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Current Cardiology Reports

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01-11-2018 | Psychological Aspects of Cardiovascular Diseases (A Steptoe, Section Editor)

The Utility of Rodent Models of Stress for Disentangling Individual Vulnerability to Depression and Cardiovascular Comorbidity

Authors: Luca Carnevali, Rosario Statello, Andrea Sgoifo

Published in: Current Cardiology Reports | Issue 11/2018

Abstract

Purpose of Review

This review offers a perspective of the utility of rodent models of stress for identifying sources of individual vulnerability to depression and cardiovascular disease comorbidity.

Recent Findings

Differential stress susceptibility is found in rodents exposed to repeated social defeat as a function of their coping style. Specifically, passive coping rodents show an increase in inflammatory processes within the brain that favour the development of depressive-like symptoms and cardiovascular abnormalities. Similarly, only a sub-group of rats develops depressive-like symptoms following chronic mild stress exposure. Cardiovascular changes differ depending on individual stress susceptibility and may be related to an imbalance in the autonomic regulation of cardiac function in stress vulnerable subjects.

Summary

Rodent models of stress that take into account individual phenotypic variations are useful for a better understanding of the role of neuroinflammatory and autonomic processes in the development of comorbid depression and cardiovascular disease under stressful conditions.

Cohen BE, Edmondson D, Kronish IM. State of the art review: depression, stress, anxiety, and cardiovascular disease. Am J Hypertens. 2015;28(11):1295–302. https://doi.org/10.1093/ajh/hpv047.CrossRefPubMedPubMedCentral

Hare DL, Toukhsati SR, Johansson P, Jaarsma T. Depression and cardiovascular disease: a clinical review. Eur Heart J. 2014;35(21):1365–72. https://doi.org/10.1093/eurheartj/eht462.CrossRefPubMed

Ford DE, Mead LA, Chang PP, Cooper-Patrick L, Wang NY, Klag MJ. Depression is a risk factor for coronary artery disease in men: the precursors study. Arch Intern Med. 1998;158(13):1422–6.CrossRef

Whooley MA, de Jonge P, Vittinghoff E, Otte C, Moos R, Carney RM, et al. Depressive symptoms, health behaviors, and risk of cardiovascular events in patients with coronary heart disease. JAMA. 2008;300(20):2379–88. https://doi.org/10.1001/jama.2008.711.CrossRefPubMedPubMedCentral

Wu JR, Frazier SK, Rayens MK, Lennie TA, Chung ML, Moser DK. Medication adherence, social support, and event-free survival in patients with heart failure. Health Psychol. 2013;32(6):637–46. https://doi.org/10.1037/a0028527.CrossRefPubMed

Bautista LE, Vera-Cala LM, Colombo C, Smith P. Symptoms of depression and anxiety and adherence to antihypertensive medication. Am J Hypertens. 2012;25(4):505–11. https://doi.org/10.1038/ajh.2011.256.CrossRefPubMedPubMedCentral

Carney RM, Blumenthal JA, Catellier D, Freedland KE, Berkman LF, Watkins LL, et al. Depression as a risk factor for mortality after acute myocardial infarction. Am J Cardiol. 2003;92(11):1277–81.CrossRef

Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull. 2014;140(3):774–815. https://doi.org/10.1037/a0035302.CrossRefPubMedPubMedCentral

Sgoifo A, Carnevali L, Alfonso Mde L, Amore M. Autonomic dysfunction and heart rate variability in depression. Stress. 2015;18(3):343–52. https://doi.org/10.3109/10253890.2015.1045868.CrossRefPubMed

10.

Cohen S, Janicki-Deverts D, Miller GE. Psychological stress and disease. JAMA. 2007;298(14):1685–7. https://doi.org/10.1001/jama.298.14.1685.CrossRefPubMed

11.

van Praag HM. Can stress cause depression? Prog Neuro-Psychopharmacol Biol Psychiatry. 2004;28(5):891–907. https://doi.org/10.1016/j.pnpbp.2004.05.031.CrossRef

12.

• Carnevali L, Montano N, Statello R, Sgoifo A. Rodent models of depression-cardiovascular comorbidity: bridging the known to the new. Neurosci Biobehav Rev. 2017;76(Pt A):144–53. https://doi.org/10.1016/j.neubiorev.2016.11.006. An up-to-date review on the use of chronic stress paradigms for modelling aspects of human depression/CVD comorbidity in rodents . CrossRefPubMed

13.

Sgoifo A, Carnevali L, Grippo AJ. The socially stressed heart. Insights from studies in rodents. Neurosci Biobehav Rev. 2014;39:51–60. https://doi.org/10.1016/j.neubiorev.2013.12.005.CrossRefPubMed

14.

