticotrophin-releasing factor and vasopressin systems in the adult rat brain. International Journal of Developmental Neuroscience, 26, 259–268.Google Scholar
Eisenberg, D. T. A., & Hayes, M. G. (2011). Testing the null hypothesis: Comments on culture–gene coevolution of individualism–collectivism and the serotonin transporter gene. Processes in Biological Science, 278, 329–332.Google Scholar
Elliott, E., Ezra-Nevo, G., Regev, L., Neufeld-Cohen, A., & Chen, A. (2010). Resilience to social stress coincides with functional DNA methylation of the Crf gene in adult mice. Nature Neuroscience, 13, 1351–1353.Google Scholar
Ellis, B. J., Boyce, W. T., Belsky, J., Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2011). Differential susceptibility to the environment: An evolutionary–neurodevelopmental theory. Development and Psychopathology, 23, 7–28.CrossRefGoogle Scholar
Flandreau, E. I., Ressler, K. J., Owens, M. J., & Nemeroff, C. B. (2012). Chronic overexpression of corticotropin-releasing factor from the central amygdala produces HPA axis hyperactivity and behavioral anxiety associated with gene-expression changes in the hippocampus and paraventricular nucleus of the hypothalamus. Psychoneuroendocrinology, 37, 27–38.CrossRefGoogle ScholarPubMed
Forster, G. L., Feng, N., Watt, M. J., Korzan, W. J., Mouw, N. J., Summers, C. H., et al. (2006). Corticotropin-releasing factor in the dorsal raphe elicits temporally distinct serotonergic responses in the limbic system in relation to fear behavior. Neuroscience, 141, 1047–1055.CrossRefGoogle ScholarPubMed
Forster, G. L., Pringle, R. B., Mouw, N. J., Vuong, S. M., Watt, M. J., Burke, A. R., et al. (2008). Corticotropin-releasing factor in the dorsal raphe nucleus increases medial prefrontal cortical serotonin via type 2 receptors and median raphe nucleus activity. European Journal of Neuroscience, 28, 299–310.Google Scholar
Francis, D. D., Diorio, J., Plotsky, P. M., & Meaney, M. J. (2002). Environmental enrichment reverses the effects of maternal separation on stress reactivity. Journal of Neuroscience, 22, 7840–7843.Google Scholar
Gluckman, P. D., Hanson, M. A., & Beedle, A. S. (2007). Early life events and their consequences for later disease: A life history and evolutionary perspective. American Journal of Human Biology, 19, 1–19.Google Scholar
Gotlib, I. H., Joormann, J., Minor, K. L., & Hallmayer, J. (2008). HPA axis reactivity: A mechanism underlying the associations among 5-HTTLPR, stress, and depression. Biological Psychiatry, 63, 847–851.Google Scholar
Hammack, S. E., Cooper, M. A., & Lezak, K. R. (2012). Overlapping neurobiology of learned helplessness and conditioned defeat: Implications for PTSD and mood disorders. Neuropharmacology, 62, 565–575.Google Scholar
Hammack, S. E., Pepin, J. L., DesMarteau, J. S., Watkins, L. R., & Maier, S. F. (2003). Low doses of corticotropin-releasing hormone injected in the dorsal raphe nucleus block the behavioral consequences of uncontrollable stress. Behavior and Brain Research, 147, 55–64.Google Scholar
Hammack, S. E., Schmid, M. J., LoPresti, M. L., Der-Avakian, A., Pellymounter, M. A., Foster, A. C., et al. (2003). Corticotropin releasing hormone type 2 receptors in the dorsal raphe nucleus mediate the behavioral consequences of uncontrollable stress. Journal of Neuroscience, 23, 1019–1025.Google Scholar
Heim, C., Plotsky, P. M., & Nemeroff, C. B. (2004). Importance of studying the contributions of early adverse experience to neurobiological findings in depression. Neuropsychopharmacology, 29, 641–648.CrossRefGoogle ScholarPubMed
