Animal Models of Post‐Traumatic Stress Disorder

Hagit Cohen1, Michael A. Matar1, Zohar Joseph2

1 Israel Ministry of Health Mental Health Center, Anxiety and Stress Research Unit, Faculty of Health Sciences, Ben‐Gurion University of the Negev, Beer‐Sheva, Israel, 2 The Chaim Sheba Medical Center, Sackler Medical School, Tel‐Aviv University, Tel Hashomer, Israel
Publication Name:  Current Protocols in Neuroscience
Unit Number:  Unit 9.45
DOI:  10.1002/0471142301.ns0945s64
Online Posting Date:  July, 2013
GO TO THE FULL TEXT: PDF or HTML at Wiley Online Library

Abstract

Animal behavioral studies have commonly regarded the entire group of animals subjected to the study conditions as homogeneous, disregarding individual differences in response patterns. The following discussion will focus on a method of analyzing data that aims to model clinical diagnostic criteria applied to individual patterns of response using data from behavioral measures, and employing cut‐off scores to distinguish between extremes of response versus non‐response and the sizeable proportion of study subjects in‐between them. This protocol unit will present the concept of the model and its background, provide detailed protocols for each of its components, and present a selection of studies employing and examining the model, alongside the underlying translational rationale of each. Curr. Protoc. Neurosci. 64:9.45.1‐9.45.18. © 2013 by John Wiley & Sons, Inc.

Keywords: post‐traumatic stress disorder; animal model; cut‐off behavioral criteria; anxiety; resilience; vulnerability; elevated plus‐maze; acoustic startle response; freezing

     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Table of Contents

  • Introduction
  • Basic Protocol 1: The Predator‐Scent Stress (PSS) Paradigm
  • Basic Protocol 2: Assessment of Overall Exploratory Behavior Using the Elevated Plus Maze (EPM) and Quantification of Hyper‐Alertness Using the Acoustic Startle Response (ASR)
  • Basic Protocol 3: Classification According to Cut‐Off Behavioral Criteria (CBC)
  • Basic Protocol 4: Exposure to Trauma Cues
  • Commentary
  • Literature Cited
  • Figures
     
 
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Materials

Basic Protocol 1: The Predator‐Scent Stress (PSS) Paradigm

  Materials
  • Naïve experimental subject (rat or mouse) of appropriate strain, sex, and age: we routinely use male and female Sprague Dawley rats (180 to 350 g), but Lewis, Fischer (F344), and Wistar strains have also been proven to be suitable for this protocol
  • Well‐soiled cat litter bedding (in use by the cat for 2 days, sifted for stools)
  • Fresh, unused cat litter bedding
  • Quiet yard or quiet test room away from disturbances
  • Quiet yard or quiet test room away from disturbances‐for sham exposure
  • Predator scent stress (PSS) test apparatus: The apparatus consists of a 40 × 40 × 40–cm chamber of transparent Plexiglas with transparent roof (Fig. )
  • Plexiglas behavioral arena 40 × 40 × 40 with transparent roof (for sham exposure)
  • Timer

Basic Protocol 2: Assessment of Overall Exploratory Behavior Using the Elevated Plus Maze (EPM) and Quantification of Hyper‐Alertness Using the Acoustic Startle Response (ASR)

  Materials
  • Exposed/control experimental subject (rat or mouse) of appropriate strain, sex, and age
  • Pharmacological agents to be tested/appropriate drug vehicle for control injections (optional)
  • Elevated plus maze (EPM) apparatus (see Fig. )
  • Quiet test room away from disturbances, illuminated either brightly (300 radiometric lux) or dimly (30 radiometric lux)
  • Video camera and monitor (optional: television/monitor screen connected to the video camera, located in an adjacent room)
  • Transporting and home cages
  • Damp cloths (for cleaning cages)
  • Acoustic startle response (ASR) apparatus (see Fig. )
  • Vibration isolation platform (startle recording device): device that reflects and absorbs waves of oscillatory energy, extending from the working gear or electrical equipment, with the aid of vibration insulation (vibration isolation is the process of isolating an object, such as a piece of equipment, from the source of vibrations)
  • Automated test system or keyboard for scoring behaviors

Basic Protocol 3: Classification According to Cut‐Off Behavioral Criteria (CBC)

  Materials
  • EPM data
  • ASR data
NOTE: Please refer closely to Figure for the steps below.

