Abstract
Post-traumatic stress disorder (PTSD) is clinically defined in DSM-4 by exposure to a significantly threatening and/or horrifying event and the presence of a certain number of symptoms from each of three symptom clusters at least one month after the event. Since humans clearly do not respond homogeneously to a potentially traumatic experience, the heterogeneity in animal responses might be regarded as confirming the validity of animal studies, rather than as representing a problem. A model of diagnostic criteria for psychiatric disorders could therefore be applied to animal responses to augment the validity of study data, providing that the criteria for classification are clearly defined, reliably reproducible and yield results that conform to findings in human subjects. The method described herein was developed in an attempt to model diagnostic criteria in terms of individual patterns of response by using behavioral measures and determining cut-off scores to distinguish between extremes of response or non-response, leaving a sizeable proportion of subjects in a middle group, outside each set of cut-off criteria. The cumulative results of our studies indicate that the contribution of animal models can be further enhanced by classifying individual animal study subjects according to their response patterns. The animal model also enables the researcher to go one step further and correlate specific anatomic, bio-molecular and physiological parameters with the degree and pattern of the individual behavioral response and introduces “prevalence rates” as a parameter. The translational value of the classification method and future directions are discussed.
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References
Adamec R (1997) Transmitter systems involved in neural plasticity underlying increased anxiety and defense–implications for understanding anxiety following traumatic stress. Neurosci Biobehav Rev 21:755–765
Adamec RE, Shallow T (1993) Lasting effects on rodent anxiety of a single exposure to a cat. Physiol Behav 54:101–109
Adamec R, Kent P, Anisman H, Shallow T, Merali Z (1998) Neural plasticity, neuropeptides and anxiety in animals—implications for understanding and treating affective disorder following traumatic stress in humans. Neurosci Biobehav Rev 23:301–318
Adamec R, Head D, Blundell J, Burton P, Berton O (2006a) Lasting anxiogenic effects of feline predator stress in mice: sex differences in vulnerability to stress and predicting severity of anxiogenic response from the stress experience. Physiol Behav 88:12–29
Adamec R, Strasser K, Blundell J, Burton P, McKay DW (2006b) Protein synthesis and the mechanisms of lasting change in anxiety induced by severe stress. Behav Brain Res 167:270–286
Adamec RE, Blundell J, Burton P (2006c) Relationship of the predatory attack experience to neural plasticity, pCREB expression and neuroendocrine response. Neurosci Biobehav Rev 30:356–375
Adamec R, Muir C, Grimes M, Pearcey K (2007) Involvement of noradrenergic and corticoid receptors in the consolidation of the lasting anxiogenic effects of predator stress. Behav Brain Res 179:192–207
Akirav I, Maroun M (2007) The role of the medial prefrontal cortex-amygdala circuit in stress effects on the extinction of fear. Neural Plast 2007:30873
American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, Washington, DC
Apfelbach R, Blanchard CD, Blanchard RJ, Hayes RA, McGregor IS (2005) The effects of predator odors in mammalian prey species: a review of field and laboratory studies. Neurosci Biobehav Rev 29:1123–1144
Blanchard RJ, Blanchard DC (1990) Anti-predator defense as models of fear and anxiety. In: Blanchard RJ, Parmigiani S (eds) Brain. Harwood Academic, London
Blanchard RJ, Blanchard DC, Rodgers J, Weiss SM (1990) The characterization and modelling of antipredator defensive behavior. Neurosci Biobehav Rev 14:463–472
Blanchard RJ, Shepherd JK, Rodgers RJ, Magee L, Blanchard DC (1993) Attenuation of antipredator defensive behavior in rats following chronic treatment with imipramine. Psychopharmacology 110:245–253
Blanchard RJ, Nikulina JN, Sakai RR, McKittrick C, McEwen B, Blanchard DC (1998) Behavioral and endocrine change following chronic predatory stress. Physiol Behav 63:561–569