Heiming, R. S., & Sachser, N. (2010). Consequences of serotonin transporter genotype and early adversity on behavioral profile—Pathology or adaptation? Frontiers in Neuroscience, 4, Article 187.Google Scholar
Heuser, I., Bissette, G., Dettling, M., Schweiger, U., Gotthardt, U., Schmider, J., et al. (1998). Cerebrospinal fluid concentrations of corticotropin-releasing hormone, vasopressin, and somatostatin in depressed patients and healthy controls: Response to amitriptyline treatment. Depression and Anxiety, 8, 71–79.3.0.CO;2-N>CrossRefGoogle ScholarPubMed
Homberg, J. R., & Contet, C. (2009). Deciphering the interaction of the corticotropin-releasing factor and serotonin brain systems in anxiety-related disorders. Journal of Neuroscience, 29, 13743–13745.CrossRefGoogle ScholarPubMed
Homberg, J. R., & Lesch, K.-P. (2011). Looking on the bright side of serotonin transporter gene variation. Biological Psychiatry, 69, 513–519.Google Scholar
Homberg, J. R., Olivier, J. D. A., Smits, B. M. G., Mul, J. D., Mudde, J., Verheul, M., et al. (2007). Characterization of the serotonin transporter knockout rat: A selective change in the functioning of the serotonergic system. Neuroscience, 146, 1662–1676.Google Scholar
Hsu, S., & Hsueh, A. (2001). Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nature Medicine, 7, 605–611.CrossRefGoogle ScholarPubMed
Huot, R. L., Gonzalez, M. E., Ladd, C. O., Thrivikraman, K. V., & Plotsky, P. M. (2004). Foster litters prevent hypothalamic-pituitary-adrenal axis sensitization mediated by neonatal maternal separation. Psychoneuroendocrinology, 29, 279–289.Google Scholar
Itoi, K., Horiba, N., Tozawa, F., Sakai, Y., Sakai, K., Abe, K., et al. (1996). Major role of 3',5'-cyclic adenosine monophosphate-dependent protein kinase A pathway in corticotropin-releasing factor gene expression in the rat hypothalamus in vivo. Endocrinology, 137, 2389–2396.CrossRefGoogle Scholar
Jørgensen, H., Knigge, U., Kjaer, A., Møller, M., & Warberg, J. (2002). Serotonergic stimulation of corticotropin-releasing hormone and pro-opiomelanocortin gene expression. Journal of Neuroendocrinology, 14, 788–795.Google Scholar
Karg, K., Burmeister, M., Shedden, K., & Sen, S. (2011). The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Archives of General Psychiatry, 68, 444–454.Google Scholar
Kaufman, J., Yang, B.-Z., Douglas-Palumberi, H., Houshyar, S., Lipschitz, D., Krystal, J. H., et al. (2004). Social supports and serotonin transporter gene moderate depression in maltreated children. Proceedings of the National Academy of Sciences, 101, 17316–17321.CrossRefGoogle ScholarPubMed
Keen-Rhinehart, E., Michopoulos, V., Toufexis, D. J., Martin, E. I., Nair, H., Ressler, K. J., et al. (2009). Continuous expression of corticotropin-releasing factor in the central nucleus of the amygdala emulates the dysregulation of the stress and reproductive axes. Molecular Psychiatry, 14, 37–50.Google Scholar
Kim, H.-R., Hwang, K.-A., Kim, K.-C., & Kang, I. (2007). Down-regulation of IL-7Ralpha expression in human T cells via DNA methylation. Journal of Immunology, 178, 5473–5479.Google Scholar
Kovács, K. J., & Sawchenko, P. E. (1996). Sequence of stress-induced alterations in indices of synaptic and transcriptional activation in parvocellular neurosecretory neurons. Journal of Neuroscience, 16, 262–273.CrossRefGoogle ScholarPubMed
Ladd, C. O., Thrivikraman, K. V., Huot, R. L., & Plotsky, P. M. (2005). Differential neuroendocrine responses to chronic variable stress in adult Long Evans rats exposed to handling–maternal separation as neonates. Psychoneuroendocrinology, 30, 520–533.Google Scholar
Lee, T. I., & Young, R. A. (2000). Transcription of eukaryotic protein-coding genes. Annual Review of Genetics, 34, 77–137.CrossRefGoogle ScholarPubMed
Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., et al. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274, 1527–1531.Google Scholar
Lewis, K., Li, C., Perrin, M., Blount, A., Kunitake, K., Donaldson, C., et al. (2001). Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proceedings of the National Academy of Sciences, 98, 7570–7575.Google Scholar
Lowry, C. A., Rodda, J. E., Lightman, S. L., & Ingram, C. D. (2000). Corticotropin-releasing factor increases in vitro firing rates of serotonergic neurons in the rat dorsal raphe nucleus: Evidence for activation of a topographically organized mesolimbocortical serotonergic system. Journal of Neuroscience, 20, 7728–7736.Google Scholar
Ma, X. M., Levy, A., & Lightman, S. L. (1997). Rapid changes in heteronuclear RNA for corticotrophin-releasing hormone and arginine vasopressin in response to acute stress. Journal of Neuroendocrinology, 152, 81–89.Google ScholarPubMed
Macrì, S., & Würbel, H. (2006). Developmental plasticity of HPA and fear responses in rats: A critical review of the maternal mediation hypothesis. Hormones and Behavior, 50, 667–680.Google Scholar
Makino, S., Shibasaki, T., Yamauchi, N., Nishioka, T., Mimoto, T., Wakabayashi, I., et al. (1999). Psychological stress increased corticotropin-releasing hormone mRNA and content in the central nucleus of the amygdala but not in the hypothalamic paraventricular nucleus in the rat. Brain Research, 850, 136–143.Google Scholar
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonté, B., Szyf, M., et al. (2009). Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nature Neuroscience, 12, 342–348.CrossRefGoogle ScholarPubMed
Meaney, M. J. (2010). Epigenetics and the biological definition of Gene × Environment interactions. Child Development, 81, 41–79.Google Scholar
Merchenthaler, I., Vigh, S., Petrusz, P., & Schally, A. V. (1982). Immunocytochemical localization of corticotropin-releasing factor (CRF) in the rat brain. American Journal of Anatomy, 165, 385–396.CrossRefGoogle ScholarPubMed
Moore, L. D., Le, T., & Fan, G. (2013). DNA methylation and its basic function. Neuropsychopharmacology, 38, 23–38.Google Scholar
Morin, S. M., Ling, N., Liu, X.-J., Kahl, S. D., & Gehlert, D. R. (1999). Differential distribution of urocortin- and corticotropin-releasing factor-like immunoreactivities in the rat brain. Neuroscience, 92, 281–291.CrossRefGoogle ScholarPubMed
Mueller, B. R., & Bale, T. L. (2008). Sex-specific programming of offspring emotionality after stress early in pregnancy. Journal of Neuroscience, 28, 9055–9065.Google Scholar
Murgatroyd, C., Patchev, A. V., Wu, Y., Micale, V., Bockmühl, Y., Fischer, D., et al. (2009). Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nature Neuroscience, 12, 1559–1566.Google Scholar
Murphy, E. P., & Conneely, O. M. (1997). Neuroendocrine regulation of the hypothalamic pituitary adrenal axis by the nurr1/nur77 subfamily of nuclear receptors. Molecular Endocrinology, 11, 39–47.CrossRefGoogle ScholarPubMed
Nederhof, E., & Schmidt, E. V. (2012). Mismatch or cumulative stress: Toward an integrated hypothesis of programming effects. Physiology & Behavior, 106, 691–700.Google Scholar
Nemeroff, C. B., Bissette, G., Akil, H., & Fink, M. (1991). Neuropeptide concentrations in the cerebrospinal fluid of depressed patients treated with electroconvulsive therapy: Corticotrophin-releasing factor, beta-endorphin and somatostatin. British Journal of Psychiatry, 158, 59–63.Google Scholar
Nemeroff, C. B., Widerlov, E., Bissette, G., Walleus, H., Karlsson, I., Eklund, K., et al. (1984). Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science, 226, 1342–1344.Google Scholar
