The development of post-traumatic stress disorder (PTSD) in humans includes a number of symptoms, the main being intrusive memories of the trauma, psychological and physiological hyperreactivity on reminding of the trauma, and increased anxiety, and specific memory impairments. Current models of PTSD in animals address the last three of these symptoms but do not provide for study of spontaneously arising intrusive memories or their neural basis. The study reported here uses contemporary methods for continuous monitoring of behavior and showed that the development of PTSD in mice was accompanied by specific changes in spontaneous behavior in their home cages. These changes were long-lasting and included decreased exploratory activity and elevated anxiety. Thus, we showed that mice display the behavioral manifestations of human-typical spontaneously arising PTSD symptoms which in humans are associated with intrusive memories of the trauma. In addition, studies of neuron electrical activity-dependent expression of transcription factor c-Fos showed that the brains of mice with PTSD, even when the animal was at rest and not receiving external reminders of the trauma experienced, showed increased spontaneous activity in the cingulate and retrosplenial cortex, amygdala, thalamus, and periaqueductal gray matter. Thus, our studies demonstrated the spontaneous manifestations of PTSD in a mouse model at both the behavioral and neural levels.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Adamec, R. E. and Shallow, T., “Lasting effects on rodent anxiety of a single exposure to a cat,” Physiol. Behav., 54, 101–109 (1993).
Barth, A. L., Gerkin, R. C., and Dean, K. L., “Alteration of neuronal firing properties after in vivo experience in a FosGFP transgenic mouse,” J. Neurosci., 24, No. 29, 6466–6475 (2004).
Belzung, C. and Griebel, G., “Measuring normal and pathological anxiety-like behaviour in mice: a review,” Behav. Brain Res., 125, 141–149 (2001).
Berardi, A., Trezza, V., Palmery, M., et al., “An updated animal model capturing both the cognitive and emotional features of post-traumatic stress disorder (PTSD),” Front. Behav. Neurosci., 8, 142 (2014), eCollection.
Brewin, C. R., “Memory and forgetting,” Curr. Psychiatry Rep., 20, No. 10, 87 (2018).
Brown, V. M., LaBar, K. S., Haswell, C. C., et al., “Altered resting-state functional connectivity of basolateral and centromedial amygdala complexes in posttraumatic stress disorder,” Neuropsychopharmacology, 39, No. 2, 351–359 (2014).
Clausen, A. N., Francisco, A. J., Thelen, J., et al., “PTSD and cognitive symptoms relate to inhibition-related prefrontal activation and functional connectivity,” Depress. Anxiety, 34, No. 5, 427–436 (2017).
Cohen, H., Kozlovsky, N., Alona, C., et al., “Animal model for PTSD: from clinical concept to translational research,” Neuropharmacology, 62, 715–724 (2012).
Dahlhoff, M., Siegmund, A., Golub, Y., et al., “AKT/GSK-3beta/beta-catenin signalling within hippocampus and amygdala reflects genetically determined differences in posttraumatic stress disorder like symptoms,” Neuroscience, 169, 1216–1226 (2010).
Della Valle, R., Mohammadmirzaei, N., and Knox, D., “Single prolonged stress alters neural activation in the periacqueductal gray and midline thalamic nuclei during emotional learning and memory,” Learn. Mem., 26, No. 10, 403–411 (2019).
Falconer, E., Allen, A., Felmingham, K. L., et al., “Inhibitory neural activity predicts response to cognitive-behavioral therapy for posttraumatic stress disorder,” J. Clin. Psychiatry, 74, No. 9, 895–901 (2013).
Fenster, R. J., Lebois, L. A. M., Ressler, K. J., and Suh, J., “Brain circuit dysfunction in post-traumatic stress disorder: from mouse to man,” Nat. Rev. Neurosci., 19, No. 9, 535–551 (2018).
Franklin, K. B. J. and Paxinos, G., The Mouse Brain in Stereotaxic Coordinates, Academic Press, New York (2007), 3rd ed.
Gvozdanovic, G. A., Stampfli, P., Seifritz, E., and Rasch, B., “Neural correlates of experimental trauma memory retrieval,” Hum. Brain Mapp., 38, No. 7, 3592–3602 (2017).
