Skip to main content Accessibility help

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

  • Rick H. A. van der Doelen (a1), Ilse A. Arnoldussen (a1), Hussein Ghareh (a1), Liselot van Och (a1), Judith R. Homberg (a1) and Tamás Kozicz (a1)...


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.


Corresponding author

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:


Hide All
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, 256266.
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, 12941303.
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, 112.
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, 3952.
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, 314319.
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, 525557.
Belsky, J., Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2007). For better and for worse: Differential susceptibility to environmental influences. Psychological Science, 16, 300305.
Belsky, J., Jonassaint, C., Pluess, M., Stanton, M., Brummett, B., & Williams, R. (2009). Vulnerability genes or plasticity genes? Molecular Psychiatry, 14, 746754.
Binder, E. B., & Nemeroff, C. B. (2010). The CRF system, stress, depression and anxiety—Insights from human genetic studies. Molecular Psychiatry, 15, 574588.
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, 288299.
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, 666683.
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.
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, 386389.
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, 136142.
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, 10551064.
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, 11251138.
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, 259268.
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, 329332.
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, 13511353.
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, 728.
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, 2738.
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, 10471055.
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, 299310.
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, 78407843.
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, 119.
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, 847851.
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, 565575.
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, 5564.
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, 10191025.
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, 641648.
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.
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, 7179.
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, 1374313745.
Homberg, J. R., & Lesch, K.-P. (2011). Looking on the bright side of serotonin transporter gene variation. Biological Psychiatry, 69, 513519.
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, 16621676.
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, 605611.
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, 279289.
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, 23892396.
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, 788795.
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, 444454.
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, 1731617321.
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, 3750.
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, 54735479.
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, 262273.
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, 520533.
Lee, T. I., & Young, R. A. (2000). Transcription of eukaryotic protein-coding genes. Annual Review of Genetics, 34, 77137.
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, 15271531.
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, 75707575.
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, 77287736.
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, 8189.
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, 667680.
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, 136143.
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, 342348.
Meaney, M. J. (2010). Epigenetics and the biological definition of Gene × Environment interactions. Child Development, 81, 4179.
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, 385396.
Moore, L. D., Le, T., & Fan, G. (2013). DNA methylation and its basic function. Neuropsychopharmacology, 38, 2338.
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, 281291.
Mueller, B. R., & Bale, T. L. (2008). Sex-specific programming of offspring emotionality after stress early in pregnancy. Journal of Neuroscience, 28, 90559065.
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, 15591566.
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, 3947.
Nederhof, E., & Schmidt, E. V. (2012). Mismatch or cumulative stress: Toward an integrated hypothesis of programming effects. Physiology & Behavior, 106, 691700.
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, 5963.
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, 13421344.
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, 17351739.
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, 122134.
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, 373379.
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, 443468.
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, 216230.
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, 21922204.
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, 10701074.
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, 520525.
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, 242267.
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, 649674.
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, 436444.
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, 13721376.
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, 714728.
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, 317326.
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, 812824.
Retson, T. A., & Van Bockstaele, E. J. (2013). Coordinate regulation of noradrenergic and serotonergic brain regions by amygdalar neurons. Journal of Chemical Neuroanatomy, 52, 919.
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, 28432848.
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, 24622471.
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, 1524.
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, 308319.
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, 159169.
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, 312319.
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.
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, 179192.
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, 10851092.
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, 331333.
Uher, R. (2010). The role of genetic variation in the causation of mental illness: An evolution-informed framework. Molecular Psychiatry, 14, 10721082.
Ulrich-Lai, Y. M., & Herman, J. P. (2009). Neural regulation of endocrine and autonomic stress responses. Nature Reviews Neuroscience, 10, 397409.
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, 13941397.
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, 2937.
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, 287292.
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.
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, 12441245.
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.
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, 405407.
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, 27272736.
Vollmayr, B., & Henn, F. A. (2001). Learned helplessness in the rat: Improvements in validity and reliability. Brain Research Protocols, 8, 17.
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, 12911308.
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, 786799.
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, 7683.
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, 847854.
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, 10871094.
Yao, M., & Denver, R. J. (2007). Regulation of vertebrate corticotropin-releasing factor genes. General and Comparative Endocrinology, 153, 200216.
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, 25182531.

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

  • Rick H. A. van der Doelen (a1), Ilse A. Arnoldussen (a1), Hussein Ghareh (a1), Liselot van Och (a1), Judith R. Homberg (a1) and Tamás Kozicz (a1)...


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed