Advertisement

Amnesia for Early Life Stress Does Not Preclude the Adult Development of Posttraumatic Stress Disorder Symptoms in Rats

  • Andrew M. Poulos
    Correspondence
    Address correspondence to Andrew M. Poulos, Ph.D., University at Albany, Department of Psychology, 1400 Washington Ave, Albany, NY 12222
    Affiliations
    Department of Psychology, Brain Research Institute, Los Angeles, Los Angeles, California

    UCLA Behavioral Testing Core, Brain Research Institute, Los Angeles, Los Angeles, California
    Search for articles by this author
  • Maxine Reger
    Affiliations
    Department of Psychology, Brain Research Institute, Los Angeles, Los Angeles, California

    UCLA Brain Injury Research Center, Department of Neurosurgery, David Geffen School of Medicine, Los Angeles, Los Angeles, California
    Search for articles by this author
  • Nehali Mehta
    Affiliations
    Department of Psychology, Brain Research Institute, Los Angeles, Los Angeles, California
    Search for articles by this author
  • Irina Zhuravka
    Affiliations
    Department of Psychology, Brain Research Institute, Los Angeles, Los Angeles, California

    UCLA Behavioral Testing Core, Brain Research Institute, Los Angeles, Los Angeles, California
    Search for articles by this author
  • Sarah S. Sterlace
    Affiliations
    Department of Psychology, Brain Research Institute, Los Angeles, Los Angeles, California
    Search for articles by this author
  • Camille Gannam
    Affiliations
    Department of Psychology, Brain Research Institute, Los Angeles, Los Angeles, California
    Search for articles by this author
  • David A. Hovda
    Affiliations
    UCLA Brain Injury Research Center, Department of Neurosurgery, David Geffen School of Medicine, Los Angeles, Los Angeles, California
    Search for articles by this author
  • Christopher C. Giza
    Affiliations
    UCLA Brain Injury Research Center, Department of Neurosurgery, David Geffen School of Medicine, Los Angeles, Los Angeles, California

    Department of Pediatrics, Division of Pediatric Neurology, Mattel Children’s Hospital, Los Angeles, Los Angeles, California
    Search for articles by this author
  • Michael S. Fanselow
    Affiliations
    Department of Psychology, Brain Research Institute, Los Angeles, Los Angeles, California

    UCLA Behavioral Testing Core, Brain Research Institute, Los Angeles, Los Angeles, California

    Department of Psychiatry and Biobehavioral Sciences, UCLA Integrative Center for Learning and Memory, Los Angeles, Los Angeles, California

    Department of Medical and Molecular Pharmacology, University of California, Los Angeles, Los Angeles, California
    Search for articles by this author
Published:November 13, 2013DOI:https://doi.org/10.1016/j.biopsych.2013.10.007

      Background

      Traumatic experience can result in life-long changes in the ability to cope with future stressors and emotionally salient events. These experiences, particularly during early development, are a significant risk factor for later life anxiety disorders such as posttraumatic stress disorder (PTSD). However, because traumatic experience typically results in strong episodic memories, it is not known whether such long-term memories are necessary for particular features of PTSD, such as enhanced fear and anxiety. Here, we used a fear conditioning procedure in juvenile rats before maturation of the neural systems supporting declarative memory to assess the necessity of early memory to the later life development of PTSD-related symptoms.

      Methods

      Nineteen-day old rats were exposed to unpredictable and inescapable footshocks, and fear memory for the shock context was assessed during adulthood. Thereafter, adult animals were either exposed to single-trial fear conditioning or elevated plus maze or sacrificed for basal diurnal corticosterone and quantification of neuronal glucocorticoid and neuropeptide Y receptors.

      Results

      Early trauma exposed rats displayed stereotypic footshock reactivity, yet by adulthood, hippocampus-dependent contextual fear-related memory was absent. However, adult rats showed sensitized fear learning, aberrant basal circadian fluctuations of corticosterone, increased amygdalar glucocorticoid receptors, decreased time spent in the open arm of an elevated plus maze, and an odor aversion associated with early-life footshocks.

      Conclusions

      These results suggest that traumatic experience during developmental periods of hippocampal immaturity can promote lifelong changes in symptoms and neuropathology associated with human PTSD, even if there is no explicit memory of the early trauma.