Noskova, T., Pivac, N., Nedic, G., Kazantseva, A., Gaysina, D., Faskhutdinova, G., et al. (2008). Ethnic differences in the serotonin transporter polymorphism (5-HTTLPR) in several European populations. Progress in Neuropsychopharmacology and Biological Psychiatry, 32, 1735–1739.CrossRefGoogle ScholarPubMed
Pan, Y., Hong, Y., Zhang, Q.-Y., & Kong, L.-D. (2013). Impaired hypothalamic insulin signaling in CUMS rats: Restored by icariin and fluoxetine through inhibiting CRF system. Psychoneuroendocrinology, 38, 122–134.Google Scholar
Pergamin-Hight, L., Bakermans-Kranenburg, M. J., van IJzendoorn, M. H., & Bar-Haim, Y. (2012). Variations in the promoter region of the serotonin transporter gene and biased attention for emotional information: A meta-analysis. Biological Psychiatry, 71, 373–379.Google Scholar
Peyron, C., Petit, J.-M., Rampon, C., Jouvet, M., & Luppi, P.-H. (1998). Forebrain afferents to the rat dorsal raphe nucleus demonstrated by retrograde and anterograde tracing methods. Neuroscience, 82, 443–468.Google Scholar
Pierce, A. N., Ryals, J. M., Wang, R., & Christianson, J. A. (2014). Vaginal hypersensitivity and hypothalamic-pituitary-adrenal axis dysfunction as a result of neonatal maternal separation in female mice. Neuroscience, 263, 216–230.Google Scholar
Plotsky, P. M., Thrivikraman, K. V., Nemeroff, C. B., Caldji, C., Sharma, S., & Meaney, M. J. (2005). Long-term consequences of neonatal rearing on central corticotropin-releasing factor systems in adult male rat offspring. Neuropsychopharmacology, 30, 2192–2204.Google Scholar
Pluess, M., Belsky, J., Way, B. M., & Taylor, S. E. (2010). 5-HTTLPR moderates effects of current life events on neuroticism: Differential susceptibility to environmental influences. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 34, 1070–1074.Google Scholar
Pluess, M., Velders, F. P., Belsky, J., van IJzendoorn, M. H., Bakermans-Kranenburg, M. J., Jaddoe, V. W. V., et al. (2011). Serotonin transporter polymorphism moderates effects of prenatal maternal anxiety on infant negative emotionality. Biological Psychiatry, 69, 520–525.CrossRefGoogle ScholarPubMed
Pryce, C. R., Azzinnari, D, Spinelli, S., Seifritz, E., Tegethoff, M., & Meinlschmidt, G. (2011). Helplessness: A systematic translational review of theory and evidence for its relevance to understanding and treating depression. Pharmacology and Therapeutics, 132, 242–267.Google Scholar
Pryce, C. R., Rüedi-Bettschen, D., Dettling, A. C., Weston, A., Russig, H., Ferger, B., et al. (2005). Long-term effects of early-life environmental manipulations in rodents and primates: Potential animal models in depression research. Neuroscience & Biobehavioral Reviews, 29, 649–674.Google Scholar
Raadsheer, F. C., Hoogendijk, W. J., Stam, F. C., Tilders, F. J., & Swaab, D. F. (1994). Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology, 60, 436–444.Google Scholar
Raadsheer, F. C., Van Heerikhuize, J. J., Lucassen, P. J., Hoogendijk, W. J., Tilders, F. J., & Swaab, D. F. (1995). Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression. American Journal of Psychiatry, 152, 1372–1376.Google Scholar
Regev, L., Neufeld-Cohen, A., Tsoory, M., Kuperman, Y., Getselter, D., Gil, S., et al. (2011). Prolonged and site-specific over-expression of corticotropin-releasing factor reveals differential roles for extended amygdala nuclei in emotional regulation. Molecular Psychiatry, 16, 714–728.Google Scholar
Regev, L., Tsoory, M., Gil, S., & Chen, A. (2012). Site-specific genetic manipulation of amygdala corticotropin-releasing factor reveals its imperative role in mediating behavioral response to challenge. Biological Psychiatry, 71, 317–326.Google Scholar
