This work was supported by the CDMRP, USUHS Grants G188LE, G188MG, and G188QC (to HL), and the USUHS Center for the Study of Traumatic Stress.

<ol>
	<li>Adrien, J., Dugovic, C., Martin, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Sleep-wakefulness+patterns+in+the+helpless+rat.">Sleep-wakefulness patterns in the helpless rat.</a> Physiol. Behav. 49, 257-262 (1991).</li><li>Bai, X., Wu, J., Zhang, Q., Alesci, S., Manoli, I., Blackman, M. R., Chrousos, G. P., Goldstein, A. L., Rennert, O. M., Su, Y. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Third-generation+human+mitochondria-focused+cDNA+microarray+and+its+bioinformatic+tools+for+analysis+of+gene+expression.">Third-generation human mitochondria-focused cDNA microarray and its bioinformatic tools for analysis of gene expression.</a> Biotechniques. 42, 365-375 (2007).</li><li>Blaszczyk, J. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Startle+response+to+short+acoustic+stimuli+in+rats.">Startle response to short acoustic stimuli in rats.</a> Acta Neurobiol. Exp. (Wars.). 63, 25-30 (2003).</li><li>Braga, M. F., roniadou-Anderjaska, V., Manion, S. T., Hough, C. J., Li, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stress+impairs+alpha(1A)+adrenoceptor-mediated+noradrenergic+facilitation+of+GABAergic+transmission+in+the+basolateral+amygdala.">Stress impairs alpha(1A) adrenoceptor-mediated noradrenergic facilitation of GABAergic transmission in the basolateral amygdala.</a> Neuropsychopharmacology. 29, 45-58 (2004).</li><li>Bremner, J. D., Vythilingam, M., Vermetten, E., Anderson, G., Newcomer, J. W., Charney, D. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+glucocorticoids+on+declarative+memory+function+in+major+depression.">Effects of glucocorticoids on declarative memory function in major depression.</a> Biol. Psychiatry. 55, 811-815 (2004).</li><li>Garrick, T., Morrow, N., Eth, S., Marciano, D., Shalev, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Psychophysiologic+parameters+of+traumatic+stress+disorder+in+rats.">Psychophysiologic parameters of traumatic stress disorder in rats.</a> Ann. N.Y. Acad. Sci. 821, 533-537 (1997).</li><li>Garrick, T., Morrow, N., Shalev, A. Y., Eth, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stress-induced+enhancement+of+auditory+startle:+an+animal+model+of+posttraumatic+stress+disorder.">Stress-induced enhancement of auditory startle: an animal model of posttraumatic stress disorder.</a> Psychiatry. 64, 346-354 (2001).</li><li>Hsiao, Y. H., Su, Y. A., Tsai, H. D., Mason, J. T., Chou, M. C., Man, Y. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Increased+invasiveness+and+aggressiveness+in+breast+epithelia+with+cytoplasmic+p63+expression.">Increased invasiveness and aggressiveness in breast epithelia with cytoplasmic p63 expression.</a> Int. J. Biol. Sci. 6, 428-442 (2010).</li><li>Jiang, X., Xing, G., Yang, C., Verma, A., Zhang, L., Li, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stress+Impairs+5-HT(2A)+Receptor-Mediated+Serotonergic+Facilitation+of+GABA+Release+in+Juvenile+Rat+Basolateral+Amygdala.">Stress Impairs 5-HT(2A) Receptor-Mediated Serotonergic Facilitation of GABA Release in Juvenile Rat Basolateral Amygdala.</a> Neuropsychopharmacology. , (2008).</li><li>Jiang, X., Zhang, Z. J., Zhang, S., Gamble, E. H., Jia, M., Ursano, R. J., Li, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=5-HT2A+receptor+antagonism+by+MDL+11,939+during+inescapable+stress+prevents+subsequent+exaggeration+of+acoustic+startle+response+and+reduced+body+weight+in+rats.">5-HT2A receptor antagonism by MDL 11,939 during inescapable stress prevents subsequent exaggeration of acoustic startle response and reduced body weight in rats.</a> J. Psychopharmacol. , (2009).</li><li>Maher, H. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Sleep+deprivation:+are+you+a+victim.">Sleep deprivation: are you a victim.</a> AAOHN. J. 54, 548 (2006).</li><li>Maier, S. F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Exposure+to+the+stressor+environment+prevents+the+temporal+dissipation+of+behavioral+depression/learned+helplessness.">Exposure to the stressor environment prevents the temporal dissipation of behavioral depression/learned helplessness.</a> Biol. Psychiatry. 49, 763-773 (2001).</li><li>North, C. S., Suris, A. M., Davis, M., Smith, R. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Toward+validation+of+the+diagnosis+of+posttraumatic+stress+disorder.">Toward validation of the diagnosis of posttraumatic stress disorder.</a> Am. J. Psychiatry. 166, 34-41 (2009).