Deep brain stimulation in a rat model of post-traumatic stress disorder modifies forebrain neuronal activity and serum corticosterone

Document Type: Original Article


1 Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

2 Neuroscience Research Centre, Baqiyatallah University of Medical Sciences, Tehran, Iran


Objective(s): Post-traumatic stress disorder (PTSD), one of the most devastating kinds of anxiety disorders, is the consequence of a traumatic event followed by intense fear. In rats with contextual fear conditioning (CFC), a model of PTSD caused by CFC (electrical foot shock chamber), deep brain stimulation (DBS) alleviates CFC abnormalities.
Materials and Methods: Forty Male Wistar rats (220–250 g) were divided into 5 groups (n=8) and underwent stereotactic surgery to implant electrodes in the right basolateral nucleus of the amygdala (BLn). After 7 days, some animals received a foot shock, followed by another 7-day treatment schedule (DBS treatment). Next, freezing behavior was measured as a predicted response in the absence of the foot shock (re-exposure time). Blood serum corticosterone levels and amygdala c-Fos protein expression were assessed using Enzyme-linked immunosorbent assay (ELISA) and Western blot, respectively. Furthermore, freezing behaviors by re-exposure time test and general anxiety by elevated plus-maze (EPM) were evaluated.
Results: PTSD decreased serum corticosterone levels and increased both amygdala c-Fos expression and freezing behaviors. Therefore, DBS treatment significantly (P<0.001) enhanced serum corticosterone levels and could significantly (P<0.001) reduce both c-Fos protein expression and freezing behaviors’ duration. However, DBS treatment has no effect on the general anxiety in PTSD rats.
Conclusion: We argue that these outcomes might demonstrate the mechanism of DBS treatment, a complete therapeutic strategy, in PTSD patients.