Armario A, Nadal R. Individual differences and the characterization of animal models of psychopathology: a strong challenge and a good opportunity. Front Pharmacol. 2013;4:137. https://doi.org/10.3389/fphar.2013.00137.CrossRefPubMedPubMedCentral

15.

•• de Boer SF, Buwalda B, Koolhaas JM. Untangling the neurobiology of coping styles in rodents: Towards neural mechanisms underlying individual differences in disease susceptibility. Neurosci Biobehav Rev. 2017;74(Pt B):401–22. https://doi.org/10.1016/j.neubiorev.2016.07.008. This interesting review summarizes behavioural, neuroendocrine, and neurobiological features associated with different coping styles in rodents that may explain differential disease susceptibility . CrossRefPubMed

16.

Koolhaas JM, Korte SM, De Boer SF, Van Der Vegt BJ, Van Reenen CG, Hopster H, et al. Coping styles in animals: current status in behavior and stress-physiology. Neurosci Biobehav Rev. 1999;23(7):925–35.CrossRef

17.

Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131(2):391–404. https://doi.org/10.1016/j.cell.2007.09.018.CrossRefPubMed

18.

Koolhaas JM, de Boer SF, Buwalda B, Meerlo P. Social stress models in rodents: towards enhanced validity. Neurobiol Stress. 2017;6:104–12. https://doi.org/10.1016/j.ynstr.2016.09.003.CrossRefPubMed

19.

Carnevali L, Trombini M, Graiani G, Madeddu D, Quaini F, Landgraf R, et al. Low vagally-mediated heart rate variability and increased susceptibility to ventricular arrhythmias in rats bred for high anxiety. Physiol Behav. 2014;128:16–25. https://doi.org/10.1016/j.physbeh.2014.01.033.CrossRefPubMed

20.

Carnevali L, Mastorci F, Audero E, Graiani G, Rossi S, Macchi E, et al. Stress-induced susceptibility to sudden cardiac death in mice with altered serotonin homeostasis. PLoS One. 2012;7(7):e41184. https://doi.org/10.1371/journal.pone.0041184.CrossRefPubMedPubMedCentral

21.

Statello R, Carnevali L, Paterlini S, Gioiosa L, Bertocchi I, Oberto A, et al. Reduced NPY Y1 receptor hippocampal expression and signs of decreased vagal modulation of heart rate in mice. Physiol Behav. 2017;172:31–9. https://doi.org/10.1016/j.physbeh.2016.07.017.CrossRefPubMed

22.

Sgoifo A, De Boer SF, Buwalda B, Korte-Bouws G, Tuma J, Bohus B, et al. Vulnerability to arrhythmias during social stress in rats with different sympathovagal balance. Am J Phys. 1998;275(2 Pt 2):H460–6.

23.

Veenema AH, Meijer OC, de Kloet ER, Koolhaas JM. Genetic selection for coping style predicts stressor susceptibility. J Neuroendocrinol. 2003;15(3):256–67.CrossRef

24.

Wood SK, Bhatnagar S. Resilience to the effects of social stress: evidence from clinical and preclinical studies on the role of coping strategies. Neurobiol Stress. 2015;1:164–73. https://doi.org/10.1016/j.ynstr.2014.11.002.CrossRefPubMed

25.

Coppens CM, de Boer SF, Koolhaas JM. Coping styles and behavioural flexibility: towards underlying mechanisms. Philos Trans R Soc Lond Ser B Biol Sci. 2010;365(1560):4021–8. https://doi.org/10.1098/rstb.2010.0217.CrossRef

26.

Hawley DF, Bardi M, Everette AM, Higgins TJ, Tu KM, Kinsley CH, et al. Neurobiological constituents of active, passive, and variable coping strategies in rats: integration of regional brain neuropeptide Y levels and cardiovascular responses. Stress. 2010;13(2):172–83. https://doi.org/10.3109/10253890903144621.CrossRefPubMed

27.

Miczek KA. A new test for aggression in rats without aversive stimulation: differential effects of d-amphetamine and cocaine. Psychopharmacology. 1979;60(3):253–9.CrossRef

28.

Hammels C, Pishva E, De Vry J, van den Hove DL, Prickaerts J, van Winkel R, et al. Defeat stress in rodents: from behavior to molecules. Neurosci Biobehav Rev. 2015;59:111–40. https://doi.org/10.1016/j.neubiorev.2015.10.006.CrossRefPubMed

29.

