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Individual responses of rodents in modelling of affective disorders and in their treatment: prospective review

  • Haim Einat (a1) (a2) (a3), Itamar Ezer (a1), Nirit Z Kara (a1) (a2) and Catherine Belzung (a4)

Abstract

Introduction

Lack of good animal models for affective disorders, including major depression and bipolar disorder, is noted as a major bottleneck in attempts to study these disorders and develop better treatments. We suggest that an important approach that can help in the development and use of better models is attention to variability between model animals.

Results

Differences between mice strains were studied for some decades now, and sex differences get more attention than in the past. It is suggested that one factor that is mostly neglected, individual variability within groups, should get much more attention. The importance of individual differences in behavioral biology and ecology was repeatedly mentioned but its application to models of affective illness or to the study of drug response was not heavily studied. The standard approach is to overcome variability by standardization and by increasing the number of animals per group.

Conclusions

Possibly, the individuality of specific animals and their unique responses to a variety of stimuli and drugs, can be helpful in deciphering the underlying biology of affective behaviors as well as offer better prediction of drug responses in patients.

Copyright

Corresponding author

*Author for correspondence: Haim Einat, Professor, School of Behavioral Sciences, Tel Aviv-Yaffo Academic College, 14 Rabenu Yeruham St., Tel-Aviv, Israel. Tel: (972)3 680 2536; Fax: (972)3 6802526; E-mail: haimh@mta.ac.il