Basic Protocol 4: Exposure to Trauma Cues

  Materials
  • Fresh, unused cat litter bedding
  • Experimental subject (rat or mouse) of appropriate strain, sex, and age
  • Quiet yard or test room
  • Trauma‐cue apparatus: Plexiglas behavioral arena 40 × 40 × 40–cm—identical to sham‐exposure
  • Video camera and monitor (optional: television/monitor screen connected to the video camera, located in an adjacent room)
  • Automated test system or keyboard for scoring behaviors
NOTE:Timing of trauma cue: assessments: Since the clinical symptom stands out because it occurs long after the actual event, the test must be timed accordingly. It is preferable to allow extended periods of time, certainly no less than 8 days. Many of our studies span a 30‐day period and the trauma‐cue exposure is thus performed on day 31, 24 hr after the EPM and ASR assessments and in a separate environment (free of traces of odors associated with anxiety).
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library

Figures

Videos

Literature Cited

Literature Cited
   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, R.E. and Shallow, T. 1993. Lasting effects on rodent anxiety of a single exposure to a cat. Physiol. Behav. 54:101‐109.
   Adamec, R., Head, D., Blundell, J., Burton, P., and 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., and McKay, D.W. 2006b. Protein synthesis and the mechanisms of lasting change in anxiety induced by severe stress. Behav. Brain Res. 167:270‐286.
   Adamec, R.E., Blundell, J., and 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., and 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.
   American Psychiatric Association 1994. Diagnostic and Statistical Manual of Mental Disorders, 4 ed. American Psychiatric Association, Washington, D.C.
   B'aszczyk, J.W. 2003. Startle response to short acoustic stimuli in rats. Acta Neurobiol. Exp. 63:25‐30.
   Blanchard, R.J., Blanchard, D.C., Rodgers, J., and Weiss, S.M. 1990. The characterization and modelling of antipredator defensive behavior. Neurosci. Biobehav. Rev. 14:463‐472.
   Blanchard, R.J., Griebel, G., Henrie, J.A., and Blanchard, D.C. 1997. Differentiation of anxiolytic and panicolytic drugs by effects on rat and mouse defense test batteries. Neurosci. Biobehav. Rev. 21:783‐789.
   Blanchard, R.J., Nikulina, J.N., Sakai, R.R., McKittrick, C., McEwen, B., and Blanchard, D.C. 1998. Behavioral and endocrine change following chronic predatory stress. Physiol. Behav. 63:561‐569.
   Blanchard, R.J., Yang, M., Li, C.I., Gervacio, A., and Blanchard, D.C. 2001. Cue and context conditioning of defensive behaviors to cat odor stimuli. Neurosci. Biobehav. Rev. 25:587‐595.
   Blanchard, D.C., Griebel, G., and Blanchard, R.J. 2003. Conditioning and residual emotionality effects of predator stimuli: Some reflections on stress and emotion. Prog. Neuropsychopharmacol. Biol. Psychiatry 27:1177‐1185.
   Breslau, N., Davis, G.C., Andreski, P., and 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, R.C., Chilcoat, H.D., Schultz, L.R., Davis, G.C., and Andreski, P. 1998. Trauma and posttraumatic stress disorder in the community: The 1996 Detroit Area Survey of Trauma. Arch. Gen. Psychiatry 55:626‐632.
   Bryant, R.A. 2006. Recovery after the tsunami: timeline for rehabilitation. J. Clin. Psychiatry 67:50‐55.
   Cohen, H. and 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., Zohar, J., Matar, M.A., Zeev, K., Loewenthal, U., and 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., Kaplan, Z., Matar, M., Loewenthal, U., Kozlovsky, N., and Zohar, J. 2006a. Anisomycin, a protein synthesis inhibitor, disrupts traumatic memory consolidation and attenuates post‐traumatic stress response in rats. Biol. Psychiatry 60:767‐776.
   Cohen, H., Matar, M., Richter‐Levin, G., and Zohar, J. 2006b. The contribution of an animal model towards uncovering biological risk factors for PTSD. Ann. N.Y. Acad. Sci. 1071:335‐350.