Blanchard DC, Griebel G, Blanchard RJ (2003) Conditioning and residual emotionality effects of predator stimuli: some reflections on stress and emotion. Prog Neuropsychopharmacol Biol Psychiatry 27:1177–1185
Blechert J, Michael T, Vriends N, Margraf J, Wilhelm FH (2007) Fear conditioning in posttraumatic stress disorder: evidence for delayed extinction of autonomic, experiential, and behavioural responses. Behav Res Ther 45:2019–2033
Blundell J, Adamec R, Burton P (2005) Role of NMDA receptors in the syndrome of behavioral changes produced by predator stress. Physiol Behav 86:233–243
Borsboom D (2008) Psychometric perspectives on diagnostic systems. J Clin Psychol 64:1089–1108
Bouton ME (2004) Context and behavioral processes in extinction. Learn Mem 11:485–494
Bremner JD, Licinio J, Darnell A, Krystal JH, Owens MJ, Southwick SM et al (1997) Elevated CSF corticotropin-releasing factor concentrations in posttraumatic stress disorder. Am J Psychiatry 154:624–629
Breslau N, Davis GC, Andreski P, Peterson E (1991) Traumatic events and posttraumatic stress disorder in an urban population of young adults. Arch Gen Psychiatry 48:216–222
Breslau N, Kessler RC, Chilcoat HD, Schultz LR, Davis GC, Andreski P (1998) Trauma and posttraumatic stress disorder in the community: the 1996 Detroit Area Survey of Trauma. Arch Gen Psychiatry 55:626–632
Broekman BF, Olff M, Boer F (2007) The genetic background to PTSD. Neurosci Biobehav Rev 31:348–362
Cabib S, Orsini C, Le Moal M, Piazza P (2000) Abolition and reversal of strain differences in behavioral responses to drugs of abuse after a brief experience. Science 289:463–465
Cabib S, Puglisi-Allegra S, Ventura R (2002) The contribution of comparative studies in inbred strains of mice to the understanding of the hyperactive phenotype. Behav Brain Res 13:103–109
Caspi A, Moffitt T (2006) Gene-environment interactions in psychiatry: joining forces with neuroscience. Nat Rev Neurosci 7:583–590
Clinchy M, Schulkin J, Zanette LY, Sheriff MJ, McGowan PO, Boonstra R (2011) The neurological ecology of fear: insights neuroscientists and ecologists have to offer one another. Front Behav Neurosci 4:21
Cohen H, Zohar J (2004) Animal models of post traumatic stress disorder: the use of cut off behavioral criteria. Ann N Y Acad Sci 1032:167–178
Cohen H, Friedberg S, Michael M, Kotler M, Zeev K (1996) Interaction of CCK-4 induced anxiety and post-cat exposure anxiety in rats. Depress Anxiety 4:144–145
Cohen H, Kaplan Z, Kotler M (1999) CCK-antagonists in a rat exposed to acute stress: implication for anxiety associated with post-traumatic stress disorder. Depress Anxiety 10:8–17
Cohen H, Benjamin J, Kaplan Z, Kotler M (2000) Administration of high-dose ketoconazole, an inhibitor of steroid synthesis, prevents posttraumatic anxiety in an animal model. Eur Neuropsychopharmacol 10:429–435
Cohen H, Joseph Z, Matar M (2003) The relevance of differential response to trauma in an animal model of post-traumatic stress disorder. Biol Psychiatry 53:463–473
Cohen H, Zohar J, Matar MA, Zeev K, Loewenthal U, Richter-Levin G (2004) Setting apart the affected: the use of behavioral criteria in animal models of post traumatic stress disorder. Neuropsychopharmacology 29:1962–1970
Cohen H, Zohar J, Matar MA, Kaplan Z, Geva AB (2005) Unsupervised fuzzy clustering analysis supports behavioral cutoff criteria in an animal model of posttraumatic stress disorder. Biol Psychiatry 58:640–650
Cohen H, Matar MA, Richter-Levin G, Zohar J (2006a) The contribution of an animal model toward uncovering biological risk factors for PTSD. Ann N Y Acad Sci 1071:335–350
Cohen H, Ziv Y, Cardon M, Kaplan Z, Matar MA, Gidron Y et al (2006b) Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells. J Neurobiol 66:552–563
Cohen H, Zohar J, Gidron Y, Matar AM, Belkind D, Loewenthal U et al (2006c) Blunted HPA axis response to stress influences susceptibility to posttraumatic stress response in rats. Biol Psychiatry 15:1208–1218
Cohen H, Kaplan Z, Matar MA, Loewenthal U, Zohar J, Richter-Levin G (2007a) Long-lasting behavioral effects of juvenile trauma in an animal model of PTSD associated with a failure of the autonomic nervous system to recover. Eur Neuropsychopharmacol 17:464–677