Ressler, K. J., Bradley, B., Mercer, K. B., Deveau, T. C., Smith, A. K., Gillespie, C. F., et al. (2010). Polymorphisms in CRHR1 and the serotonin transporter loci: Gene × Gene × Environment interactions on depressive symptoms. American Journal of Medical Genetics, 153B, 812–824.Google Scholar
Retson, T. A., & Van Bockstaele, E. J. (2013). Coordinate regulation of noradrenergic and serotonergic brain regions by amygdalar neurons. Journal of Chemical Neuroanatomy, 52, 9–19.Google Scholar
Reyes, T. M., Lewis, K., Perrin, M. H., Kunitake, K. S., Vaughan, J., Arias, C. A., et al. (2001). Urocortin II: A member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proceedings of the National Academy of Sciences, 98, 2843–2848.Google Scholar
Risch, N., Herrell, R., Lehner, T., Liang, K.-Y., Eaves, L., Hoh, J., et al. (2009). Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: A meta-analysis. Journal of the American Medical Association, 301, 2462–2471.Google Scholar
Rouwette, T., Klemann, K., Gaszner, B., Scheffer, G. J., Roubos, E. W., Scheenen, W. J. J. M., et al. (2011). Differential responses of corticotropin-releasing factor and urocortin 1 to acute pain stress in the rat brain. Neuroscience, 183, 15–24.Google Scholar
Sink, K. S., Walker, D. L., Freeman, S. M., Flandreau, E. I., Ressler, K. J., & Davis, M. (2013). Effects of continuously enhanced corticotropin releasing factor expression within the bed nucleus of the stria terminalis on conditioned and unconditioned anxiety. Molecular Psychiatry, 18, 308–319.Google Scholar
Smits, B. M. G., Mudde, J. B., Van de Belt, J., Verheul, M., Olivier, J., Homberg, J., et al. (2006). Generation of gene knockouts and mutant models in the laboratory rat by ENU-driven target-selected mutagenesis. Pharmacogenetics and Genomics, 16, 159–169.Google Scholar
Stein, M. B., Schork, N. J., & Gelernter, J. (2008). Gene-by-environment (serotonin transporter and childhood maltreatment) interaction for anxiety sensitivity, an intermediate phenotype for anxiety disorders. Neuropsychopharmacology, 33, 312–319.Google Scholar
Sterrenburg, L., Gaszner, B., Boerrigter, J., Santbergen, L., Bramini, M., Elliott, E., et al. (2011). Chronic stress induces sex-specific alterations in methylation and expression of corticotropin-releasing factor gene in the rat. PLOS ONE, 6, e28128.Google Scholar
Sterrenburg, L., Gaszner, B., Boerrigter, J., Santbergen, L., Bramini, M., Roubos, E. W., et al. (2012). Sex-dependent and differential responses to acute restraint stress of corticotropin-releasing factor-producing neurons in the rat paraventricular nucleus, central amygdala, and bed nucleus of the stria terminalis. Journal of Neuroscience Research, 90, 179–192.Google Scholar
Stout, S. C., Owens, M. J., & Nemeroff, C. B. (2002). Regulation of corticotropin-releasing factor neuronal systems and hypothalamic-pituitary-adrenal axis activity by stress and chronic antidepressant treatment. Journal of Pharmacology and Experimental Therapeutics, 300, 1085–1092.Google Scholar
Sutton, R. E., Koob, G. F., Le Moal, M., Rivier, J., & Vale, W. W. (1982). Corticotropin releasing factor produces behavioral activation in rats. Nature, 297, 331–333.Google Scholar
Uher, R. (2010). The role of genetic variation in the causation of mental illness: An evolution-informed framework. Molecular Psychiatry, 14, 1072–1082.CrossRefGoogle Scholar
Ulrich-Lai, Y. M., & Herman, J. P. (2009). Neural regulation of endocrine and autonomic stress responses. Nature Reviews Neuroscience, 10, 397–409.Google Scholar
