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Enhancing the Utility of Preclinical Research in Neuropsychiatry Drug Development

  • Arie KaffmanEmail author
  • Jordon D. White
  • Lan Wei
  • Frances K. Johnson
  • John H. Krystal
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 2011)

Abstract

Most large pharmaceutical companies have downscaled or closed their clinical neuroscience research programs in response to the low clinical success rate for drugs that showed tremendous promise in animal experiments intended to model psychiatric pathophysiology. These failures have raised serious concerns about the role of preclinical research in the identification and evaluation of new pharmacotherapies for psychiatry. In the absence of a comprehensive understanding of the neurobiology of psychiatric disorders, the task of developing “animal models” seems elusive. The purpose of this review is to highlight emerging strategies to enhance the utility of preclinical research in the drug development process. We address this issue by reviewing how advances in neuroscience, coupled with new conceptual approaches, have recently revolutionized the way we can diagnose and treat common psychiatric conditions. We discuss the implications of these new tools for modeling psychiatric conditions in animals and advocate for the use of systematic reviews of preclinical work as a prerequisite for conducting psychiatric clinical trials. We believe that work in animals is essential for elucidating human psychopathology and that improving the predictive validity of animal models is necessary for developing more effective interventions for mental illness.

Key words

Animal models Predictive validity Psychiatry Systematic reviews CRF 

Notes

Acknowledgments

This work was supported by NARSAD Independent Investigator Award 2016, NIMH grant R01 MH-100078, and the Clinical Neuroscience Division of the VA National Center for PTSD.

References

  1. 1.
    O’Brien PL, Thomas CP, Hodgkin D, Levit KR, Mark TL (2014) The diminished pipeline for medications to treat mental health and substance use disorders. Psychiatr Serv 65:1433–1438PubMedPubMedCentralGoogle Scholar
  2. 2.
    Miller G (2010) Is pharma running out of brainy ideas? Science 329:502–504PubMedGoogle Scholar
  3. 3.
    Hyman SE (2010) The diagnosis of mental disorders: the problem of reification. Annu Rev Clin Psychol 6:155–179PubMedGoogle Scholar
  4. 4.
    Kaffman A, Krystal JH (2012) New frontiers in animal research of psychiatric illness. Methods Mol Biol 829:3–30PubMedPubMedCentralGoogle Scholar
  5. 5.
    Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, Fetcho RN, Zebley B, Oathes DJ, Etkin A, Schatzberg AF, Sudheimer K, Keller J, Mayberg HS, Gunning FM, Alexopoulos GS, Fox MD, Pascual-Leone A, Voss HU, Casey BJ, Dubin MJ, Liston C (2017) Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med 23:28–38PubMedGoogle Scholar
  6. 6.
    Griebel G, Holmes A (2013) 50 years of hurdles and hope in anxiolytic drug discovery. Nat Rev Drug Discov 12:667–687PubMedPubMedCentralGoogle Scholar
  7. 7.
    Nestler EJ, Hyman SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13:1161–1169PubMedPubMedCentralGoogle Scholar
  8. 8.
    Cryan JF, Markou A, Lucki I (2002) Assessing antidepressant activity in rodents: recent developments and future needs. Trends Pharmacol Sci 23:238–245PubMedGoogle Scholar
  9. 9.
    Greek R, Menache A (2013) Systematic reviews of animal models: methodology versus epistemology. Int J Med Sci 10:206–221PubMedPubMedCentralGoogle Scholar
  10. 10.
    Willner P (1984) The validity of animal models of depression. Psychopharmacology 83:1–16Google Scholar
  11. 11.
    Ban TA (2006) The role of serendipity in drug discovery. Dialogues Clin Neurosci 8:335–344PubMedPubMedCentralGoogle Scholar
  12. 12.