Cohen H, Maayan R, Touati-Werner D, Kaplan Z, Matar MA, Loewenthal U et al (2007b) Decreased circulatory levels of neuroactive steroids in behaviourally more extremely affected rats subsequent to exposure to a potentially traumatic experience. Int J Neuropsychopharmacol 10:203–209
Cohen H, Geva AB, Matar MA, Zohar J, Kaplan Z (2008a) Post-traumatic stress behavioural responses in inbred mouse strains: can genetic predisposition explain phenotypic vulnerability? Int J Neuropsychopharmacol 11:331–349
Cohen H, Matar MA, Buskila D, Kaplan Z, Zohar J (2008b) Early post-stressor intervention with high-dose corticosterone attenuates posttraumatic stress response in an animal model of posttraumatic stress disorder. Biol Psychiatry 64:708–717
Cohen H, Kozlovsky N, Savion N, Matar MA, Loewenthal U, Loewenthal N et al (2009) An association between stress-induced disruption of the hypothalamic-pituitary-adrenal axis and disordered glucose metabolism in an animal model of post-traumatic stress disorder. J Neuroendocrinol 21:898–909
De Bellis MD, Keshavan MS, Shifflett H, Iyengar S, Beers SR, Hall J, Moritz G (2002) Brain structures in pediatric maltreatment-related posttraumatic stress disorder: a sociodemographically matched study. Biol Psychiatry 52:1066–1078
Delahanty D, Raimonde A, Spoonster E (2000) Initial posttraumatic urinary cortisol levels predict subsequent PTSD symptoms in motor vehicle accident victims. Biol Psychiatry 48:940–947
Diamond DM, Campbell AM, Park CR, Woodson JC, Conrad CD, Bachstetter AD, Mervis RF (2006) Influence of predator stress on the consolidation versus retrieval of long-term spatial memory and hippocampal spinogenesis. Hippocampus 16:571–576
Dunsmoor JE, Bandettini PA, Knight DC (2007) Neural correlates of unconditioned response diminution during Pavlovian conditioning. Neuroimage 40:811-817
Endres T, Apfelbach R, Fendt M (2005) Behavioral changes induced in rats by exposure to trimethylthiazoline, a component of fox odor. Behav Neurosci 119:1004–1010
Etkin A, Wager TD (2007) Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 164:1476–1488
File SE (1993) The interplay of learning and anxiety in the elevated plus-maze. Behav Brain Res 58:199–202
File SE, Zangrossi H Jr, Sanders FL, Mabbutt PS (1993) Dissociation between behavioral and corticosterone responses on repeated exposures to cat odor. Physiol Behav 54:1109–1111
Foa EB, Kozak MJ (1986) Emotional processing of fear: exposure to corrective information. Psychol Bull 99:20–35
Griebel G, Blanchard DC, Jung A, Lee JC, Masuda CK, Blanchard RJ (1995) Further evidence that the mouse defense test battery is useful for screening anxiolytic and panicolytic drugs: effects of acute and chronic treatment with alprazolam. Neuropharmacology 34:1625–1633
Knox D, George SA, Fitzpatrick CJ, Rabinak CA, Maren S, Liberzon I (2012a) Single prolonged stress disrupts retention of extinguished fear in rats. Learn Mem 19:43–49
Knox D, Nault T, Henderson C, Liberzon I (2012b) Glucocorticoid receptors and extinction retention deficits in the single prolonged stress model. Neuroscience 223:163–173
Kozlovsky N, Matar MA, Kaplan Z, Kotler M, Zohar J, Cohen H (2007) Long-term down-regulation of BDNF mRNA in rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response. Int J Neuropsychopharmacol 10:741–758
Kozlovsky N, Matar MA, Kaplan Z, Kotler M, Zohar J, Cohen H (2008) The immediate early gene Arc is associated with behavioral resilience to stress exposure in an animal model of posttraumatic stress disorder. Eur Neuropsychopharmacol 18:107–116
Kozlovsky N, Matar MA, Kaplan Z, Zohar J, Cohen H (2009) A distinct pattern of intracellular glucocorticoid-related responses is associated with extreme behavioral response to stress in an animal model of post-traumatic stress disorder. Eur Neuropsychopharmacol 19:759–771
Le Merrer J, Becker JA, Befort K, Kieffer BL (2009) Reward processing by the opioid system in the brain. Physiol Rev 89:1379–1412
LeDoux J (1996) Emotional networks and motor control: a fearful view. Prog Brain Res 107:437–446
LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155–184
Lewitus GM, Cohen H, Schwartz M (2008) Reducing post-traumatic anxiety by immunization. Brain Behav Immun 22:1108–1114
Liberzon I, Sripada CS (2008) The functional neuroanatomy of PTSD: a critical review. Prog Brain Res 167:151–169