References

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1. Phelps, EA LeDoux, JE (2005) Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48, 175187.
2. van der Werff, SJ, van den Berg, SM, Pannekoek, JN, Elzinga, BM van der Wee, NJ (2013) Neuroimaging resilience to stress: a review. Front Behav Neurosci 7, 39.
3. Cloninger, CR, Svrakic, DM Przybeck, TR (1993) A psychobiological model of temperament and character. Arch Gen Psychiatry 50, 975990.
4. Ebstein, RP, Zohar, AH, Benjamin, J Belmaker, RH (2002) An update on molecular genetic studies of human personality traits. Appl Bioinformatics 1, 5768.
5. Cryan, JF Slattery, DA (2007) Animal models of mood disorders: recent developments. Curr Opin Psychiatry 20, 17.
6. Einat, H (2007) Different behaviors and different strains: potential new ways to model bipolar disorder. Neurosci Biobehav Rev 31, 850857.
7. Agid, Y, Buzsaki, G, Diamond, DM, Frackowiak, R, Giedd, J, Girault, JA, Grace, A, Lambert, JJ, Manji, H, Mayberg, H, Popoli, M, Prochiantz, A, Richter-Levin, G, Somogyi, P, Spedding, M, Svenningsson, P Weinberger, D (2007) How can drug discovery for psychiatric disorders be improved? Nat Rev Drug Discov 6, 189201.
8. Gould, TD Einat, H (2007) Animal models of bipolar disorder and mood stabilizer efficacy: a critical need for improvement. Neurosci Biobehav Rev 31, 825831.
9. Kafkafi, N, Agassi, J, Chesler, EJ, Crabbe, JC, Crusio, WE, Eilam, D, Gerlai, R, Golani, I, Gomez-Marin, A, Heller, R, Iraqi, F, Jaljuli, I, Karp, NA, Morgan, H, Nicholson, G, Pfaff, DW, Richter, SH, Stark, PB, Stiedl, O, Stodden, V, Tarantino, LM, Tucci, V, Valdar, W, Williams, RW, Wurbel, H Benjamini, Y (2018) Reproducibility and replicability of rodent phenotyping in preclinical studies. Neurosci Biobehav Rev 18, 3065130657.
10. Nestler, EJ Hyman, SE (2010) Animal models of neuropsychiatric disorders. Nat Neurosci 13, 11611169.
11. Insel, TR (2007) From animal models to model animals. Biol Psychiatry 62, 13371339.
12. Kronfeld-Schor, N Einat, H (2012) Circadian rhythms and depression: human psychopathology and animal models. Neuropharmacology 62, 101114.
13. Bilu, C, Einat, H Kronfeld-Schor, N (2016) Utilization of diurnal rodents in the research of depression. Drug Dev Res 77, 336345.
14. Hendrie, CA Pickles, AR (2009) Depression as an evolutionary adaptation: implications for the development of preclinical models. Med Hypotheses 72, 342347.
15. Gould, TD Gottesman, II (2006) Psychiatric endophenotypes and the development of valid animal models. Genes, Brain and Behavior 5, 113119.
16. Cosgrove, VE, Kelsoe, JR Suppes, T (2016) Toward a valid animal model of bipolar disorder: how the research domain criteria help bridge the clinical-basic science divide. Biol Psychiatry 79, 6270.
17. Malkesman, O, Scattoni, ML, Paredes, D, Tragon, T, Pearson, B, Shaltiel, G, Chen, G, Crawley, JN Manji, HK (2009) The female urine sniffing test: a novel approach for assessing reward-seeking behavior in rodents. Biol Psychiatry 67, 864871.
18. Perry, W, Minassian, A, Paulus, MP, Young, JW, Kincaid, MJ, Ferguson, EJ, Henry, BL, Zhuang, X, Masten, VL, Sharp, RF Geyer, MA (2009) A reverse-translational study of dysfunctional exploration in psychiatric disorders: from mice to men. Arch Gen Psychiatry 66, 10721080.
19. Cryan, JF Holmes, A (2005) The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov 4, 775790.
20. Stukalin, Y Einat, H (2018) Analyzing test batteries in animal models of psychopathology with multivariate analysis of variance (MANOVA): one possible approach to increase external validity. Pharmacol Biochem Behav 28, 3040230408.
21. WHO (2008) The global burden of disese: 2004 update. Geneva: World Health Organization Press.
22. Vohringer, PA Perlis, RH (2016) Discriminating between bipolar disorder and major depressive disorder. Psychiatr Clin North Am 39, 110.