    Wong EHF, Yocca F, Smith MA, Lee CM (2010) Challenges and opportunities for drug discovery in psychiatric disorders: the drug hunters’ perspective. Int J Neuropsychopharmacol 13:1269–1284PubMedGoogle Scholar
  13. 13.
    Spierling SR, Zorrilla EP (2017) Don’t stress about CRF: assessing the translational failures of CRF1 antagonists. Psychopharmacology 234:1467–1481PubMedPubMedCentralGoogle Scholar
  14. 14.
    Spencer S, Kalivas PW (2017) Glutamate transport: a new bench to bedside mechanism for treating drug abuse. Int J Neuropsychopharmacol 20:797–812PubMedPubMedCentralGoogle Scholar
  15. 15.
    Berry-Kravis E, Des Portes V, Hagerman R, Jacquemont S, Charles P, Visootsak J, Brinkman M, Rerat K, Koumaras B, Zhu L, Barth GM, Jaecklin T, Apostol G, von Raison F (2016) Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci Transl Med 8:321ra325Google Scholar
  16. 16.
    Azevedo FA, Carvalho LR, Grinberg LT, Farfel JM, Ferretti RE, Leite RE, Jacob Filho W, Lent R, Herculano-Houzel S (2009) Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol 513:532–541PubMedGoogle Scholar
  17. 17.
    van Gerven M (2017) Computational foundations of natural intelligence. Front Comput Neurosci 11:112PubMedPubMedCentralGoogle Scholar
  18. 18.
    Hyman SE (2008) A glimmer of light for neuropsychiatric disorders. Nature 455:890–893PubMedGoogle Scholar
  19. 19.
    Regier DA, Narrow WE, Clarke DE, Kraemer HC, Kuramoto SJ, Kuhl EA, Kupfer DJ (2013) DSM-5 field trials in the United States and Canada, Part II: test-retest reliability of selected categorical diagnoses. Am J Psychiatry 170:59–70PubMedGoogle Scholar
  20. 20.
    Helzer JE, Clayton PJ, Pambakian R, Reich T, Woodruff RA Jr, Reveley MA (1977) Reliability of psychiatric diagnosis. II. The test/retest reliability of diagnostic classification. Arch Gen Psychiatry 34:136–141PubMedGoogle Scholar
  21. 21.
    Helzer JE, Robins LN, Taibleson M, Woodruff RA Jr, Reich T, Wish ED (1977) Reliability of psychiatric diagnosis. I. A methodological review. Arch Gen Psychiatry 34:129–133PubMedGoogle Scholar
  22. 22.
    Pies R (2007) How “objective” are psychiatric diagnoses?: (guess again). Psychiatry (Edgmont) 4:18–22Google Scholar
  23. 23.
    Martinez G, Vernooij RW, Fuentes Padilla P, Zamora J, Bonfill Cosp X, Flicker L (2017) 18F PET with florbetapir for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev (11):CD012216Google Scholar
  24. 24.
    Villemagne VL, Dore V, Burnham SC, Masters CL, Rowe CC (2018) Imaging tau and amyloid-beta proteinopathies in Alzheimer disease and other conditions. Nat Rev Neurol 14(4):225–236PubMedGoogle Scholar
  25. 25.
    Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, Bloomfield MA, Bonoldi I, Kalk N, Turkheimer F, McGuire P, de Paola V, Howes OD (2016) Microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [(11)C]PBR28 PET brain imaging study. Am J Psychiatry 173:44–52PubMedGoogle Scholar
  26. 26.
    Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, Suridjan I, Kennedy JL, Rekkas PV, Houle S, Meyer JH (2015) Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiat 72:268–275Google Scholar
  27. 27.
    Klunk WE, Engler H, Nordberg A, Wang YM, Blomqvist G, Holt DP, Bergstrom M, Savitcheva I, Huang GF, Estrada S, Ausen B, Debnath ML, Barletta J, Price JC, Sandell J, Lopresti BJ, Wall A, Koivisto P, Antoni G, Mathis CA, Langstrom B (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann Neurol 55:306–319PubMedGoogle Scholar
  28. 28.
