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Combined Program for Ph.D

Name: Ori Koresh

I.D: 040885717

Advisor's name: Prof. Hagit Cohen

Department: Psychiatry

Research subject: Effects of stress-exposure on circadian rhythms and circadian related-genes in an animal model of PTSD


In mammals, the suprachiasmatic nuclei (SCN) of the hypothalamus act as a dominant circadian pacemaker, coordinating rhythms throughout the body and regulating daily and seasonal changes affecting locomotor activity, body temperature (via the autonomic nervous system) and endocrine function. Dysregulation of this synchronization is known to be strongly associated with various pathologies such as mood and anxiety disorders. Awakenings from sleep, exaggerated startle, increased vigilance, and physiologic reactivity are prominent symptoms of posttraumatic stress disorder (PTSD) and may indicate a maladaptive persistence of a normal psychophysiologic response to threat. Among heightened arousal symptoms in PTSD, sleep disturbances are particularly distressing and persistent. Anxiety, agitation, and body movement have been found to characterize sleep complaints in combatrelated PTSD compared to patients with primary insomnia. Moreover, an altered circadian rhythm of the hypothalamic-pituitary-adrenal (HPA) axis is reported in PTSD patients. The current experiment compares the consequences of single exposure to psychogenic stress on the long-term circadian rhythm in an animal model of PTSD, which classifies animals according to the degree of their individual behavioral response. The aims of this study was to examine the relationship between the magnitude of the behavioral response to predator-scent stress and circadian rhythmicity of heart rate, body temperature and activity, and brain levels of genes related to circadian rhythms. Animals in this currently on-going study are monitored telemetrically allowing 24-h/day sampling of heart rate, body temperature and activity level without the presence of a human, from baseline throughout 7 days following stress exposure. Subsequently their behavioral stress response pattern is assessed on the elevated plus maze and acoustic startle response paradigms for classification according to PTSD-related CBC's. Rats are sacrificed for molecular studies of selected brain areas. Behavioral PTSD-like response patterns will be correlated to circadian, physiological and molecular/gene-expression data.


The clinical manifestations of post-traumatic stress disorder (PTSD), the prototypic psychopathological outcome of exposure to extreme stress, pivot on an exaggerated and chronic form of the adaptive response to acute stress, and apparently stem from faulty processing of and/or recovery from the initial response. Unlike processes in which exposure to repeated stimuli induces a process of learning or conditioning, implying an increased efficiency in processing of data to produce the required response, the psychopathology underlying PTSD produces a paradoxical vulnerability to negative sequelae upon subsequent stress exposure. The neurobiological mechanisms involved in PTSD thus presumably include changes in synaptic efficacy and plasticity in various brain areas which, rather than improving, in fact impair the ability of the brain to respond adequately to subsequent stress response. Were it possible to correct or to induce mechanisms which would reinstate adaptive neural plasticity and remodelling, this dysfunction might be overcome.

References: •

Abraham WC, Tate WP (1997). Metaplsasticity : a new vista across the field of synaptic plasticity. Progress in Neurobiology 52, 303–323.

Cohen H, Joseph Z, Matar M (2003). The Relevance of differential response to trauma in an animal model of posttraumatic stress disorder. Biological Psychiatry 53, 463–473.

Cohen H, Zohar J (2004). Animal models of post traumatic stress disorder : the use of cut off behavioral criteria. Annals of the New York Academy of Sciences 1032, 167–178.

Cohen H, Zohar J, Gidron Y, Matar M, Belkind D, Loewenthal U, Kozlovsky N, Kaplan Z (2006d). Blunted HPA axis response to stress influences susceptibility to posttraumatic stress response in rats. Biological Psychiatry 59, 1208–1218.

Cohen, H., Kotler, M., Matar, M.A., Kaplan, Z., Miodownik, H., Cassuto, Y., 1997. Power spectral analysis of heart rate variability in posttraumatic stress disorder patients. Biol. Psychiatry 41 (5), 627– 629.

Cohen, H., Kotler, M., Matar, M.A., Kaplan, Z., Loewenthal, U., Miodownik, H., Cassuto, Y., 1998. Analysis of heart rate variability in posttraumatic stress disorder patients in response to a trauma-related reminder. Biol. Psychiatry 44 (10), 1054– 1059.

Cohen, H., Benjamin, J., Geva, A.B., Matar, M.A., Kaplan, Z., Kotler, M., 2000. Autonomic dysregulation in panic disorder and in post-traumatic stress disorder: application of power spectrum analysis of heart rate variability at rest and in response to recollection of trauma or panic attacks. Psychiatry Res. 96 (1), 1– 13.

Cohen, H., Kotler, M., Matar, M., Kaplan, Z., 2000. Normalization of heart rate variability in posttraumatic stress disorder patients following fluoxetine treatment: preliminary results [In Process Citation]. Isr. Med. Assoc. J. 2 (4), 296–301.

Hypothalamic-pituitary-adrenal dysfunction in posttraumatic stress disorder Yehuda,Rachel; Giller,Earl L.; Southwick,Steven M.; Lowy,Martin T.; Mason,John W. Biol.Psychiatry, 1991, 30, 10, 1031-1048

Modulation of serotonin and corticosteroid receptor gene expression in the rat hippocampus with circadian rhythm and stress. Holmes,Megan C.; French,Karen L.; Seckl,Jonathan R. Mol.Brain Res., 1995, 28, 2, 186-192

Opiate modulation of the pituitary-adrenal axis: effects of stress and circadian rhythm A. Grossman, R. C. Gaillard, P. McCartney, Lesley H. Rees,G. M. Besser VL;17, NO;3, PG;279-286 Departments of Endocrinology and Chemical Endocrinology, St Bartholomew's Hospital, London, EC1A 7BE


Early Post-Stressor Intervention with High-Dose Corticosterone Attenuates Posttraumatic Stress Response in an Animal Model of Posttraumatic Stress Disorder. Cohen,Hagit; Matar,Michael A.; Buskila,Dan; Kaplan,Zeev; Zohar,Joseph Biol.Psychiatry, 2008, 64, 8, 708-717


of PTSD Department: Psychiatry Advisor's name: Prof. Hagit Cohen Research subject: Effects of stress-exposure on circadian rhythms and circa...