[en] BACKGROUND: We have previously demonstrated, in mice, that antidepressant treatment can prevent relapse of PTSD-like behaviors (avoidance, hyperarousal, and anxiety) through increased activation in the infralimbic cortex (IL) of the medial prefrontal cortex. OBJECTIVE: Here, we examined whether direct high-frequency stimulation (HFS) of the IL, provoking its heightened activation (i.e., long-term potentiation, LTP), would also prevent the return of PTSD-like symptoms. METHODS: A 1.5-mA foot-shock was used to generate PTSD-like symptoms in Swiss mice. In Experiment 1, local field potentials were recorded in the IL to test whether normal IL LTP can be induced after the suppression of PTSD-like symptoms. In Experiment 2, IL HFS was applied after symptom suppression, but prior to the provocation of relapse, to test HFS effect on symptom return. RESULTS: We observed that PTSD-like state was associated with impairment in IL HFS-induced IL LTP. However, IL LTP induction was near normal when PTSD-like symptoms were suppressed. We then found that IL HFS, applied after symptom suppression, prevented symptom return. CONCLUSIONS: Increased activation of the IL may be a key mechanism preventing PTSD relapse. Prefrontal cortex deep brain stimulation may, therefore, be relevant for preventing PTSD symptom return in remitted high-risk patients.
Spivak, B., Strous, R.D., Shaked, G., Shabash, E., Kotler, M., Weizman, A., Reboxetine versus fluvoxamine in the treatment of motor vehicle accident-related posttraumatic stress disorder: a double-blind, fixed-dosage, controlled trial. J Clin Psychopharmacol 26:2 (2006), 152–156.
Berthier, M.L., Kulisevsky, J., Fernández Benitez, J.A., Gironell, A., Reactivation of posttraumatic stress disorder after minor head injury. Depress Anxiety 8:1 (1998), 43–47.
Davidson, J., Pearlstein, T., Londborg, P., Brady, K.T., Rothbaum, B., Bell, J., et al. Efficacy of sertraline in preventing relapse of posttraumatic stress disorder: results of a 28-week double-blind, placebo-controlled study. Am J Psychiatr 158:12 (2001), 1974–1981.
Martenyi, F., Brown, E.B., Zhang, H., Koke, S.C., Prakash, A., Fluoxetine v. placebo in prevention of relapse in post-traumatic stress disorder. Br J Psychiatr 181 (2002), 315–320.
Boe, H.J., Holgersen, K.H., Holen, A., Reactivation of posttraumatic stress in male disaster survivors: the role of residual symptoms. J Anxiety Disord 24:4 (2010), 397–402.
Bentefour, Y., Rakibi, Y., Bennis, M., Ba-M'hamed, S., Garcia, R., Paroxetine treatment, following behavioral suppression of PTSD-like symptoms in mice, prevents relapse by activating the infralimbic cortex. Eur Neuropsychopharmacol 26:2 (2016), 195–207.
Fernandez, M., Pissiota, A., Frans, O., von Knorring, L., Fischer, H., Fredrikson, M., Brain function in a patient with torture related post-traumatic stress disorder before and after fluoxetine treatment: a positron emission tomography provocation study. Neurosci Lett 297:2 (2001), 101–104.
Seedat, S., Warwick, J., van Heerden, B., Hugo, C., Zungu-Dirwayi, N., Van Kradenburg, J., et al. Single photon emission computed tomography in posttraumatic stress disorder before and after treatment with a selective serotonin reuptake inhibitor. J Affect Disord 80:1 (2004), 45–53.
Martenyi, F., Soldatenkova, V., Fluoxetine in the acute treatment and relapse prevention of combat-related post-traumatic stress disorder: analysis of the veteran group of a placebo-controlled, randomized clinical trial. Eur Neuropsychopharmacol 16:5 (2006), 340–349.
Bentefour, Y., Bennis, M., Garcia, R., M'hamed, S.B., Effects of paroxetine on PTSD-like symptoms in mice. Psychopharmacology (Berlin) 232:13 (2015), 2303–2312.
Sui, L., Wang, J., Li, B.M., Role of the phosphoinositide 3-kinase-Aktmammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex. Learn Mem 15:10 (2008), 762–776.
Sui, L., Wang, Y., Ju, L.H., Chen, M., Epigenetic regulation of reelin and brain-derived neurotrophic factor genes in long-term potentiation in rat medial prefrontal cortex. Neurobiol Learn Mem 97:4 (2012), 425–440.
Hamani, C., Diwan, M., Macedo, C.E., Brandão, M.L., Shumake, J., Gonzalez-Lima, F., Raymond, R., Lozano, A.M., Fletcher, P.J., Nobrega, J.N., Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats. Biol Psychiatr 67:2 (2010), 117–124.
Jiménez-Sánchez, L., Castañé A., Pérez-Caballero, L., Grifoll-Escoda, M., López-Gil, X., Campa, L., Galofré M., Berrocoso, E., Adell, A., Activation of AMPA receptors mediates the antidepressant action of deep brain stimulation of the infralimbic prefrontal cortex. Cerebr Cortex 26:6 (2016), 2778–2789.
Migues, P.V., Hardt, O., Wu, D.C., Gamache, K., Sacktor, T.C., Wang, Y.T., Nader, K., PKMzeta maintains memories by regulating GluR2-dependent AMPA receptor trafficking. Nat Neurosci 13:5 (2010), 630–634.
Garcia, R., Stress, metaplasticity, and antidepressants. Curr Mol Med 2:7 (2002), 629–638.
Gilbert, M.E., Mack, C.M., Field potential recordings in dentate gyrus of anesthetized rats: stability of baseline. Hippocampus 9:3 (1999), 277–287.