23. Fountoulakis, KN, Kasper, S, Andreassen, O, Blier, P, Okasha, A, Severus, E, Versiani, M, Tandon, R, Moller, HJ Vieta, E (2012) Efficacy of pharmacotherapy in bipolar disorder: a report by the WPA section on pharmacopsychiatry. Eur Arch Psychiatry Clin Neurosci 262(Suppl. 1):148.
24. Schumann, G, Binder, EB, Holte, A, de Kloet, ER, Oedegaard, KJ, Robbins, TW, Walker-Tilley, TR, Bitter, I, Brown, VJ, Buitelaar, J, Ciccocioppo, R, Cools, R, Escera, C, Fleischhacker, W, Flor, H, Frith, CD, Heinz, A, Johnsen, E, Kirschbaum, C, Klingberg, T, Lesch, KP, Lewis, S, Maier, W, Mann, K, Martinot, JL, Meyer-Lindenberg, A, Muller, CP, Muller, WE, Nutt, DJ, Persico, A, Perugi, G, Pessiglione, M, Preuss, UW, Roiser, JP, Rossini, PM, Rybakowski, JK, Sandi, C, Stephan, KE, Undurraga, J, Vieta, E, van der Wee, N, Wykes, T, Haro, JM Wittchen, HU (2014) Stratified medicine for mental disorders. Eur Neuropsychopharmacol 24, 550.
25. Hasler, G Wolf, A (2015) Toward stratified treatments for bipolar disorders. Eur Neuropsychopharmacol 25, 283294.
26. Crabbe, JC, Wahlsten, D Dudek, BC (1999) Genetics of mouse behavior: interactions with laboratory environment. Science 284, 16701672.
27. Lewejohann, L, Zipser, B Sachser, N (2011) “Personality” in laboratory mice used for biomedical research: a way of understanding variability? Dev Psychobiol 53, 624630.
28. Kara, N, Stukalin, Y Einat, H (2018) Revisiting the validity of the mouse forced swim test: systematic review and meta-analysis of the effects of prototypic antidepressants. Neurosci Biobehav Rev 84, 111.
29. Flaisher-Grinberg, S Einat, H (2010) Strain specific battery of tests for separate behavioral domains of mania. Front Psychiatry 1, 110.
30. Gould, TD, O’Donnell, KC, Picchini, AM Manji, HK (2007) Strain differences in lithium attenuation of d-amphetamine-induced hyperlocomotion: a mouse model for the genetics of clinical response to lithium. Neuropsychopharmacology 32, 13211333.
31. Pilz, LK, Quiles, CL, Dallegrave, E, Levandovski, R, Hidalgo, MP Elisabetsky, E (2015) Differential susceptibility of BALB/c, C57BL/6N, and CF1 mice to photoperiod changes. Rev Bras Psiquiatr 37, 185190.
32. Sugimoto, Y, Kajiwara, Y, Hirano, K, Yamada, S, Tagawa, N, Kobayashi, Y, Hotta, Y Yamada, J (2008) Mouse strain differences in immobility and sensitivity to fluvoxamine and desipramine in the forced swimming test: analysis of serotonin and noradrenaline transporter binding. Eur J Pharmacol 592, 116122.
33. Jacobson, LH Cryan, JF (2007) Feeling strained? Influence of genetic background on depression-related behavior in mice: a review. Behav Genet 37, 171213.
34. Kara, NZ Einat, H (2013) Rodent models for mania: practical approaches. Cell Tissue Res 354, 191201.
35. Ene, HM, Kara, NZ Einat, H (2015b) Introducing female black Swiss mice: minimal effects of sex in a strain-specific battery of tests for mania-like behavior and response to lithium. Pharmacology 95, 224228.
36. Franceschelli, A, Herchick, S, Thelen, C, Papadopoulou-Daifoti, Z Pitychoutis, PM (2014) Sex differences in the chronic mild stress model of depression. Behav Pharmacol 14, 14.
37. Warner, TA, Libman, MK, Wooten, KL Drugan, RC (2013) Sex differences associated with intermittent swim stress. Stress 16, 655663.
38. Bale, TL Epperson, CN (2017) Sex as a biological variable: who, what, when, why, and how. Neuropsychopharmacology 42, 386396.
39. Kokras, N Dalla, C (2014) Sex differences in animal models of psychiatric disorders. Br J Pharmacol 4, 12710.
40. Prendergast, BJ, Onishi, KG Zucker, I (2014) Female mice liberated for inclusion in neuroscience and biomedical research. Neurosci Biobehav Rev 40, 15.
41. Simpson, J, Ryan, C, Curley, A, Mulcaire, J Kelly, JP (2012) Sex differences in baseline and drug-induced behavioural responses in classical behavioural tests. Prog Neuropsychopharmacol Biol Psychiatry 37, 227236.
42. Juetten, J Einat, H (2012) Behavioral differences in black Swiss mice from separate colonies: implications for modeling domains of mania. Behav Pharmacol 23, 211214.