    Mathis CA, Bacskai BJ, Kajdasz ST, McLellan ME, Frosch MP, Hyman BT, Holt DP, Wang YM, Huang GF, Debnath ML, Klunk WE (2002) A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg Med Chem Lett 12:295–298PubMedGoogle Scholar
  29. 29.
    Bacskai BJ, Hickey GA, Skoch J, Kajdasz ST, Wang Y, Huang GF, Mathis CA, Klunk WE, Hyman BT (2003) Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice. Proc Natl Acad Sci U S A 100:12462–12467PubMedPubMedCentralGoogle Scholar
  30. 30.
    Karlstetter M, Nothdurfter C, Aslanidis A, Moeller K, Horn F, Scholz R, Neumann H, Weber BH, Rupprecht R, Langmann T (2014) Translocator protein (18 kDa) (TSPO) is expressed in reactive retinal microglia and modulates microglial inflammation and phagocytosis. J Neuroinflammation 11:3PubMedPubMedCentralGoogle Scholar
  31. 31.
    Banati RB (2002) Visualising microglial activation in vivo. Glia 40:206–217PubMedGoogle Scholar
  32. 32.
    Johnson FK, Kaffman A (2017) Early life stress perturbs the function of microglia in the developing rodent brain: new insights and future challenges. Brain Behav Immun 69:18–27PubMedPubMedCentralGoogle Scholar
  33. 33.
    Sehlin D, Fang XTT, Cato L, Antoni G, Lannfelt L, Syvanen S (2016) Antibody-based PET imaging of amyloid beta in mouse models of Alzheimer’s disease. Nat Commun 7:10759PubMedPubMedCentralGoogle Scholar
  34. 34.
    Mulholland PJ, Chandler LJ, Kalivas PW (2016) Signals from the fourth dimension regulate drug relapse. Trends Neurosci 39:472–485PubMedPubMedCentralGoogle Scholar
  35. 35.
    Jonckers E, Shah D, Hamaide J, Verhoye M, Van der Linden A (2015) The power of using functional fMRI on small rodents to study brain pharmacology and disease. Front Pharmacol 6:231PubMedPubMedCentralGoogle Scholar
  36. 36.
    Wu D, Zhang J (2016) Recent progress in magnetic resonance imaging of the embryonic and neonatal mouse brain. Front Neuroanat 10:18PubMedPubMedCentralGoogle Scholar
  37. 37.
    Johnson FK, Delpech JC, Thompson GJ, Wei L, Hao J, Herman P, Hyder F, Kaffman A (2018) Amygdala hyper-connectivity in a mouse model of unpredictable early life stress. Transl Psychiatry 8:49PubMedPubMedCentralGoogle Scholar
  38. 38.
    van der Werff SJ, Pannekoek JN, Veer IM, van Tol MJ, Aleman A, Veltman DJ, Zitman FG, Rombouts SA, Elzinga BM, van der Wee NJ (2013) Resting-state functional connectivity in adults with childhood emotional maltreatment. Psychol Med 43:1825–1836PubMedGoogle Scholar
  39. 39.
    Birn RM, Patriat R, Phillips ML, Germain A, Herringa RJ (2014) Childhood maltreatment and combat posttraumatic stress differentially predict fear-related fronto-subcortical connectivity. Depress Anxiety 31:880–892PubMedPubMedCentralGoogle Scholar
  40. 40.
    Herringa RJ, Phillips ML, Fournier JC, Kronhaus DM, Germain A (2013) Childhood and adult trauma both correlate with dorsal anterior cingulate activation to threat in combat veterans. Psychol Med 43:1533–1542PubMedGoogle Scholar
  41. 41.