Fanselow, M.S., Neural organization of the defensive behavior system responsible for fear. Psychon Bull Rev 1:4 (1994), 429–438.
Rescorla, R.A., Heth, C.D., Reinstatement of fear to an extinguished conditioned stimulus. J Exp Psychol Anim Behav Process 1:1 (1975), 88–96.
Gemmell, C., O'Mara, S.M., Long-term potentiation and paired-pulse facilitation in the prelimbic cortex of the rat following stimulation in the contralateral hemisphere in vivo. Exp Brain Res 132:2 (2000), 223–229.
Roder, S., Danober, L., Pozza, M.F., Lingenhoehl, K., Wiederhold, K.H., Olpe, H.R., Electrophysiological studies on the hippocampus and prefrontal cortex assessing the effects of amyloidosis in amyloid precursor protein 23 transgenic mice. Neuroscience 120:3 (2003), 705–720.
Garcia, R., Musleh, W., Tocco, G., Thompson, R.F., Baudry, M., Time-dependent blockade of STP and LTP in hippocampal slices following acute stress in mice. Neurosci Lett 233:1 (1997), 41–44.
Maroun, M., Richter-Levin, G., Exposure to acute stress blocks the induction of long-term potentiation of the amygdala-prefrontal cortex pathway in vivo. J Neurosci 23:11 (2003), 4406–4409.
Rocher, C., Spedding, M., Munoz, C., Jay, T.M., Acute stress-induced changes in hippocampal/prefrontal circuits in rats: effects of antidepressants. Cerebr Cortex 14:2 (2004), 224–229.
Milad, M.R., Quirk, G.J., Neurons in medial prefrontal cortex signal memory for fear extinction. Nature 420:6911 (2002), 70–74.
Hugues, S., Garcia, R., Reorganization of learning-associated prefrontal synaptic plasticity between the recall of recent and remote fear extinction memory. Learn Mem 14:8 (2007), 520–524.
Garcia, R., Spennato, G., Nilsson-Todd, L., Moreau, J.L., Deschaux, O., Hippocampal low-frequency stimulation and chronic mild stress similarly disrupt fear extinction memory in rats. Neurobiol Learn Mem 89:4 (2008), 560–566.
Deschaux, O., Motanis, H., Spennato, G., Moreau, J.L., Garcia, R., Re-emergence of extinguished auditory-cued conditioned fear following a sub-conditioning procedure: effects of hippocampal and prefrontal tetanic stimulations. Neurobiol Learn Mem 95:4 (2011), 510–518.
Zheng, X., Deschaux, O., Lavigne, J., Nachon, O., Cleren, C., Moreau, J.L., et al. Prefrontal high-frequency stimulation prevents sub-conditioning procedure-provoked, but not acute stress-provoked, reemergence of extinguished fear. Neurobiol Learn Mem 101 (2013), 33–38.
Milad, M.R., Vidal-Gonzalez, I., Quirk, G.J., Electrical stimulation of medial prefrontal cortex reduces conditioned fear in a temporally specific manner. Behav Neurosci 118:2 (2004 Apr), 389–394.
Herry, C., Garcia, R., Prefrontal cortex long-term potentiation, but not long-term depression, is associated with the maintenance of extinction of learned fear in mice. J Neurosci 22:2 (2002), 577–583.
Herry, C., Vouimba, R.M., Garcia, R., Plasticity in the mediodorsal thalamo-prefrontal cortical transmission in behaving mice. J Neurophysiol 82:5 (1999), 2827–2832.
Quirk, G.J., Likhtik, E., Pelletier, J.G., Paré D., Stimulation of medial prefrontal cortex decreases the responsiveness of central amygdala output neurons. J Neurosci 23:25 (2003), 8800–8807.
Ongür, D., Price, J.L., The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cerebr Cortex 10:3 (2000), 206–219.
Herry, C., Ciocchi, S., Senn, V., Demmou, L., Müller, C., Lüthi, A., Switching on and off fear by distinct neuronal circuits. Nature 454:7204 (2008), 600–606.
McNally, G.P., Pigg, M., Weidemann, G., Opioid receptors in the midbrain periaqueductal gray regulate extinction of pavlovian fear conditioning. J Neurosci 24:31 (2004), 6912–6919.
Perusini, J.N., Meyer, E.M., Long, V.A., Rau, V., Nocera, N., Avershal, J., et al. Induction and expression of fear sensitization caused by acute traumatic stress. Neuropsychopharmacology 41:1 (2016), 45–57.
Adamec, R., Hebert, M., Blundell, J., Long lasting effects of predator stress on pCREB expression in brain regions involved in fearful and anxious behavior. Behav Brain Res 221:1 (2011), 118–133.
Pesold, C., Treit, D., The central and basolateral amygdala differentially mediate the anxiolytic effects of benzodiazepines. Brain Res 671:2 (1995), 213–221.
Reznikov, R., Bambico, F.R., Diwan, M., Raymond, R.J., Nashed, M.G., Nobrega, J.N., Hamani, C., Prefrontal cortex deep brain stimulation improves fear and anxiety-like behavior and reduces basolateral amygdala activity in a preclinical model of posttraumatic stress disorder. Neuropsychopharmacology, 2017, 10.1038/npp.2017.207.
Denys, D., Mantione, M., Figee, M., van den Munckhof, P., Koerselman, F., Westenberg, H., et al. Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder. Arch Gen Psychiatr 67:10 (2010), 1061–1068.
Milad, M.R., Pitman, R.K., Ellis, C.B., Gold, A.L., Shin, L.M., Lasko, N.B., et al. Neurobiological basis of failure to recall extinction memory in posttraumatic stress disorder. Biol Psychiatr 66:12 (2009), 1075–1082.