Vale, W. W., Spiess, J., Rivier, C., & Rivier, J. (1981). Characterization of a 41-residue ovine hypothalamic peptide that stimulates secretion of corticotropin and beta-endorphin. Science, 213, 1394–1397.Google Scholar
Valentino, R. J., Lucki, I., & Van Bockstaele, E. J. (2010). Corticotropin-releasing factor in the dorsal raphe nucleus: Linking stress coping and addiction. Brain Research, 1314, 29–37.Google Scholar
Vaughan, J., Donaldson, C., Bittencourt, J., Perrin, M. H., Lewis, K., Sutton, S., et al. (1995) Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature, 378, 287–292.Google Scholar
Van der Doelen, R. H. A., Deschamps, W., D'Annibale, C., Peeters, D., Wevers, R. A., Zelena, D. et al. (2014). Early life adversity and serotonin transporter gene variation interact at the level of the adrenal gland to affect the adult hypothalamo-pituitary-adrenal axis. Translational Psychiatry. Advance online publication.Google Scholar
Van der Doelen, R. H. A., Kozicz, T., & Homberg, J. R. (2013). Adaptive fitness: Early life adversity improves adult stress coping in heterozygous serotonin transporter knockout rats. Molecular Psychiatry, 18, 1244–1245.Google Scholar
van IJzendoorn, M. H., Belsky, J., & Bakermans-Kranenburg, M. J. (2012). Serotonin transporter genotype 5HTTLPR as a marker of differential susceptibility? A meta-analysis of child and adolescent gene-by-environment studies. Translational Psychiatry, 2, e147.Google Scholar
van IJzendoorn, M. H., Caspers, K., Bakermans-Kranenburg, M. J., Beach, S. R. H., & Philibert, R. (2010). Methylation matters: Interaction between methylation density and serotonin transporter genotype predicts unresolved loss or trauma. Biological Psychiatry, 68, 405–407.Google Scholar
Veenema, A. H., Reber, S. O., Selch, S., Obermeier, F., & Neumann, I. D. (2008). Early life stress enhances the vulnerability to chronic psychosocial stress and experimental colitis in adult mice. Endocrinology, 149, 2727–2736.Google Scholar
Vollmayr, B., & Henn, F. A. (2001). Learned helplessness in the rat: Improvements in validity and reliability. Brain Research Protocols, 8, 1–7.Google Scholar
Walker, D. L., Miles, L. A., & Davis, M. (2009). Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like responses. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33, 1291–1308.Google Scholar
Wang, S.-S., Kamphuis, W., Huitinga, I., Zhou, J.-N., & Swaab, D. F. (2008). Gene expression analysis in the human hypothalamus in depression by laser microdissection and real-time PCR: The presence of multiple receptor imbalances. Molecular Psychiatry, 13, 786–799.Google Scholar
Waselus, M., Nazzaro, C., Valentino, R. J., & Van Bockstaele, E. J. (2009). Stress-induced redistribution of corticotropin-releasing factor receptor subtypes in the dorsal raphe nucleus. Biological Psychiatry, 66, 76–83.Google Scholar
Weaver, I. C. G., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., et al. (2004). Epigenetic programming by maternal behavior. Nature Neuroscience, 7, 847–854.Google Scholar
Wood, S. K., Zhang, X.-Y., Reyes, B. A. S., Lee, C. S., Van Bockstaele, E. J., & Valentino, R. J. (2013). Cellular adaptations of dorsal raphe serotonin neurons associated with the development of active coping in response to social stress. Biological Psychiatry, 73, 1087–1094.Google Scholar
Yao, M., & Denver, R. J. (2007). Regulation of vertebrate corticotropin-releasing factor genes. General and Comparative Endocrinology, 153, 200–216.Google Scholar
Yao, M., Stenzel-Poore, M., & Denver, R. J. (2007). Structural and functional conservation of vertebrate corticotropin-releasing factor genes: Evidence for a critical role for a conserved cyclic AMP response element. Endocrinology, 148, 2518–2531.Google Scholar