Wood SK. Individual differences in the neurobiology of social stress: implications for depression-cardiovascular disease comorbidity. Curr Neuropharmacol. 2014;12(2):205–11. https://doi.org/10.2174/1570159X11666131120224413.CrossRefPubMedPubMedCentral

30.

Wood SK, McFadden KV, Grigoriadis D, Bhatnagar S, Valentino RJ. Depressive and cardiovascular disease comorbidity in a rat model of social stress: a putative role for corticotropin-releasing factor. Psychopharmacology. 2012;222(2):325–36. https://doi.org/10.1007/s00213-012-2648-6.CrossRefPubMedPubMedCentral

31.

Wood SK, Walker HE, Valentino RJ, Bhatnagar S. Individual differences in reactivity to social stress predict susceptibility and resilience to a depressive phenotype: role of corticotropin-releasing factor. Endocrinology. 2010;151(4):1795–805. https://doi.org/10.1210/en.2009-1026.CrossRefPubMedPubMedCentral

32.

De Miguel Z, Vegas O, Garmendia L, Arregi A, Beitia G, Azpiroz A. Behavioral coping strategies in response to social stress are associated with distinct neuroendocrine, monoaminergic and immune response profiles in mice. Behav Brain Res. 2011;225(2):554–61. https://doi.org/10.1016/j.bbr.2011.08.011.CrossRefPubMed

33.

Gomez-Lazaro E, Arregi A, Beitia G, Vegas O, Azpiroz A, Garmendia L. Individual differences in chronically defeated male mice: behavioral, endocrine, immune, and neurotrophic changes as markers of vulnerability to the effects of stress. Stress. 2011;14(5):537–48. https://doi.org/10.3109/10253890.2011.562939.CrossRefPubMed

34.

Perez-Tejada J, Arregi A, Gomez-Lazaro E, Vegas O, Azpiroz A, Garmendia L. Coping with chronic social stress in mice: hypothalamic-pituitary-adrenal/sympathetic-adrenal-medullary axis activity, behavioral changes and effects of antalarmin treatment: implications for the study of stress-related psychopathologies. Neuroendocrinology. 2013;98(1):73–88. https://doi.org/10.1159/000353620.CrossRefPubMed

35.

Carnevali L, Sgoifo A. Vagal modulation of resting heart rate in rats: the role of stress, psychosocial factors, and physical exercise. Front Physiol. 2014;5:118. https://doi.org/10.3389/fphys.2014.00118.CrossRefPubMedPubMedCentral

36.

Hillebrand S, Gast KB, de Mutsert R, Swenne CA, Jukema JW, Middeldorp S, et al. Heart rate variability and first cardiovascular event in populations without known cardiovascular disease: meta-analysis and dose-response meta-regression. Europace. 2013;15(5):742–9. https://doi.org/10.1093/europace/eus341.CrossRefPubMed

37.

Thayer JF, Yamamoto SS, Brosschot JF. The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors. Int J Cardiol. 2010;141(2):122–31. https://doi.org/10.1016/j.ijcard.2009.09.543.CrossRefPubMed

38.

Carnevali L, Trombini M, Rossi S, Graiani G, Manghi M, Koolhaas JM, et al. Structural and electrical myocardial remodeling in a rodent model of depression. Psychosom Med. 2013;75(1):42–51. https://doi.org/10.1097/PSY.0b013e318276cb0d.CrossRefPubMed

39.

• Wood SK, Wood CS, Lombard CM, Lee CS, Zhang XY, Finnell JE, et al. Inflammatory factors mediate vulnerability to a social stress-induced depressive-like phenotype in passive coping rats. Biol Psychiatry. 2015;78(1):38–48. https://doi.org/10.1016/j.biopsych.2014.10.026. An interesting paper exploring the role of inflammatory processes in mediating stress-induced depressive-like symptoms in passive coping rats . CrossRefPubMed

40.

Ressler KJ, Nemeroff CB. Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders. Depress Anxiety. 2000;12(Suppl 1):2–19. https://doi.org/10.1002/1520-6394(2000)12:1+<2::AID-DA2>3.0.CO;2-4.CrossRefPubMed

41.

Serafini G. Neuroplasticity and major depression, the role of modern antidepressant drugs. World J Psychiatry. 2012;2(3):49–57. https://doi.org/10.5498/wjp.v2.i3.49.CrossRefPubMedPubMedCentral

42.

•• Wood CS, Valentino RJ, Wood SK. Individual differences in the locus coeruleus-norepinephrine system: relevance to stress-induced cardiovascular vulnerability. Physiol Behav. 2017;172:40–8. https://doi.org/10.1016/j.physbeh.2016.07.008. Discussion of the role of the locus coeruleus in mediating individual differences in vulnerability to social stress-induced cardiovascular dysfunction . CrossRefPubMed

43.