      Key Words

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Cahill L.
        The neurobiology of emotionally influenced memory. Implications for understanding traumatic memory.
        Ann N Y Acad Sci. 1997; 821: 238-246
        • Gale G.D.
        • Anagnostaras S.G.
        • Godsil B.P.
        • Mitchell S.
        • Nozawa T.
        • Sage J.R.
        • et al.
        Role of the basolateral amygdala in the storage of fear memories across the adult lifetime of the rat.
        J Neurosci. 2004; 24: 3810-3815
        • McNeil J.E.
        Can PTSD occur with amnesia for the precipitating event?.
        Cogn Neuropsychiatry. 1996; 1: 239-246
        • Layton B.S.
        • Krikorian R.
        • Dori D.
        • Martin G.A.
        • Wardi K.
        Post-traumatic stress disorder with amnesia following asphyxiation.
        Ann N Y Acad Sci. 2006; 1071: 488-490
        • Bryant R.A.
        • Creamer M.
        • O’Donnell M.
        • Silove D.
        • Clark C.R.
        • McFarlane A.C.
        Post-traumatic amnesia and the nature of post-traumatic stress disorder after mild traumatic brain injury.
        J Int Neuropsychol Soc. 2009; 15: 862-867
        • Cordón I.M.
        • Pipe M.-E.
        • Sayfan L.
        • Melinder A.
        • Goodman G.S.
        Memory for traumatic experiences in early childhood.
        Developmental Review. 2004; 24: 101-132
        • Campbell B.A.
        • Campbell E.H.
        Retention and extinction of learned fear in infant and adult rats.
        J Comp Physiol Psychol. 1962; 55: 1-8
        • Rudy J.W.
        • Morledge P.
        Ontogeny of contextual fear conditioning in rats: Implications for consolidation, infantile amnesia, and hippocampal system function.
        Behav Neurosci. 1994; 108: 227-234
        • Raineki C.
        • Holman P.
        • Debiec J.
        • Bugg M.
        • Beasley A.
        • Sullivan R.M.
        Functional emergence of the hippocampus in context learning in infant rats.
        Hippocampus. 2010; 20: 1037-1046
        • Mckee R.D.
        • Squire L.R.
        On the development of declarative memory.
        J Exp Psychol Learn Mem Cogn. 1993; 19: 397-404
        • Josselyn S.A.
        • Frankland P.W.
        Infantile amnesia: A neurogenic hypothesis.
        Learn Mem. 2012; 10: 423-433
        • Rudy J.W.
        Contextual conditioning and auditory cue conditioning dissociate during development.
        Behav Neurosci. 1993; 107: 887-891
        • Esmorís-Arranz F.J.
        • Méndez C.
        • Spear N.E.
        Contextual fear conditioning differs for infant, adolescent, and adult rats.
        Behav Processes. 2008; 78: 340-350
        • Ehrlich I.
        • Humeau Y.
        • Grenier F.
        • Ciocchi S.
        • Herry C.
        • Luthi A.
        Amygdala inhibitory circuits and the control of fear memory.
        Neuron. 2009; 62: 757-771
        • Johansen J.P.
        • Cain C.K.
        • Ostroff L.E.
        • LeDoux J.E.
        Molecular mechanisms of fear learning and memory.
        Cell. 2011; 147: 509-524
        • Tronson N.C.
        • Corcoran K.A.
        • Jovasevic V.
        • Radulovic J.
        Fear conditioning and extinction: Emotional states encoded by distinct signaling pathways.
        Trends Neurosci. 2012; 35: 145-155
        • Maren S.
        • Quirk G.J.
        Neuronal signalling of fear memory.
        Nat Rev Neurosci. 2004; 5: 844-852
        • Fanselow M.S.
        • Poulos A.M.
        The neuroscience of mammalian associative learning.
        Annu Rev Psychol. 2005; 56: 207-234
        • Ladd C.O.
        • Huot R.L.
        • Thrivikraman K.V.
        • Nemeroff C.B.
        • Meaney M.J.
        • Plotsky P.M.
        Long-term behavioral and neuroendocrine adaptations to adverse early experience.
        Prog Brain Res. 2000; 122: 81-103
        • McEwen B.S.
        Physiology and neurobiology of stress and adaptation: Central role of the brain.
        Physiol Rev. 2007; 87: 873-904
        • Kosten T.A.
        • Lee H.J.
        • Kim J.J.
        Early life stress impairs fear conditioning in adult male and female rats.
        Brain Res. 2006; 1087: 142-150
        • Landers M.S.
        • Sullivan R.G.
        The development and neurobiology of infant attachment and fear.
        Dev Neurosci. 2012; 34: 101-114
        • Rau V.
        • DeCola J.P.
        • Fanselow M.S.
        Stress-induced enhancement of fear learning: An animal model of posttraumatic stress disorder.
        Neurosci Biobehav Rev. 2005; 29: 1207-1223
        • Poulos A.M.
        • Li V.
        • Sterlace S.
        • Tokushige F.
        • Ponnusamy R.
        • Fanselow M.S.