43. Fitzpatrick, CJ, Gopalakrishnan, S, Cogan, ES, Yager, LM, Meyer, PJ, Lovic, V, Saunders, BT, Parker, CC, Gonzales, NM, Aryee, E, Flagel, SB, Palmer, AA, Robinson, TE Morrow, JD (2013) Variation in the form of Pavlovian conditioned approach behavior among outbred male Sprague-Dawley rats from different vendors and colonies: sign-tracking vs. goal-tracking. PLoS One 8, e75042.
44. Sparks, LM, Sciascia, JM, Ayorech, Z Chaudhri, N (2014) Vendor differences in alcohol consumption and the contribution of dopamine receptors to Pavlovian-conditioned alcohol-seeking in Long-Evans rats. Psychopharmacology (Berl) 231, 753764.
45. Pena-Oliver, Y, Sanchez-Roige, S, Stephens, DN Ripley, TL (2014) Alpha-synuclein deletion decreases motor impulsivity but does not affect risky decision making in a mouse gambling task. Psychopharmacology (Berl) 231, 24932506.
46. Becker, JB Cha, JH (1989) Estrous cycle-dependent variation in amphetamine-induced behaviors and striatal dopamine release assessed with microdialysis. Behav Brain Res 35, 117125.
47. Milad, MR, Igoe, SA, Lebron-Milad, K Novales, JE (2009) Estrous cycle phase and gonadal hormones influence conditioned fear extinction. Neuroscience 164, 887895.
48. Verma, P, Hellemans, KG, Choi, FY, Yu, W Weinberg, J (2009) Circadian phase and sex effects on depressive/anxiety-like behaviors and HPA axis responses to acute stress. Physiol Behav 99, 276285.
49. Overstreet, DH, Friedman, E, Mathe, AA Yadid, G (2005) The Flinders Sensitive Line rat: a selectively bred putative animal model of depression. Neurosci Biobehav Rev 29, 739759.
50. Kara, NZ, Flaisher-Grinberg, S, Anderson, GW, Agam, G Einat, H (2018) Mood-stabilizing effects of rapamycin and its analog temsirolimus: relevance to autophagy. Behav Pharmacol 29, 379384.
51. Touma, C, Bunck, M, Glasl, L, Nussbaumer, M, Palme, R, Stein, H, Wolferstatter, M, Zeh, R, Zimbelmann, M, Holsboer, F Landgraf, R (2008) Mice selected for high versus low stress reactivity: a new animal model for affective disorders. Psychoneuroendocrinology 33, 839862.
52. Bougarel, L, Guitton, J, Zimmer, L, Vaugeois, JM El Yacoubi, M (2011) Behaviour of a genetic mouse model of depression in the learned helplessness paradigm. Psychopharmacology (Berl) 215, 595605.
53. Wegener, G, Mathe, AA Neumann, ID (2012) Selectively bred rodents as models of depression and anxiety. Curr Top Behav Neurosci 12, 139187.
54. Cervantes, MC Delville, Y (2007) Individual differences in offensive aggression in golden hamsters: a model of reactive and impulsive aggression? Neuroscience 150, 511521.
55. Cohen, H, Zohar, J Matar, M (2003) The relevance of differential response to trauma in an animal model of posttraumatic stress disorder. Biol Psychiatry 53, 463473.
56. Matar, MA, Zohar, J Cohen, H (2013) Translationally relevant modeling of PTSD in rodents. Cell Tissue Res 354, 127139.
57. Cohen, R Kronfeld-Schor, N (2006) Individual variability and photic entrainment of circadian rhythms in golden spiny mice. Physiol Behav 87, 563574.
58. Freund, J, Brandmaier, AM, Lewejohann, L, Kirste, I, Kritzler, M, Kruger, A, Sachser, N, Lindenberger, U Kempermann, G (2013) Emergence of individuality in genetically identical mice. Science 340, 756759.
59. Jakovcevski, M, Schachner, M Morellini, F (2008) Individual variability in the stress response of C57BL/6J male mice correlates with trait anxiety. Genes Brain Behav 7, 235243.
60. Jama, A, Cecchi, M, Calvo, N, Watson, SJ Akil, H (2008) Inter-individual differences in novelty-seeking behavior in rats predict differential responses to desipramine in the forced swim test. Psychopharmacology (Berl) 198, 333340.
61. Khemissi, W, Farooq, RK, Le Guisquet, AM, Sakly, M Belzung, C (2014) Dysregulation of the hypothalamus-pituitary-adrenal axis predicts some aspects of the behavioral response to chronic fluoxetine: association with hippocampal cell proliferation. Front Behav Neurosci 8, 340.