    Wang L, Dai Z, Peng H, Tan L, Ding Y, He Z, Zhang Y, Xia M, Li Z, Li W, Cai Y, Lu S, Liao M, Zhang L, Wu W, He Y, Li L (2014) Overlapping and segregated resting-state functional connectivity in patients with major depressive disorder with and without childhood neglect. Hum Brain Mapp 35:1154–1166PubMedGoogle Scholar
  42. 42.
    Cisler JM, James GA, Tripathi S, Mletzko T, Heim C, Hu XP, Mayberg HS, Nemeroff CB, Kilts CD (2013) Differential functional connectivity within an emotion regulation neural network among individuals resilient and susceptible to the depressogenic effects of early life stress. Psychol Med 43:507–518PubMedGoogle Scholar
  43. 43.
    Dean AC, Kohno M, Hellemann G, London ED (2014) Childhood maltreatment and amygdala connectivity in methamphetamine dependence: a pilot study. Brain Behav 4:867–876PubMedPubMedCentralGoogle Scholar
  44. 44.
    Philip NS, Sweet LH, Tyrka AR, Price LH, Bloom RF, Carpenter LL (2013) Decreased default network connectivity is associated with early life stress in medication-free healthy adults. Eur Neuropsychopharmacol 23:24–32PubMedGoogle Scholar
  45. 45.
    Wiegert JS, Mahn M, Prigge M, Printz Y, Yizhar O (2017) Silencing neurons: tools, applications, and experimental constraints. Neuron 95:504–529PubMedPubMedCentralGoogle Scholar
  46. 46.
    Jiang J, Cui H, Rahmouni K (2017) Optogenetics and pharmacogenetics: principles and applications. Am J Physiol Regul Integr Comp Physiol 313:R633–R645PubMedPubMedCentralGoogle Scholar
  47. 47.
    Galvan A, Stauffer WR, Acker L, El-Shamayleh Y, Inoue KI, Ohayon S, Schmid MC (2017) Nonhuman primate optogenetics: recent advances and future directions. J Neurosci 37:10894–10903PubMedPubMedCentralGoogle Scholar
  48. 48.
    Anthony TE, Dee N, Bernard A, Lerchner W, Heintz N, Anderson DJ (2014) Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. Cell 156:522–536PubMedPubMedCentralGoogle Scholar
  49. 49.
    Pena CJ, Kronman HG, Walker DM, Cates HM, Bagot RC, Purushothaman I, Issler O, Loh YE, Leong T, Kiraly DD, Goodman E, Neve RL, Shen L, Nestler EJ (2017) Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2. Science 356:1185–1188PubMedPubMedCentralGoogle Scholar
  50. 50.
    Varghese M, Keshav N, Jacot-Descombes S, Warda T, Wicinski B, Dickstein DL, Harony-Nicolas H, De Rubeis S, Drapeau E, Buxbaum JD, Hof PR (2017) Autism spectrum disorder: neuropathology and animal models. Acta Neuropathol 134:537–566PubMedPubMedCentralGoogle Scholar
  51. 51.
    Monteiro P, Feng G (2017) SHANK proteins: roles at the synapse and in autism spectrum disorder. Nat Rev Neurosci 18:147–157PubMedGoogle Scholar
  52. 52.
    Wapinski OL, Vierbuchen T, Qu K, Lee QY, Chanda S, Fuentes DR, Giresi PG, Ng YH, Marro S, Neff NF, Drechsel D, Martynoga B, Castro DS, Webb AE, Sudhof TC, Brunet A, Guillemot F, Chang HY, Wernig M (2013) Hierarchical mechanisms for direct reprogramming of fibroblasts to neurons. Cell 155:621–635PubMedGoogle Scholar
  53. 53.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872PubMedGoogle Scholar
  54. 54.
    Parr CJC, Yamanaka S, Saito H (2017) An update on stem cell biology and engineering for brain development. Mol Psychiatry 22:808–819PubMedGoogle Scholar
  55. 55.