        Persistence of fear memories across time requires the basolateral amygdala complex.
        Proc Natl Acad Sci U S A. 2009; 106: 11737-11741
        • Vermetten E.
        • Bremner J.D.
        Olfaction as a traumatic reminder in posttraumatic stress disorder: Case reports and review.
        J Clin Psychiatry. 2003; 64: 202-207
        • Bowers W.J.
        • Gingras M.A.
        • Amit Z.
        Time-dependent exacerbation of amphetamine-induced taste aversion following exposure to footshock.
        Psychopharmacology (Berl). 1996; 125: 43-49
        • Rudy J.W.
        • Sutherland R.J.
        The hippocampal formation is necessary for rats to learn and remember configural discriminations.
        Behav Brain Res. 1989; 34 (978–109)
        • Young S.L.
        • Bohenek D.L.
        • Fanselow M.S.
        NMDA processes mediate anterograde amnesia of contextual fear conditioning induced by hippocampal damage: Immunization against amnesia by context preexposure.
        Behav Neurosci. 1994; 108: 19-29
        • Kim J.J.
        • Fanselow M.S.
        Modality-specific retrograde amnesia of fear.
        Science. 1992; 256: 675-677
        • Rudy J.W.
        • Sutherland R.J.
        Configural association theory and the hippocampal formation: An appraisal and reconfiguration.
        Hippocampus. 1995; 5: 375-389
        • Phillips R.G.
        • LeDoux J.E.
        Differential contributions of amygdala and hippocampus to contextual fear conditioning.
        Behav Neurosci. 1992; 106: 274-285
        • Sullivan R.M.
        • Landers M.
        • Yeaman B.
        • Wilson D.A.
        Good memories of bad events in infancy.
        Nature. 2000; 407: 38-39
        • Pugh C.R.
        • Tremblay D.
        • Fleshner M.
        • Rudy R.W.
        A selective role for corticosterone in contextual-fear conditioning.
        Behav Neurosci. 1997; 111: 503-511
        • Yehuda R.
        • Teicher M.H.
        • Levengood R.A.
        • Trestman R.L.
        • Siever L.J.
        Circadian regulation of basal cortisol levels in posttraumatic stress disorder.
        Ann N Y Acad Sci. 1994; 746: 378-380
        • Lanius R.A.
        • Frewen P.A.
        • Vermetten E.
        • Yehuda R.
        Fear conditioning and early life vulnerabilities: Two distinct pathways of emotional dysregulation and brain dysfunction in PTSD [published online ahead of print December 10].
        Eur J Psychotraumatol. 2010;
        • Yehuda R.
        • Seckl J.
        Minireview: Stress-related psychiatric disorders with low cortisol levels: A metabolic hypothesis.
        Endocrinology. 2011; 152: 4496-4503
        • Geuze E.
        • van Wingen G.A.
        • van Zuiden M.
        • Rademaker A.R.
        • Vermetten E.
        • Kavelaars A.
        • et al.
        Glucocorticoid receptor number predicts increase in amygdala activity after severe stress.
        Psychoneuroendocrinology. 2012; 37: 1837-1844
        • Kavushansky A.
        • Richter-Levin G.
        Effects of stress and corticosterone on activity and plasticity in the amygdala.
        J Neurosci Res. 2006; 84: 1580-1587
        • Conrad C.D.
        • MacMillan D.D.
        • Tsekhanov S.
        • Wright R.L.
        • Baran S.E.
        • Fuchs R.A.
        Influence of chronic corticosterone and glucocorticoid receptors antagonism in the amygdala on fear conditioning.
        Neurobiol Learn Mem. 2004; 81: 185-199
        • Rasmussen A.M.
        • Hauger R.L.
        • Morgan C.A.
        • Bremner J.D.
        • Charney D.S.
        • Southwick S.M.
        Low baseline and yohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-related PTSD.
        Biol Psychiatry. 2000; 47: 526-539
        • Sah R.
        • Ekhator N.N.
        • Strawn J.R.
        • Sallee F.R.
        • Baker D.G.
        • Horn P.S.
        • Geracioti Jr, T.D.
        Low cerebrospinal fluid neuropeptide Y concentrations in posttraumatic stress disorder.
        Biol Psychiatry. 2009; 66: 705-707
        • Verma D.
        • Tasan R.O.
        • Herzog H.
        • Sperk G.
        NPY controls fear conditioning and fear extinction by combined action on Y1 and Y2 receptors.
        Br J Pharmacol. 2012; 166: 1461-1473
        • Gutman A.R.
        • Yang Y.
        • Ressler K.J.
        • Davis M.
        The role of neuropeptide Y in the expression and extinction of fear-potentiated startle.
        J Neurosci. 2008; 28: 12682-12690
        • McKlveen J.M.
        • Myers B.
        • Flak J.N.
        • Budzikova J.
        • Solomon M.B.
        • Seroogy K.B.
        • Herman J.P.
        Role of the prefrontal cortex glucocorticoid receptors in stress and emotion.
        Biol Psychiatry. 2013; 74: 672-679