62. Krishnan, V, Han, MH, Graham, DL, Berton, O, Renthal, W, Russo, SJ, Laplant, Q, Graham, A, Lutter, M, Lagace, DC, Ghose, S, Reister, R, Tannous, P, Green, TA, Neve, RL, Chakravarty, S, Kumar, A, Eisch, AJ, Self, DW, Lee, FS, Tamminga, CA, Cooper, DC, Gershenfeld, HK Nestler, EJ (2007) Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131, 391404.
63. Larrieu, T, Cherix, A, Duque, A, Rodrigues, J, Lei, H, Gruetter, R Sandi, C (2017) Hierarchical status predicts behavioral vulnerability and nucleus accumbens metabolic profile following chronic social defeat stress. Curr Biol 27, 22022210.
64. Malatynska, E Knapp, RJ (2005) Dominant-submissive behavior as models of mania and depression. Neurosci Biobehav Rev 29, 715737.
65. Nesher, E, Koman, I, Gross, M, Tikhonov, T, Bairachnaya, M, Salmon-Divon, M, Levin, Y, Gerlitz, G, Michaelevski, I, Yadid, G Pinhasov, A (2015) Synapsin IIb as a functional marker of submissive behavior. Sci Rep 5, 10287.
66. Palencia, M, Diaz-Moran, S, Mont-Cardona, C, Canete, T, Blazquez, G, Martinez-Membrives, E, Lopez-Aumatell, R, Tobena, A Fernandez-Teruel, A (2013) Helplessness-like escape deficits of NIH-HS rats predict passive behavior in the forced swimming test: relevance for the concurrent validity of rat models of depression. World Journal of Neuroscience 3, 8392.
67. Pitychoutis, PM, Pallis, EG, Mikail, HG Papadopoulou-Daifoti, Z (2011) Individual differences in novelty-seeking predict differential responses to chronic antidepressant treatment through sex- and phenotype-dependent neurochemical signatures. Behav Brain Res 223, 154168.
68. Shishkina, GT, Kalinina, TS, Berezova, IV, Bulygina, VV Dygalo, NN (2010) Resistance to the development of stress-induced behavioral despair in the forced swim test associated with elevated hippocampal Bcl-xl expression. Behav Brain Res 213, 218224.
69. Vaugeois, JM, Passera, G, Zuccaro, F Costentin, J (1997) Individual differences in response to imipramine in the mouse tail suspension test. Psychopharmacology (Berl) 134, 387391.
70. Feder, A, Nestler, EJ Charney, DS (2009) Psychobiology and molecular genetics of resilience. Nat Rev Neurosci 10, 446457.
71. Pinhasov, A, Ilyin, SE, Crooke, J, Amato, FA, Vaidya, AH, Rosenthal, D, Brenneman, DE Malatynska, E (2005) Different levels of gamma-synuclein mRNA in the cerebral cortex of dominant, neutral and submissive rats selected in the competition test. Genes Brain Behav 4, 6064.
72. Nesher, E, Gross, M, Lisson, S, Tikhonov, T, Yadid, G Pinhasov, A (2013) Differential responses to distinct psychotropic agents of selectively bred dominant and submissive animals. Behav Brain Res 236, 225235.
73. Cohen, H Zohar, J (2004) An animal model of posttraumatic stress disorder: the use of cut-off behavioral criteria. Ann N Y Acad Sci 1032, 167178.
74. Cohen, H, Kozlovsky, N, Alona, C, Matar, MA Joseph, Z (2012) Animal model for PTSD: from clinical concept to translational research. Neuropharmacology 62, 715724.
75. Daskalakis, NP, Cohen, H, Cai, G, Buxbaum, JD Yehuda, R (2014) Expression profiling associates blood and brain glucocorticoid receptor signaling with trauma-related individual differences in both sexes. Proc Natl Acad Sci U S A 111, 1352913534.
76. Abel, EL Hannigan, JH (1992) Effects of chronic forced swimming and exposure to alarm substance: physiological and behavioral consequences. Physiol Behav 52, 781785.
77. Ene, HM, Kara, NZ, Barak, N, Reshef Ben-Mordechai, T Einat, H (2015a) Effects of repeated asenapine in a battery of tests for anxiety-like behaviours in mice. Acta Neuropsychiatr 11, 17.
78. Geyer, MA (2008) Developing translational animal models for symptoms of schizophrenia or bipolar mania. Neurotox Res 14, 7178.
79. Blanchard, RJ, Kaawaloa, JN, Hebert, MA Blanchard, DC (1999) Cocaine produces panic-like flight responses in mice in the mouse defense test battery. Pharmacol Biochem Behav 64, 523528.
80. Crawley, JN (1999) Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests. Brain Res 835, 1826.
81. Bailey, KR, Rustay, NR Crawley, JN (2006) Behavioral phenotyping of transgenic and knockout mice: practical concerns and potential pitfalls. Ilar J 47, 124131.