•• Finnell JE, Wood SK. Neuroinflammation at the interface of depression and cardiovascular disease: evidence from rodent models of social stress. Neurobiol Stress. 2016;4:1–14. https://doi.org/10.1016/j.ynstr.2016.04.001. A thorough review of rodent studies investigating the role of stress-induced neuroinflammation in the co-occurrence of depression and cardiovascualr disease . CrossRefPubMedPubMedCentral

44.

Harro J. Animal models of depression vulnerability. Curr Top Behav Neurosci. 2013;14:29–54. https://doi.org/10.1007/7854_2012_221.CrossRefPubMed

45.

Nollet M, Le Guisquet AM, Belzung C. Models of depression: unpredictable chronic mild stress in mice. Curr Protoc Pharmacol. 2013;Chapter 5:Unit 5 65. https://doi.org/10.1002/0471141755.ph0565s61.CrossRefPubMed

46.

Willner P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol Stress. 2017;6:78–93. https://doi.org/10.1016/j.ynstr.2016.08.002.CrossRefPubMed

47.

Willner P. Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology. 2005;52(2):90–110. https://doi.org/10.1159/000087097.CrossRefPubMed

48.

Christensen T, Bisgaard CF, Wiborg O. Biomarkers of anhedonic-like behavior, antidepressant drug refraction, and stress resilience in a rat model of depression. Neuroscience. 2011;196:66–79. https://doi.org/10.1016/j.neuroscience.2011.08.024.CrossRefPubMed

49.

Henningsen K, Palmfeldt J, Christiansen S, Baiges I, Bak S, Jensen ON, et al. Candidate hippocampal biomarkers of susceptibility and resilience to stress in a rat model of depression. Mol Cell Proteomics. 2012;11(7):M111.016428. https://doi.org/10.1074/mcp.M111.016428.CrossRefPubMedPubMedCentral

50.

Palmfeldt J, Henningsen K, Eriksen SA, Muller HK, Wiborg O. Protein biomarkers of susceptibility and resilience to stress in a rat model of depression. Mol Cell Neurosci. 2016;74:87–95. https://doi.org/10.1016/j.mcn.2016.04.001.CrossRefPubMed

51.

Grippo AJ, Beltz TG, Johnson AK. Behavioral and cardiovascular changes in the chronic mild stress model of depression. Physiol Behav. 2003;78(4–5):703–10.CrossRef

52.

Grippo AJ, Beltz TG, Weiss RM, Johnson AK. The effects of chronic fluoxetine treatment on chronic mild stress-induced cardiovascular changes and anhedonia. Biol Psychiatry. 2006;59(4):309–16. https://doi.org/10.1016/j.biopsych.2005.07.010.CrossRefPubMed

53.

Grippo AJ, Moffitt JA, Johnson AK. Evaluation of baroreceptor reflex function in the chronic mild stress rodent model of depression. Psychosom Med. 2008;70(4):435–43. https://doi.org/10.1097/PSY.0b013e31816ff7dd.CrossRefPubMedPubMedCentral

54.

Halaris A. Inflammation-associated co-morbidity between depression and cardiovascular disease. Curr Top Behav Neurosci. 2017;31:45–70. https://doi.org/10.1007/7854_2016_28.CrossRefPubMed

55.

Bouzinova EV, Moller-Nielsen N, Boedtkjer DB, Broegger T, Wiborg O, Aalkjaer C, et al. Chronic mild stress-induced depression-like symptoms in rats and abnormalities in catecholamine uptake in small arteries. Psychosom Med. 2012;74(3):278–87. https://doi.org/10.1097/PSY.0b013e31824c40a9.CrossRefPubMed

56.

Aalkjaer C, Heagerty AM, Mulvany MJ. In vitro characteristics of vessels from patients with essential hypertension. J Clin Hypertens. 1987;3(3):317–22.PubMed

57.

Bouzinova EV, Norregaard R, Boedtkjer DM, Razgovorova IA, Moeller AM, Kudryavtseva O, et al. Association between endothelial dysfunction and depression-like symptoms in chronic mild stress model of depression. Psychosom Med. 2014;76(4):268–76. https://doi.org/10.1097/PSY.0000000000000062.CrossRefPubMed

58.

Joynt KE, Whellan DJ, O'Connor CM. Depression and cardiovascular disease: mechanisms of interaction. Biol Psychiatry. 2003;54(3):248–61.CrossRef

59.