Main Subjects

1. Langevin J-P, De Salles AAF, Kosoyan HP, Krahl SE. Deep brain stimulation of the amygdala alleviates post-traumatic stress disorder symptoms in a rat model. J Psychiatr Res 2010; 44:1241-1245.
2. Delgado MR, Olsson A, Phelps EA. Extending animal models of fear conditioning to humans. Biol Psychol 2006; 73:39-48.
3. Milad MR, Rauch SL, Pitman RK, Quirk GJ. Fear extinction in rats: implications for human brain imaging and anxiety disorders. Biol Psychol 2006; 73:61-71.
4. Yehuda R, LeDoux J. Response variation following trauma: a translational neuroscience approach to understanding PTSD. Neuron 2007; 56:19-32.
5. Shin LM, Wright CI, Cannistraro PA, Wedig MM, McMullin K, Martis B, et al. A functional magnetic resonance imaging study of amygdala and medial prefrontal cortex responses to overtly presented fearful faces in posttraumatic stress disorder. Archives of general psychiatry 2005; 62:273-281.
6. Shin LM, Orr SP, Carson MA, Rauch SL, Macklin ML, Lasko NB, et al. Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Archives of general psychiatry. 2004; 61:168-176.
7. Protopopescu X, Pan H, Tuescher O, Cloitre M, Goldstein M, Engelien W, et al. Differential time courses and specificity of amygdala activity in posttraumatic stress disorder subjects and normal control subjects. Biological psychiatry. 2005; 57: 464-473.
8. Yehuda R. Status of Glucocorticoid Alterations in Post‐traumatic Stress Disorder. Annals of the New York Academy of Sciences 2009; 1179:56-69.
9. Franzini A, Broggi G, Cordella R, Dones I, Messina G. Deep-brain stimulation for aggressive and disruptive behavior. World neurosurgery 2013; 80:S29 e11-4.
10.    Marin MF, Camprodon JA, Dougherty DD, Milad MR. Device‐based brain stimulation to augment fear extinction: implications for ptsd treatment and beyond. Depression and anxiety. 2014; 31:269-278.
11.    Stidd DA, Vogelsang K, Krahl SE, Langevin J-P, Fellous J-M. Amygdala Deep Brain Stimulation Is Superior to Paroxetine Treatment in a Rat Model of Posttraumatic Stress Disorder. Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation 2013; 6:837-844.
12.    Rosa M, Giannicola G, Marceglia S, Fumagalli M, Barbieri S, Priori A. Neurophysiology of deep brain stimulation. Int Rev Neurobiol 2012; 107:23-55.
13.    de Koning PP, Figee M, Endert E, Storosum JG, Fliers E, Denys D. Deep brain stimulation for obsessive–compulsive disorder is associated with cortisol changes. Psychoneuroendocrinology 2013; 38:1455-1459.
14.    Stidd DA, Vogelsang K, Krahl SE, Langevin J-P, Fellous J-M. Amygdala deep brain stimulation is superior to paroxetine treatment in a rat model of posttraumatic stress disorder. Brain stimulation 2013; 6:837-844.
15.    Hamani C, Nóbrega JN. Deep brain stimulation in clinical trials and animal models of depression. European Journal of Neuroscience 2010; 32:1109-1117.
16.    Creed MC, Hamani C, Nobrega JN. Effects of repeated deep brain stimulation on depressive-and anxiety-like behavior in rats: comparing entopeduncular and subthalamic nuclei. Brain stimulation. 2013; 6:506-514.
17.    Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005;45:651-660.
18.    Yu H, Neimat JS. The treatment of movement disorders by deep brain stimulation. Neurotherapeutics 2008; 5:26-36.
19.    McIntyre CC, Savasta M, Kerkerian-Le Goff L, Vitek JL. Uncovering the mechanism (s) of action of deep brain stimulation: activation, inhibition, or both. Clinical Neurophysiology 2004;115:1239-1248.
20.    Koenigs M, Grafman J. Posttraumatic stress disorder: the role of medial prefrontal cortex and amygdala. The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry. 2009; 15:540-548.
21.    Asalgoo S, Tat M, Sahraei H, Pirzad G. Crocin as a psychoactive agent can be target regulation of Hypothalamic-Pituitary-Adrenal axis activity. Frontiers in Neuroscience 2017; 11:668.
22.    De Kloet C, Vermetten E, Geuze E, Kavelaars A, Heijnen C, Westenberg H. Assessment of HPA-axis function in posttraumatic stress disorder: pharmacological and non-pharmacological challenge tests, a review. J Psychiatr Res 2006; 40:550-567.
23.    Sahraei H, Fatahi Z, Eidi A, Haeri-Rohani A, Hooshmandi Z, Shekarforoush S, et al. Inhibiting Post Traumatic Stress Disorder (PTSD) induced by electric shock using ethanol extract of saffron in rats. J Biol Res Thessalon 2012;18:320-327.
24.    Davies MF, Tsui J, Flannery JA, Li X, DeLorey TM, Hoffman BB. Activation of a (2) adrenergic receptors suppresses fear conditioning: expression of c-Fos and phosphorylated CREB in mouse amygdala. Neuropsychopharmacology 2004; 29:229-239.
25.    Frances Davies M, Tsui J, Flannery JA, Li X, DeLorey TM, Hoffman BB. Activation of [alpha]2 Adrenergic Receptors Suppresses Fear Conditioning: Expression of c-Fos and Phosphorylated CREB in Mouse Amygdala. Neuropsychopharmacology 2003; 29:229-239.
26.    Paxinos G, Franklin KB. The mouse brain in stereotaxic coordinates: Gulf Professional Publishing; 2004.
27.    Cordero MI, Venero C, Kruyt ND, Sandi C. Prior exposure to a single stress session facilitates subsequent contextual fear conditioning in rats: Evidence for a role of corticosterone. Hormones and Behavior 2003; 44:338-345.
28.    Ranjbaran M, Aghaei H, Hajihoseinlou V, Sahraei H, Ranjbaran K. Transient Inactivation of Shell Part of Nucleus Accumbens Inhibits and Exacerbates Stress-Induced Metabolic Alterations in Wistar Rats. Basic and clinical neuroscience 2017; 8:121.
29.    Blechert J, Michael T, Vriends N, Margraf J, Wilhelm FH. Fear conditioning in posttraumatic stress disorder: evidence for delayed extinction of autonomic, experiential, and behavioural responses. Behaviour research and therapy 2007;45:2019-2033.
30.    Kvetnansky R, Sabban EL, Palkovits M. Catecholaminergic systems in stress: structural and molecular genetic approaches. Physiological reviews 2009; 89:535-606.
31.    Schiller D, Monfils M-H, Raio CM, Johnson DC, LeDoux JE, Phelps EA. Preventing the return of fear in humans using reconsolidation update mechanisms. Nature. 2010; 463:49-53.
32.    Calleja-Castillo JM, De La Cruz-Aguilera DL, Manjarrez J, Velasco-Velázquez MA, Morales-Espinoza G, Moreno-Aguilar J, et al. Chronic deep brain stimulation of the hypothalamic nucleus in Wistar rats alters circulatory levels of corticosterone and proinflammatory cytokines. Clinical and Developmental Immunology 2013; 2013.
33.    Petrov T, Krukoff TL, Jhamandas JH. Chemically defined collateral projections from the pons to the central nucleus of the amygdala and hypothalamic paraventricular nucleus in the rat. Cell and tissue research 1994; 277:289-295.
34.    Knapska E, Maren S. Reciprocal patterns of c-Fos expression in the medial prefrontal cortex and amygdala after extinction and renewal of conditioned fear. Learning & Memory 2009; 16:486-493.
35.    Hall J, Thomas KL, Everitt BJ. Fear memory retrieval induces CREB phosphorylation and Fos expression within the amygdala. European Journal of Neuroscience 2001;13:1453-1458.
36.    Huguet G, Kadar E, Temel Y, Lim LW. Electrical Stimulation Normalizes c-Fos Expression in the Deep Cerebellar Nuclei of Depressive-like Rats: Implication of Antidepressant Activity. The Cerebellum 2017;16:398-410.
37. Petrov T, Jhamandas JH, Krukoff TL. Electrical stimulation of the central nucleus of the amygdala induces fos-like immunoreactivity in the hypothalamus of the rat: a quantitative study. Molecular brain research 1994; 22:333-340.