    Brennand K, Savas JN, Kim Y, Tran N, Simone A, Hashimoto-Torii K, Beaumont KG, Kim HJ, Topol A, Ladran I, Abdelrahim M, Matikainen-Ankney B, Chao SH, Mrksich M, Rakic P, Fang G, Zhang B, Yates JR III, Gage FH (2015) Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Mol Psychiatry 20:361–368PubMedGoogle Scholar
  56. 56.
    Madison JM, Zhou F, Nigam A, Hussain A, Barker DD, Nehme R, van der Ven K, Hsu J, Wolf P, Fleishman M, O’Dushlaine C, Rose S, Chambert K, Lau FH, Ahfeldt T, Rueckert EH, Sheridan SD, Fass DM, Nemesh J, Mullen TE, Daheron L, McCarroll S, Sklar P, Perlis RH, Haggarty SJ (2015) Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities. Mol Psychiatry 20:703–717PubMedPubMedCentralGoogle Scholar
  57. 57.
    Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS, Carson CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo EH, Goldstein LS (2012) Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells. Nature 482:216–220PubMedPubMedCentralGoogle Scholar
  58. 58.
    Yi F, Danko T, Botelho SC, Patzke C, Pak C, Wernig M, Sudhof TC (2016) Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Science 352:aaf2669PubMedPubMedCentralGoogle Scholar
  59. 59.
    Testolin A, Stoianov I, Zorzi M (2017) Letter perception emerges from unsupervised deep learning and recycling of natural image features. Nat Hum Behav 1:843Google Scholar
  60. 60.
    Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K, Sanislow C, Wang P (2010) Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 167:748–751PubMedGoogle Scholar
  61. 61.
    Delgado MR, Nearing KI, Ledoux JE, Phelps EA (2008) Neural circuitry underlying the regulation of conditioned fear and its relation to extinction. Neuron 59:829–838PubMedPubMedCentralGoogle Scholar
  62. 62.
    LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184PubMedGoogle Scholar
  63. 63.
    Widiger TA, Clark LA (2000) Toward DSM-V and the classification of psychopathology. Psychol Bull 126:946–963PubMedGoogle Scholar
  64. 64.
    Gordon J (2018) The future of RDoC. National Institute of Mental Health, Bethesda, MDGoogle Scholar
  65. 65.
    Lohr KN (2004) Rating the strength of scientific evidence: relevance for quality improvement programs. Int J Qual Health Care 16:9–18PubMedGoogle Scholar
  66. 66.
    Sandercock P, Roberts I (2002) Systematic reviews of animal experiments. Lancet 360:586PubMedGoogle Scholar
  67. 67.
    Horn J, Limburg M (2001) Calcium antagonists for ischemic stroke: a systematic review. Stroke 32:570–576PubMedGoogle Scholar
  68. 68.
    Horn J, de Haan RJ, Vermeulen M, Luiten PG, Limburg M (2001) Nimodipine in animal model experiments of focal cerebral ischemia: a systematic review. Stroke 32:2433–2438PubMedGoogle Scholar
  69. 69.
    Hooijmans CR, Ritskes-Hoitinga M (2013) Progress in using systematic reviews of animal studies to improve translational research. PLoS Med 10:e1001482PubMedPubMedCentralGoogle Scholar
  70. 70.
    van der Worp HB, Macleod MR, Kollmar R, European Stroke Research Network for, H (2010) Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials? J Cereb Blood Flow Metab 30:1079–1093PubMedPubMedCentralGoogle Scholar
  71. 71.
    Khan MS, Boileau I, Kolla N, Mizrahi R (2018) A systematic review of the role of the nociceptin receptor system in stress, cognition, and reward: relevance to schizophrenia. Transl Psychiatry 8:38PubMedPubMedCentralGoogle Scholar
  72. 72.