Harricharan, S., Rabellino, D., Frewen, P. A., et al., “fMRI functional connectivity of the periaqueductal gray in PTSD and its dissociative subtype,” Brain Behav., 6, No. 12, e00579 (2016).
Holter, S. M., Einicke, J., Sperling, B., et al., “Tests for anxiety-related behavior in mice,” Curr. Protoc. Mouse Biol., 5, No. 4, 291–309 (2015).
Hopper, J. W., Frewen, P. A., van der Kolk, B. A., and Lanius, R. A., “Neural correlates of reexperiencing, avoidance, and dissociation in PTSD: symptom dimensions and emotion dysregulation in responses to script-driven trauma imagery,” J. Trauma Stress, 20, No. 5, 713–725 (2007).
Jeong, H., Chung, Y. A., Ma, J., et al., “Diverging roles of the anterior insula in trauma-exposed individuals vulnerable or resilient to posttraumatic stress disorder,” Sci. Rep., 9, No. 1, 15539 (2019).
Jud, C., Schmutz, I., Hampp, G., et al., “A guideline for analyzing circadian wheel-running behavior in rodents under different lighting conditions,” Biol. Proced. Online, 7, 101–116 (2005).
Kekelidze, Zh. I. and Portnova, A. A., “Diagnostic criteria for post-traumatic stress disorder,” Zh. Nevrol. Psikhiat., 109, 4–7 (2009).
Kessler, R. C., “Posttraumatic stress disorder: the burden to the individual and to society,” J. Clin. Psychiatry, 61, No. 5, 4–14 (2000).
Kwapis, J. L., Jarome, T. J., Lee, J. L., and Helmstetter, F. J., “The retrosplenial cortex is involved in the formation of memory for context and trace fear conditioning,” Neurobiol. Learn. Mem., 123, 110–116 (2015).
Lanius, R. A., Vermetten, E., Loewenstein, R. J., et al., “Emotion modulation in PTSD: Clinical and neurobiological evidence for a dissociative subtype,” Am. J. Psychiatry, 167, No. 6, 640–647 (2010).
Lguensat, A., Bentefour, Y., Bennis, M., et al., “Susceptibility and resilience to PTSD-like symptoms in mice are associated with opposite dendritic changes in the prelimbic and infralimbic cortices following trauma,” Neuroscience, 418, 166–176 (2019).
Liberzon, I., Khan, S., and Young, E., “Animal models of posttraumatic stress disorder,” in: Handbook of Stress and the Brain, Steckler, T. et al. (eds.), Elsevier, Amsterdam (2005) Vol. 5, Pt. 2, pp. 231–250.
Lister, R. G., “The use of a plus-maze to measure anxiety in the mouse,” Psychopharmacology (Berlin), 92, 180–185 (1987).
Molchanova, E. S., “Post-traumatic stress and acute stress disorders in DSM-V format: amendments and previous problems,” Med. Psikh. Ross., 6, No. 1, 2 (2014).
Osuch, E. A., Benson, B., Geraci, M., et al., “Regional cerebral blood flow correlated with flashback intensity in patients with posttraumatic stress disorder,” Biol. Psychiatry, 50, No. 4, 246–253 (2001).
Penzo, M. A., Robert, V., Tucciarone, J., et al., “The paraventricular thalamus controls a central amygdala fear circuit,” Nature, 519, No. 7544, 455–459 (2015).
Pissiota, A., Frans, O., Fernandez, M., et al., “Neurofunctional correlates of posttraumatic stress disorder: a PET symptom provocation study,” Eur. Arch. Psychiatry Clin. Neurosci., 252, No. 2, 68–75 (2002).
Polak, A. R., Witteveen, A. B., Reitsma, J. B., and Olff, M., “The role of executive function in posttraumatic stress disorder: a systematic review,” J. Affect. Disord., 141, 11–21 (2012).
Rabellino, D., Densmore, M., Frewen, P. A., et al., “Aberrant functional connectivity of the amygdala complexes in PTSD during conscious and subconscious processing of trauma-related stimuli,” PLoS One, 11, No. 9, e0163097 (2016).
Robinson, L. and Riedel, G., “Comparison of automated home-cage monitoring systems: emphasis on feeding behaviour, activity and spatial learning following pharmacological interventions,” J. Neurosci. Meth., 234, 13–25 (2014).