   Cohen, H., Matar, M., Buskila, D., Kaplan, Z., and Zohar, J. 2008. Early post‐stressor intervention with high dose corticosterone attenuates post‐traumatic stress response in an animal model of PTSD. Biol. Psychiatry 64:708‐717.
   Cohen, H., Kozlovsky, N., Matar, M.A., Kaplan, Z., and Zohar, J. 2010. Mapping the brain pathways of traumatic memory: Inactivation of protein kinase M zeta in different brain regions disrupts traumatic memory processes and attenuates traumatic stress responses in rats. Eur. Neuropsychopharmacol. 20:253‐271.
   Davidson, J.R. 2006. Pharmacologic treatment of acute and chronic stress following trauma. J Clin. Psychiatry 67:S34‐S39.
   Diamond, D.M., Campbell, A.M., Park, C.R., Woodson, J.C., Conrad, C.D., Bachstetter, A.D., and Mervis, R.F. 2006. Influence of predator stress on the consolidation versus retrieval of long‐term spatial memory and hippocampal spinogenesis. Hippocampus 16:571‐576.
   Ekman, P., Friesen, W.V., and Simons, R.C. 1985. Is the startle reaction an emotion? J. Pers. Soc. Psychol. 49:1416‐1426.
   Fairbank, J.A., Schlenger, W.E., Saigh, P.A., and Davidson, J.R.T. 1995. An epidemiologic profile of post‐traumatic stress disorder: Prevalence, comorbidity, and risk factors. In Neurobiological and Clinical Consequences of Stress: From Normal Adaptation to PTSD (M.J. Friedman, D.S. Charney, and A.Y. Deutch, eds.) pp. 415‐427. Lippincott‐Raven, Philadelphia.
   File, S.E., Zangrossi, H. Jr., Sanders, F.L., and Mabbutt, P.S. 1993. Dissociation between behavioral and corticosterone responses on repeated exposures to cat odor. Physiol. Behav. 54:1109‐1111.
   Foa, E.B., Stein, D.J., and McFarlane, A.C. 2006. Symptomatology and psychopathology of mental health problems after disaster. J. Clin. Psychiatry 67:15‐25.
   Graham, F.K. 1979. Distinguishing among orienting, defense, and startle reflexes. In The Orienting Reflex in Humans (H.D. Kimmel EHvOaJFO, ed.) pp 137‐167. Lawrence Erlbaum Associates Publishers, Hillsdale, N.J.
   Griebel, G., Blanchard, D.C., Jung, A., Lee, J.C., Masuda, C.K., and Blanchard, R.J. 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.
   Helzer, J., Robins, L., and McEvoy, L. 1987. Post‐traumatic stress disorder in the general population. Findings of the epidemiologic catchment area survey. N. Engl. J. Med. 317:1630‐1634.
   Kozlovsky, N., Matar, M.A., Kaplan, Z., Zohar, J., and Cohen, H. 2009. The role of the galaninergic system in modulating stress‐related responses in an animal model of posttraumatic stress disorder. Biol. Psychiatry 65:383‐391.
   Landis, C. and Hunt, W. 1939. The Startle Pattern. Farrar & Rinehart, Oxford, U.K.
   Nutt, D. and Davidson, J. 2000. Post‐Traumatic Stress Disorder Diagnosis, Management and Treatment. Taylor & Francis, London.
   Pellow, S. and File, S.E. 1986. Anxiolytic and anxiogenic drug effects on exploratory activity in an elevated plus‐maze: A novel test of anxiety in the rat. Pharmacol. Biochem. Behav. 24:525‐529.
   Pellow, S., Chopin, P., File, S.E., and Briley, M. 1985. Validation of open:closed arm entries in an elevated plus‐maze as a measure of anxiety in the rat. J. Neurosci. Methods 14:149‐167.
   Peri, T., Ben‐Shakhar, G., Orr, S.P., and Shalev, A.Y. 2000. Psychophysiologic assessment of aversive conditioning in posttraumatic stress disorder. Biol. Psychiatry 47:512‐519.
   Resnick, H., Yehuda, R., Pitman, R., and Foy, D. 1995. Effect of previous trauma on acute plasma cortisol level following rape. Am. J. Psychiatry 152:1675‐1677.
   Shalev, A.Y. 2002. Acute stress reactions in adults. Biol. Psychiatry 51:532‐543.
   Shore, J., Vollmer, W., and Tatum, E. 1989. Community patterns of posttraumatic stress disorders. J. Nerv. Ment. Dis. 177:681‐685.
GO TO THE FULL PROTOCOL:
PDF or HTML at Wiley Online Library