    Kaffman A, Meaney MJ (2007) Neurodevelopmental sequelae of postnatal maternal care in rodents: clinical and research implications of molecular insights. J Child Psychol Psychiatry 48:224–244PubMedGoogle Scholar
  73. 73.
    Mignot EJ (2014) History of narcolepsy at Stanford University. Immunol Res 58:315–339PubMedPubMedCentralGoogle Scholar
  74. 74.
    Scammell TE (2003) The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 53:154–166PubMedGoogle Scholar
  75. 75.
    Winrow CJ, Renger JJ (2014) Discovery and development of orexin receptor antagonists as therapeutics for insomnia. Br J Pharmacol 171:283–293PubMedGoogle Scholar
  76. 76.
    Wang M, Ramos BP, Paspalas CD, Shu Y, Simen A, Duque A, Vijayraghavan S, Brennan A, Dudley A, Nou E, Mazer JA, McCormick DA, Arnsten AF (2007) Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129:397–410PubMedGoogle Scholar
  77. 77.
    Arnsten AF, Wang M (2016) Targeting prefrontal cortical systems for drug development: potential therapies for cognitive disorders. Annu Rev Pharmacol Toxicol 56:339–360PubMedPubMedCentralGoogle Scholar
  78. 78.
    Connor DF, Arnsten AFT, Pearson GS, Greco GF (2014) Guanfacine extended release for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. Expert Opin Pharmacol 15:1601–1610Google Scholar
  79. 79.
    von Budingen HC, Hauser SL, Ouallet JC, Tanuma N, Menge T, Genain CP (2004) Epitope recognition on the myelin/oligodendrocyte glycoprotein differentially influences disease phenotype and antibody effector functions in autoimmune demyelination. Eur J Immunol 34:2072–2083Google Scholar
  80. 80.
    von Budingen HC, Tanuma N, Villoslada P, Ouallet JC, Hauser SL, Genain CP (2001) Immune responses against the myelin/oligodendrocyte glycoprotein in experimental autoimmune demyelination. J Clin Immunol 21:155–170Google Scholar
  81. 81.
    von Budingen HC, Hauser SL, Fuhrmann A, Nabavi CB, Lee JI, Genain CP (2002) Molecular characterization of antibody specificities against myelin/oligodendrocyte glycoprotein in autoimmune demyelination. Proc Natl Acad Sci U S A 99:8207–8212Google Scholar
  82. 82.
    Dolgin E (2016) Therapies: progressive steps. Nature 540:S7–S9PubMedGoogle Scholar
  83. 83.
    Gelfand JM, Cree BAC, Hauser SL (2017) Ocrelizumab and other CD20+ B-cell-depleting therapies in multiple sclerosis. Neurotherapeutics 14(4):835–841PubMedPubMedCentralGoogle Scholar
  84. 84.
    Sanders J, Nemeroff C (2016) The CRF system as a therapeutic target for neuropsychiatric disorders. Trends Pharmacol Sci 37:1045–1054PubMedPubMedCentralGoogle Scholar
  85. 85.
    Bale TL, Vale WW (2004) CRF and CRF receptors: role in stress responsivity and other behaviors. Annu Rev Pharmacol Toxicol 44:525–557PubMedGoogle Scholar
  86. 86.
    Henckens MJ, Deussing JM, Chen A (2016) Region-specific roles of the corticotropin-releasing factor-urocortin system in stress. Nat Rev Neurosci 17:636–651PubMedGoogle Scholar
  87. 87.
    Gray TS (1993) Amygdaloid CRF pathways. Role in autonomic, neuroendocrine, and behavioral responses to stress. Ann N Y Acad Sci 697:53–60PubMedGoogle Scholar
  88. 88.
    Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB (1999) The role of corticotropin-releasing factor in depression and anxiety disorders. J Endocrinol 160:1–12PubMedGoogle Scholar
  89. 89.