</li><li>Orr, S. P., Metzger, L. J., Pitman, R. K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Psychophysiology+of+post-traumatic+stress+disorder.">Psychophysiology of post-traumatic stress disorder.</a> Psychiatr. Clin. North Am. 25, 271-293 (2002).</li><li>Orr, S. P., Roth, W. T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Psychophysiological+assessment:+clinical+applications+for+PTSD.">Psychophysiological assessment: clinical applications for PTSD.</a> J. Affect. Disord. 61, 225-240 (2000).</li><li>Pitman, R. K., Orr, S. P., Shalev, A. Y., Metzger, L. J., Mellman, T. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Psychophysiological+alterations+in+post-traumatic+stress+disorder.">Psychophysiological alterations in post-traumatic stress disorder.</a> Semin. Clin. Neuropsychiatry. 4, 234-241 (1999).</li><li>Servatius, R. J., Ottenweller, J. E., Natelson, B. H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Delayed+startle+sensitization+distinguishes+rats+exposed+to+one+or+three+stress+sessions:+Further+evidence+toward+an+animal+model+of+PTSD.">Delayed startle sensitization distinguishes rats exposed to one or three stress sessions: Further evidence toward an animal model of PTSD.</a> Biological Psychiatry. 38, 539-546 (1995).</li><li>Su, Y. A., Zhang, Q., Su, D. M., Tang, M. X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rat+Mitochondrion-Neuron+Focused+Microarray+(rMNChip)+and+Bioinformatics+Tools+for+Rapid+Identification+of+Differential+Pathways+in+Brain+Tissues.">Rat Mitochondrion-Neuron Focused Microarray (rMNChip) and Bioinformatics Tools for Rapid Identification of Differential Pathways in Brain Tissues.</a> Int. J. Biol. Sci. 7, 308-322 (2011).</li><li>Su, D. M., Zhang, Q., Wang, X., He, P., Zhu, Y. J., Zhao, J., Rennert, O. M., Su, Y. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Two+types+of+human+malignant+melanoma+cell+lines+revealed+by+expression+patterns+of+mitochondrial+and+survival-apoptosis+genes:+implications+for+malignant+melanoma+therapy.+Mol.">Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy. Mol.</a> Cancer Ther. , (2009).</li><li>Su, Y. A., Li, H., He, P., Webster, M. J., Zhang, Q., Zhang, L., Wang, X., Su, D. M., Ursano, R. J., Rennert, O. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Identification+of+stress-responsive+genes,+canonical+pathways,+molecular+networks+and+drug+targets+in+brain+tissues+of+human+and+animals+for+systems-biology+study+of+post-traumatic+stress+disorder.">Identification of stress-responsive genes, canonical pathways, molecular networks and drug targets in brain tissues of human and animals for systems-biology study of post-traumatic stress disorder.</a> , (2009).</li><li>Su, Y. A., Wu, J., Zhang, L., Zhang, Q., Su, D. M., He, P., Wang, B. D., Li, H., Webster, M. J., Rennert, O. M., Ursano, R. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dysregulated+mitochondrial+genes+and+networks+with+drug+targets+in+postmortem+brain+of+patients+with+posttraumatic+stress+disorder+(PTSD)+revealed+by+human+mitochondria-focused+cDNA+microarrays.">Dysregulated mitochondrial genes and networks with drug targets in postmortem brain of patients with posttraumatic stress disorder (PTSD) revealed by human mitochondria-focused cDNA microarrays.</a> Int. J Biol. Sci. 4, 223-235 (2008).</li><li>Su, Y. A., Yang, J., Tao, L., Nguyen, H., He, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Undetectable+and+Decreased+Expression+of+KIAA1949+(Phostensin)+Encoded+on+Chromosome+6p21.33+in+Human+Breast+Cancers+Revealed+by+Transcriptome+Analysis.">Undetectable and Decreased Expression of KIAA1949 (Phostensin) Encoded on Chromosome 6p21.33 in Human Breast Cancers Revealed by Transcriptome Analysis.</a> J. Cancer. 1, 38-50 (2010).</li><li>Yehuda, R., Yang, R. K., Buchsbaum, M. S., Golier, J. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Alterations+in+cortisol+negative+feedback+inhibition+as+examined+using+the+ACTH+response+to+cortisol+administration+in+PTSD.">Alterations in cortisol negative feedback inhibition as examined using the ACTH response to cortisol administration in PTSD.</a> Psychoneuroendocrinology. 31, 447-451 (2006).</li><li>Zhang, Q., Wu, J., Nguyen, A., Wang, B. D., He, P., Laurent, G. S., Rennert, O. M., Su, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Molecular+mechanism+underlying+differential+apoptosis+between+human+melanoma+cell+lines+UACC903+and+UACC903(+6)+revealed+by+mitochondria-focused+cDNA+microarrays.">Molecular mechanism underlying differential apoptosis between human melanoma cell lines UACC903 and UACC903(+6) revealed by mitochondria-focused cDNA microarrays.</a> Apoptosis. 13, 993-1004 (2008).</li></ol>