82. Lucki, I, Dalvi, A Mayorga, AJ (2001) Sensitivity to the effects of pharmacologically selective antidepressants in different strains of mice. Psychopharmacology (Berl) 155, 315322.
83. Can, A, Blackwell, RA, Piantadosi, SC, Dao, DT, O’Donnell, KC Gould, TD (2011) Antidepressant-like responses to lithium in genetically diverse mouse strains. Genes Brain Behav 10, 434443.
84. Sade, Y, Kara, NZ, Toker, L, Bersudsky, Y, Einat, H Agam, G (2014) Beware of your mouse strain; differential effects of lithium on behavioral and neurochemical phenotypes in Harlan ICR mice bred in Israel or the USA. Pharmacol Biochem Behav 124C, 3639.
85. Kara, NZ, Karpel, O, Toker, L, Agam, G, Belmaker, RH Einat, H (2014) Chronic oral carbamazepine treatment elicits mood-stabilising effects in mice. Acta Neuropsychiatr 26, 2934.
86. Adams, B, Fitch, T, Chaney, S Gerlai, R (2002) Altered performance characteristics in cognitive tasks: comparison of the albino ICR and CD1 mouse strains. Behav Brain Res 133, 351361.
87. Willner, P (1995) Animal models of depression: validity and applications. In Gessa GL, Fratta W, Pani L and Serra G editors Depression and mania: from neurobiology to treatment, vol 49. Advances in Biochemical Psychopharmacology. New York: Raven Press pp. 1942.
88. Belzung, C (2001) The genetic basis of the pharmacological effects of anxiolytics: a review based on rodent models. Behav Pharmacol 12, 451460.
89. Crawley, JN Paylor, R (1997) A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice. Horm Behav 31, 197211.
90. Ducottet, C Belzung, C (2004) Behaviour in the elevated plus-maze predicts coping after subchronic mild stress in mice. Physiol Behav 81, 417426.
91. Kalueff, AV, Keisala, T, Minasyan, A, Kuuslahti, M Tuohimaa, P (2006) Temporal stability of novelty exploration in mice exposed to different open field tests. Behav Processes 72, 104112.
92. Kabbaj, M, Devine, DP, Savage, VR Akil, H (2000) Neurobiological correlates of individual differences in novelty-seeking behavior in the rat: differential expression of stress-related molecules. J Neurosci 20, 69836988.
93. Shankman, SA, Klein, DN, Torpey, DC, Olino, TM, Dyson, MW, Kim, J, Durbin, CE, Nelson, BD Tenke, CE (2011) Do positive and negative temperament traits interact in predicting risk for depression? A resting EEG study of 329 preschoolers. Dev Psychopathol 23, 551562.
94. Forbes, EE Dahl, RE (2012) Research review: altered reward function in adolescent depression: what, when and how? J Child Psychol Psychiatry 53, 315.
95. Dietz, DM, Tapocik, J, Gaval-Cruz, M Kabbaj, M (2005) Dopamine transporter, but not tyrosine hydroxylase, may be implicated in determining individual differences in behavioral sensitization to amphetamine. Physiol Behav 86, 347355.
96. Clapcote, SJ, Lazar, NL, Bechard, AR, Wood, GA Roder, JC (2005) NIH Swiss and black Swiss mice have retinal degeneration and performance deficits in cognitive tests. Comp Med 55, 310316.
97. Serfilippi, LM, Pallman, DR, Gruebbel, MM, Kern, TJ Spainhour, CB (2004) Assessment of retinal degeneration in outbred albino mice. Comp Med 54, 6976.
98. Ising, M, Horstmann, S, Kloiber, S, Lucae, S, Binder, EB, Kern, N, Kunzel, HE, Pfennig, A, Uhr, M Holsboer, F (2007) Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression – a potential biomarker? Biol Psychiatry 62, 4754.
99. Kempermann, G, Kuhn, HG Gage, FH (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature 386, 493495.
100. Shamir, A, Shaltiel, G, Greenberg, ML, Belmaker, RH Agam, G (2003) The effect of lithium on expression of genes for inositol biosynthetic enzymes in mouse hippocampus; a comparison with the yeast model. Brain Res Mol Brain Res 115, 104110.

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Individual responses of rodents in modelling of affective disorders and in their treatment: prospective review

  • Haim Einat (a1) (a2) (a3), Itamar Ezer (a1), Nirit Z Kara (a1) (a2) and Catherine Belzung (a4)

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