    Seckl JR (2008) Glucocorticoids, developmental ‘programming’ and the risk of affective dysfunction. Prog Brain Res 167:17–34PubMedGoogle Scholar
  90. 90.
    Rhen T, Cidlowski JA (2005) Antiinflammatory action of glucocorticoids—new mechanisms for old drugs. N Engl J Med 353:1711–1723PubMedGoogle Scholar
  91. 91.
    Ramamoorthy S, Cidlowski JA (2016) Corticosteroids: mechanisms of action in health and disease. Rheum Dis Clin N Am 42:15–31, viiGoogle Scholar
  92. 92.
    De Francesco PN, Valdivia S, Cabral A, Reynaldo M, Raingo J, Sakata I, Osborne-Lawrence S, Zigman JM, Perello M (2015) Neuroanatomical and functional characterization of CRF neurons of the amygdala using a novel transgenic mouse model. Neuroscience 289:153–165PubMedPubMedCentralGoogle Scholar
  93. 93.
    Bolton JL, Molet J, Regev L, Chen Y, Rismanchi N, Haddad E, Yang DZ, Obenaus A, Baram TZ (2018) Anhedonia following early-life adversity involves aberrant interaction of reward and anxiety circuits and is reversed by partial silencing of amygdala corticotropin-releasing hormone gene. Biol Psychiatry 83:137–147PubMedGoogle Scholar
  94. 94.
    Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, Chavkin C, Phillips PE (2012) Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature 490:402–406PubMedPubMedCentralGoogle Scholar
  95. 95.
    Chen Y, Bender RA, Frotscher M, Baram TZ (2001) Novel and transient populations of corticotropin-releasing hormone-expressing neurons in developing hippocampus suggest unique functional roles: a quantitative spatiotemporal analysis. J Neurosci 21:7171–7181PubMedPubMedCentralGoogle Scholar
  96. 96.
    Ivy AS, Rex CS, Chen Y, Dube C, Maras PM, Grigoriadis DE, Gall CM, Lynch G, Baram TZ (2010) Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors. J Neurosci 30:13005–13015PubMedPubMedCentralGoogle Scholar
  97. 97.
    Chen Y, Baram TZ (2016) Toward understanding how early-life stress reprograms cognitive and emotional brain networks. Neuropsychopharmacology 41:197–206PubMedGoogle Scholar
  98. 98.
    Ivy AS, Brunson KL, Sandman C, Baram TZ (2008) Dysfunctional nurturing behavior in rat dams with limited access to nesting material: a clinically relevant model for early-life stress. Neuroscience 154:1132–1142PubMedPubMedCentralGoogle Scholar
  99. 99.
    Kolber BJ, Boyle MP, Wieczorek L, Kelley CL, Onwuzurike CC, Nettles SA, Vogt SK, Muglia LJ (2010) Transient early-life forebrain corticotropin-releasing hormone elevation causes long-lasting anxiogenic and despair-like changes in mice. J Neurosci 30:2571–2581PubMedPubMedCentralGoogle Scholar
  100. 100.
    Brunson KL, Grigoriadis DE, Lorang MT, Baram TZ (2002) Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain. Exp Neurol 176:75–86PubMedGoogle Scholar
  101. 101.
    Wang XD, Su YA, Wagner KV, Avrabos C, Scharf SH, Hartmann J, Wolf M, Liebl C, Kuhne C, Wurst W, Holsboer F, Eder M, Deussing JM, Muller MB, Schmidt MV (2013) Nectin-3 links CRHR1 signaling to stress-induced memory deficits and spine loss. Nat Neurosci 16:706–713PubMedGoogle Scholar
  102. 102.
    Wang XD, Labermaier C, Holsboer F, Wurst W, Deussing JM, Muller MB, Schmidt MV (2012) Early-life stress-induced anxiety-related behavior in adult mice partially requires forebrain corticotropin-releasing hormone receptor 1. Eur J Neurosci 36:2360–2367PubMedGoogle Scholar
  103. 103.