Liberzon I, Krstov M, Young EA (1997) Stress-restress: effects on ACTH and fast feedback. Psychoneuroendocrinology 22:443–453
Maren S (2001) Neurobiology of Pavlovian fear conditioning. Annu Rev Neurosci 24:897–931
Maren S, Chang CH (2006) Recent fear is resistant to extinction. Proc Natl Acad Sci U S A 103:18020–18025
Mason JW, Giller EL, Kosten TR, Ostroff RB, Podd L (1986) Urinary free-cortisol levels in posttraumatic stress disorder patients. J Nerv Ment Dis 174:145–149
Matar MA, Cohen H, Kaplan Z, Zohar J (2006) The effect of early poststressor intervention with sertraline on behavioral responses in an animal model of post-traumatic stress disorder. Neuropsychopharmacology 31:2610–2618
Mazor A, Matar M, Kozlovsky N, Zohar J, Kaplan Z, Cohen H (2009) Gender-related qualitative differences in baseline and post stress anxiety responses are not reflected in the incidence of criterion-based PTSD-like behavior patterns. World J Biol Psychiatry 10:856–869
Milad MR, Rauch SL, Pitman RK, Quirk GJ (2006) Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol 73:61–71
Moffitt T, Caspi A, Rutter M (2006) Measured gene-environment interactions in psychopathology. Perspect Psychol Sci 1:5–27
Myers KM, Davis M (2002) Behavioral and neural analysis of extinction. Neuron 36:567–584
Nutt D, Davidson J (2000) Post-traumatic stress disorder diagnosis, management and treatment. Taylor & Francis, London
Pitman R, Orr S (1990) Twenty-four hour urinary cortisol and catecholamine excretion in combat-related posttraumatic stress disorder. Biol Psychiatry 27:245–247
Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW et al (2012) Biological studies of post-traumatic stress disorder. Nat Rev Neurosci 13:769–787
Rasmusson AM, Lipschitz DS, Wang S, Hu S, Vojvoda D, Bremner JD et al (2001) Increased pituitary and adrenal reactivity in premenopausal women with posttraumatic stress disorder. Biol Psychiatry 50:965–977
Rauch SL, Shin LM, Phelps EA (2006) Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research–past, present, and future. Biol Psychiatry 60:376–382
Resick PA, Bovin MJ, Calloway AL, Dick AM, King MW, Mitchell KS et al (2012) A critical evaluation of the complex PTSD literature: implications for DSM-5. J Trauma Stress 25:241–251
Resnick H, Yehuda R, Pitman R, Foy D (1995) Effect of previous trauma on acute plasma cortisol level following rape. Am J Psychiatry 152:1675–1677
Roseboom PH, Nanda SA, Bakshi VP, Trentani A, Newman SM, Kalin NH (2007) Predator threat induces behavioral inhibition, pituitary-adrenal activation and changes in amygdala CRF-binding protein gene expression. Psychoneuroendocrinology 32:44–55
Schelling G, Kilger E, Roozendaal B, de Quervain DJ, Briegel J, Dagge A et al (2004) Stress doses of hydrocortisone, traumatic memories, and symptoms of posttraumatic stress disorder in patients after cardiac surgery: a randomized study. Biol Psychiatry 55:627–633
Sullivan M, Gratton A (1998) Relationships between stress-induced increases in medial prefrontal cortical dopamine and plasma corticosterone levels in rats: role of cerebral laterality. Neuroscience 83:81–91
Takahashi LK, Nakashima BR, Hong H, Watanabe K (2005) The smell of danger: a behavioral and neural analysis of predator odor-induced fear. Neurosci Biobehav Rev 29:1157–1167
Yamamoto S, Morinobu S, Takei S, Fuchikami M, Matsuki A, Yamawaki S, Liberzon I (2009) Single prolonged stress: toward an animal model of posttraumatic stress disorder. Depress Anxiety 26:1110–1117
Yehuda R (2005) Neuroendocrine aspects of PTSD. Handb Exp Pharmacol 169:371-403
Yehuda R, LeDoux J (2007) Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 56:19–32
Yehuda R, Morris A, Labinsky E, Zemelman S, Schmeidler J (2007) Ten-year follow-up study of cortisol levels in aging holocaust survivors with and without PTSD. J Trauma Stress 20:757–761
Zohar J, Yahalom H, Kozlovsky N, Cwikel-Hamzany S, Matar MA, Kaplan Z et al (2011) High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies. Eur Neuropsychopharmacol 21:796–809
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Matar, M.A., Zohar, J. & Cohen, H. Translationally relevant modeling of PTSD in rodents. Cell Tissue Res 354, 127–139 (2013). https://doi.org/10.1007/s00441-013-1687-6
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DOI: https://doi.org/10.1007/s00441-013-1687-6