Matchkov VV, Kravtsova VV, Wiborg O, Aalkjaer C, Bouzinova EV. Chronic selective serotonin reuptake inhibition modulates endothelial dysfunction and oxidative state in rat chronic mild stress model of depression. Am J Physiol Regul Integr Comp Physiol. 2015;309(8):R814–23. https://doi.org/10.1152/ajpregu.00337.2014.CrossRefPubMed

60.

Nolen-Hoeksema S. Emotion regulation and psychopathology: the role of gender. Annu Rev Clin Psychol. 2012;8:161–87. https://doi.org/10.1146/annurev-clinpsy-032511-143109.CrossRefPubMed

61.

Shanmugasegaram S, Russell KL, Kovacs AH, Stewart DE, Grace SL. Gender and sex differences in prevalence of major depression in coronary artery disease patients: a meta-analysis. Maturitas. 2012;73(4):305–11. https://doi.org/10.1016/j.maturitas.2012.09.005.CrossRefPubMedPubMedCentral

62.

Marcus SM, Young EA, Kerber KB, Kornstein S, Farabaugh AH, Mitchell J, et al. Gender differences in depression: findings from the STAR*D study. J Affect Disord. 2005;87(2–3):141–50. https://doi.org/10.1016/j.jad.2004.09.008.CrossRefPubMed

63.

Sloan DM, Kornstein SG. Gender differences in depression and response to antidepressant treatment. Psychiatr Clin N Am. 2003;26(3):581–94.CrossRef

64.

Moller-Leimkuhler AM. Gender differences in cardiovascular disease and comorbid depression. Dialogues Clin Neurosci. 2007;9(1):71–83.PubMedPubMedCentral

65.

Plante GE. Depression and cardiovascular disease: a reciprocal relationship. Metabolism. 2005;54(5 Suppl 1):45–8. https://doi.org/10.1016/j.metabol.2005.01.013.CrossRefPubMed

66.

Franceschelli A, Herchick S, Thelen C, Papadopoulou-Daifoti Z, Pitychoutis PM. Sex differences in the chronic mild stress model of depression. Behav Pharmacol. 2014;25(5–6):372–83. https://doi.org/10.1097/FBP.0000000000000062.CrossRefPubMed

67.

Rincon-Cortes M, Grace AA. Sex-dependent effects of stress on immobility behavior and VTA dopamine neuron activity: modulation by ketamine. Int J Neuropsychopharmacol. 2017;20(10):823–32. https://doi.org/10.1093/ijnp/pyx048.CrossRefPubMedPubMedCentral

68.

Stanley SC, Brooks SD, Butcher JT, d'Audiffret AC, Frisbee SJ, Frisbee JC. Protective effect of sex on chronic stress- and depressive behavior-induced vascular dysfunction in BALB/cJ mice. J Appl Physiol (1985). 2014;117(9):959–70. https://doi.org/10.1152/japplphysiol.00537.2014.CrossRef

69.

Chakrabarti S, Morton JS, Davidge ST. Mechanisms of estrogen effects on the endothelium: an overview. Can J Cardiol. 2014;30(7):705–12. https://doi.org/10.1016/j.cjca.2013.08.006.CrossRefPubMed

70.

Grippo AJ, Sullivan NR, Damjanoska KJ, Crane JW, Carrasco GA, Shi J, et al. Chronic mild stress induces behavioral and physiological changes, and may alter serotonin 1A receptor function, in male and cycling female rats. Psychopharmacology. 2005;179(4):769–80. https://doi.org/10.1007/s00213-004-2103-4.CrossRefPubMed

71.

Koledova VV, Khalil RA. Sex hormone replacement therapy and modulation of vascular function in cardiovascular disease. Expert Rev Cardiovasc Ther. 2007;5(4):777–89. https://doi.org/10.1586/14779072.5.4.777.CrossRefPubMed

72.

• Brooks SD, Hileman SM, Chantler PD, Milde SA, Lemaster KA, Frisbee SJ, et al. Protection from vascular dysfunction in female rats with chronic stress and depressive symptoms. Am J Physiol Heart Circ Physiol. 2018;314(5):H1070–H84. https://doi.org/10.1152/ajpheart.00647.2017. A recent rodent study exploring sex differences in cardiovascular disturbances associated with stress and depression . CrossRefPubMed

Title: The Utility of Rodent Models of Stress for Disentangling Individual Vulnerability to Depression and Cardiovascular Comorbidity
Authors: Luca Carnevali
Rosario Statello
Andrea Sgoifo
Publication date: 01-11-2018
Publisher: Springer US
Published in: Current Cardiology Reports / Issue 11/2018
Print ISSN: 1523-3782
Electronic ISSN: 1534-3170
DOI: https://doi.org/10.1007/s11886-018-1064-x

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