    Bolton JL, Molet J, Ivy A, Baram TZ (2017) New insights into early-life stress and behavioral outcomes. Curr Opin Behav Sci 14:133–139PubMedPubMedCentralGoogle Scholar
  104. 104.
    Refojo D, Schweizer M, Kuehne C, Ehrenberg S, Thoeringer C, Vogl AM, Dedic N, Schumacher M, von Wolff G, Avrabos C, Touma C, Engblom D, Schutz G, Nave KA, Eder M, Wotjak CT, Sillaber I, Holsboer F, Wurst W, Deussing JM (2011) Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science 333:1903–1907PubMedGoogle Scholar
  105. 105.
    Piazza PV, Deroche-Gamonet V (2013) A multistep general theory of transition to addiction. Psychopharmacology 229:387–413PubMedPubMedCentralGoogle Scholar
  106. 106.
    Namba MD, Tomek SE, Olive MF, Beckmann JS, Gipson CD (2018) The winding road to relapse: forging a new understanding of cue-induced reinstatement models and their associated neural mechanisms. Front Behav Neurosci 12:17PubMedPubMedCentralGoogle Scholar
  107. 107.
    Epstein DH, Preston KL, Stewart J, Shaham Y (2006) Toward a model of drug relapse: an assessment of the validity of the reinstatement procedure. Psychopharmacology 189:1–16PubMedPubMedCentralGoogle Scholar
  108. 108.
    Kasanetz F, Deroche-Gamonet V, Berson N, Balado E, Lafourcade M, Manzoni O, Piazza PV (2010) Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science 328:1709–1712PubMedGoogle Scholar
  109. 109.
    Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ, Graham D, Tsankova NM, Bolanos CA, Rios M, Monteggia LM, Self DW, Nestler EJ (2006) Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311:864–868PubMedGoogle Scholar
  110. 110.
    Bourke CH, Glasper ER, Neigh GN (2014) SSRI or CRF antagonism partially ameliorate depressive-like behavior after adolescent social defeat. Behav Brain Res 270:295–299PubMedGoogle Scholar
  111. 111.
    Ayala AR, Pushkas J, Higley JD, Ronsaville D, Gold PW, Chrousos GP, Pacak K, Calis KA, Gerald M, Lindell S, Rice KC, Cizza G (2004) Behavioral, adrenal, and sympathetic responses to long-term administration of an oral corticotropin-releasing hormone receptor antagonist in a primate stress paradigm. J Clin Endocrinol Metab 89:5729–5737PubMedGoogle Scholar
  112. 112.
    Habib KE, Weld KP, Rice KC, Pushkas J, Champoux M, Listwak S, Webster EL, Atkinson AJ, Schulkin J, Contoreggi C, Chrousos GP, McCann SM, Suomi SJ, Higley JD, Gold PW (2000) Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Proc Natl Acad Sci U S A 97:6079–6084PubMedPubMedCentralGoogle Scholar
  113. 113.
    Walker D, Yang Y, Ratti E, Corsi M, Trist D, Davis M (2009) 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 34:1533–1542PubMedGoogle Scholar
  114. 114.
    Garcia-Garcia AL, Newman-Tancredi A, Leonardo ED (2014) 5-HT(1A) [corrected] receptors in mood and anxiety: recent insights into autoreceptor versus heteroreceptor function. Psychopharmacology 231:623–636PubMedGoogle Scholar
  115. 115.
    Gross C, Hen R (2004) The developmental origins of anxiety. Nat Rev Neurosci 5:545–552PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Arie Kaffman
    • 1
    Email author
  • Jordon D. White
    • 1
  • Lan Wei
    • 1
  • Frances K. Johnson
    • 1
  • John H. Krystal
    • 1
  1. 1.Department of PsychiatryYale University School of MedicineNew HavenUSA

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