No conflicts of interest declared.

The diagnosis of PTSD is based on self reported psychiatric symptoms (DSM IV) by potential subjects. No well defined biomarker is currently available to access the pathophysiological status of potential PTSD patients. PTSD is a disorder provoked by life threatening traumatic events and the main psychiatric symptoms remain present in the survivor's life for months and even years after the initial events. The most prominent and persistent symptoms revealed in patients with PTSD are hypervigilance, delayed exaggerated startle response 14, 15, 16 and an apparent compromise of the HPA axis. In humans these symptoms remain, or appear with a delay of three months, after cessation of the traumatic stressor 24. Our current model for biomarker studies of PTSD employs restraint and tail shocks repeated for three continuous days (2-hr sessions of 40, 2 mA tailshocks) - the inescapable tail-shock model (ITS) in rats weighing 150 gram. This ITS model has been shown to mimic to a substantial extent the pathophysiology of PTSD 17, 7, 4, 10. Our lab and other labs have verified that the ITS model of stress in rats induces behavioral and neurobiological alterations that are similar to those found in PTSD subjects 17, 7, 10, 9. Specifically, these stressed rats exhibit (1) a delayed and exaggerated startle response appearing several days after stressor cessation, which given the compressed time scale of the rat's life compared to a humans, corresponds to the one to three months delay of symptoms in PTSD patients(DSM-IV-TR PTSD Criterian D/E 13), (2) enhanced plasma corticosterone (CORT) for several (10) days, indicating compromise of the hypothalamopituitary axis (HPA), and (3) retarded body weight gain after stressor cessation, corresponding to the dysfunction of metabolic regulation of PTSD. There is no evidence in the literature that fox odor, predator exposure, or fear potentiated startle response, exhibit these persistent behavioral and neuroendocrinologic phenotypes associated with PTSD.
Rats exposed to a single stress session (1DS) have exhibited transient, but not the persistent abnormalities displayed by 3DS rats 17 The present experiment compared the startle response of 3DS and 1DS rats 4, 7, and 10 days after stressor cessation. Consistent with previous work, stressed rats exhibited elevated basal plasma CORT levels the first day post stress 17. These CORT levels were sensitive to the number of stressor exposures with higher CORT levels in 3DS rats than in 1DS rats. As for startle response, the 1DS rats exhibit an exaggerated startle response 7 days post stressor, whereas startle sensitization only becomes apparent 10 days post stressor in 3DS rats. Thus, the appearance of an exaggerated startle response after stressor cessation appears to be related to the number of stress session exposures. The 3DS stressed model appears to be useful to gain insight into the altered expression of biomarkers associated with the symptoms of PTSD and the key measurable behavioral phenotypes associated with the timing following the cessation of stress. Genomic results presented provide proof of principle for applying rMNChip and bioinformatics tools to identify differential pathways, and gene and protein biomarkers, which will greatly facilitate systems-biological study and understanding of molecular mechanisms underlying complex and multifactorial neurologic disorders, including PTSD.
While our paradigm does not delve into the cognitive and more complex behavioral aspects of PTSD, we note that altered sleep patterns in the ITS model 1 correspond to the difficulty falling and staying asleep and the nightmares of PTSD patients 11 (DSM-IV-TR PTSD Criteria D 13), and the deficiencies in escape/avoidance learning and learning of an appetitive task in the ITS model 12 corresponds to the poor concentrations and memory deficits of PTSD 5 (DSM-IV-TR PTSD Criteria C 13). The current model correlates well with the key symptoms characteristic of PTSD and provides a good model for correlating peripheral biomarkers of PTSD, which can be collected from patients, with central, mechanistic biomarkers, which cannot 6.