Robinson, L., Plano, A., Cobb, S., and Riedel, G., “Long-term home cage activity scans reveal lowered exploratory behaviour in symptomatic female Rett mice,” Behav. Brain Res., 250, 148–156 (2013).
Rybnikova, E. A., Mironova, V. I., Tyul’kova, E. I., and Samoilov, M. O., “The anxiolytic effect of mild hypobaric hypoxia in a model of post-traumatic stress disorder in rats,” Zh. Vyssh. Nerv. Deyat., 58, No. 4, 486–492 (2008).
Rybnikova, E. A., Vorob’ev, M. G., and Samoilov, M. O., “Hypoxic post-conditioning corrects behavioral impairments in rats in a model of post-traumatic stress disorder,” Zh. Vyssh. Nerv. Deyat., 62, No. 3, 364 (2012).
Schoner, J., Heinz, A., Endres, M., et al., “Post-traumatic stress disorder and beyond: an overview of rodent stress models,” J. Cell. Mol. Med., 21, No. 10, 2248–2256 (2017).
Shin, L. M., Whalen, P. J., Pitman, R. K., et al., “An fMRI study of anterior cingulate function in posttraumatic stress disorder,” Biol. Psychiatry, 50, No. 12, 932–942 (2001).
Siegmund, A. and Wotjak, C. T., “A mouse model of posttraumatic stress disorder that distinguishes between conditioned and sensitised fear,” J. Psychiatr. Res., 41, 848–860 (2007a).
Siegmund, A. and Wotjak, C. T., “Hyperarousal does not depend on trauma- related contextual memory in an animal model of posttraumatic stress disorder,” Physiol. Behav., 90, 103–107 (2007b).
Siegmund, A. and Wotjak, C. T., “Toward an animal model of posttraumatic stress disorder,” Ann. N. Y. Acad. Sci., 1071, 324–334 (2006).
Spiers, J. G., Chen, H. C., Steyn, F. J., et al., “Noninvasive assessment of altered activity following restraint in mice using an automated physiological monitoring system,” Stress, 20, No. 1, 59–67 (2017).
Toropova, K. A. and Anokhin, K. V., “Modeling of post-traumatic stress disorder in mice: nonlinear dependence on the strength of the traumatic action,” Zh. Vyssh. Nerv. Deyat., 68, No. 3, 378–394 (2018).
Urbach, Y. K., Raber, K. A., Canneva, F., et al., “Automated phenotyping and advanced data mining exemplified in rats transgenic for Huntington’s disease,” J. Neurosci. Meth., 234, 38–53 (2014).
Walf, A. A. and Frye, C. A., “The use of the elevated plus maze as an assay of anxiety-related behavior in rodents,” Nat. Protoc., 2, 322–328 (2007).
Wang, T., Liu, J., Zhang, J., et al., “Altered resting-state functional activity in posttraumatic stress disorder: A quantitative meta-analysis,” Sci. Rep., 6, 27131 (2016).
Yehuda, R. and Antelman, S. M., “Criteria for rationally evaluating animal models of posttraumatic stress disorder,” Biol. Psychiatry, 33, 479–486 (1993).
Zhang, Y., Fukushima, H., and Kida, S., “Induction and requirement of gene expression in the anterior cingulate cortex and medial prefrontal cortex for the consolidation of inhibitory avoidance memory,” Mol. Brain, 4, 4 (2011).
Zhong, Y., Zhang, R., Li, K., et al., “Altered cortical and subcortical local coherence in PTSD: evidence from resting-state fMRI,” Acta Radiol., 56, No. 6, 746–753 (2015).
Author information
Authors and Affiliations
Corresponding author
Additional information
Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 70, No. 5, pp. 668–681, September–October, 2020.
Rights and permissions
About this article
Cite this article
Toropova, K.A., Ivashkina, O.I., Ivanova, A.A. et al. Long-Term Changes in Spontaneous Behavior and c-Fos Expression in the Brain in Mice in the Resting State in a Model of Post-Traumatic Stress Disorder. Neurosci Behav Physi 51, 629–638 (2021). https://doi.org/10.1007/s11055-021-01116-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11055-021-01116-z