biomarkers in an animal model for revealing neural, hematologic, and behavioral correlates of ptsd

Identification of biomarkers representing the evolution of the pathophysiology of Post Traumatic Stress Disorder (PTSD) is vitally important, not only for objective diagnosis but also for the evaluation of therapeutic efficacy and resilience to trauma. Ongoing research is directed at identifying molecular biomarkers for PTSD, including traumatic stress induced proteins, transcriptomes, genomic variances and genetic modulators, using biologic samples from subjects' blood, saliva, urine, and postmortem brain tissues. However, the correlation of these biomarker molecules in peripheral or postmortem samples to altered brain functions associated with psychiatric symptoms in PTSD remains unresolved. Here, we present an animal model of PTSD in which both peripheral blood and central brain biomarkers, as well as behavioral phenotype, can be collected and measured, thus providing the needed correlation of the central biomarkers of PTSD, which are mechanistic and pathognomonic but cannot be collected from people, with the peripheral biomarkers and behavioral phenotypes, which can.
Our animal model of PTSD employs restraint and tail shocks repeated for three continuous days - the inescapable tail-shock model (ITS) in rats. This ITS model mimics the pathophysiology of PTSD 17, 7, 4, 10. We and others have verified that the ITS model induces behavioral and neurobiological alterations similar to those found in PTSD subjects 17, 7, 10, 9. Specifically, these stressed rats exhibit (1) a delayed and exaggerated startle response appearing several days after stressor cessation, which given the compressed time scale of the rat's life compared to a humans, corresponds to the one to three months delay of symptoms in PTSD patients (DSM-IV-TR PTSD Criterian D/E 13), (2) enhanced plasma corticosterone (CORT) for several days, indicating compromise of the hypothalamopituitary axis (HPA), and (3) retarded body weight gain after stressor cessation, indicating dysfunction of metabolic regulation.
The experimental paradigms employed for this model are: (1) a learned helplessness paradigm in the rat assayed by measurement of acoustic startle response (ASR) and a charting of body mass; (2) microdissection of the rat brain into regions and nuclei; (3) enzyme-linked immunosorbent assay (ELISA) for blood levels of CORT; (4) a gene expression microarray plus related bioinformatics tools 18. This microarray, dubbed rMNChip, focuses on mitochondrial and mitochondria-related nuclear genes in the rat so as to specifically address the neuronal bioenergetics hypothesized to be involved in PTSD.

Watch this Scientific Journal Video about Biomarkers in an Animal Model for Revealing Neural, Hematologic, and Behavioral Correlates of PTSD at JoVE.com

Biomarkers in an Animal Model for Revealing Neural, Hematologic, and Behavioral Correlates of PTSD

We describe a rat model of post traumatic stress disorder (PTSD) that reveals the persistent alterations in neuroendocrine function and the delayed long-term, exaggerated fear response, characteristic of PTSD patients. The animal model and methods described here are useful for correlating biomarkers in brain nuclei, which are mechanistic but cannot be measured in patients, with biomarkers in peripheral white blood cells, which can.

Identification of biomarkers representing the evolution of the pathophysiology of Post Traumatic Stress Disorder (PTSD) is vitally important, not only for ...

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15.8K Görüntüleme.  Uniformed Services University of the Health Sciences, Bethesda, Maryland. Biz TSSB hastalarının karakteristik nöroendokrin fonksiyonlarda kalıcı değişikliklere ve gecikmiş uzun vadeli, abartılı bir korku tepkisi, ortaya travma sonrası stres bozukluğu (TSSB) bir sıçan modelinde tarif. Hayvan modeli ve burada tarif edilen yöntemler, fakat mekanistik çevresel beyaz kan hücrelerindeki biyolojik olan hastalarda ölçülemez beyin çekirdeklerinde biyo, kutu arasında ilişki için yararlıdır.