Enhancement of acoustic prepulse inhibition by contextual fear conditioning in mice is maintained even after contextual fear extinction Daisuke Ishii a , Daisuke Matsuzawa a , Yuko Fujita c , Chihiro Sutoh a , Hiroyuki Ohtsuka a , Shingo Matsuda a , Nobuhisa Kanahara b , Kenji Hashimoto c , Masaomi Iyo b , Eiji Shimizu a, ⁎ a Department of Integrative Neurophysiology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chiba 260-8670, Japan b Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba University Graduate School of Medicine 1-8-1 Inohana, Chuouku, Chiba 260-8670 Japan c Division of Clinical Neuroscience, Center of Forensic Mental Health, Chiba University, 1-8-1 Inohana, Chuouku, Chiba, 260-8670, Japan abstract article info Article history: Received 6 August 2009 Received in revised form 31 October 2009 Accepted 31 October 2009 Available online 14 November 2009 Keywords: Contextual fear conditioning Fear extinction PPI PTSD Sensorimotor gating Prepulse inhibition (PPI) of the acoustic startle response is one of the few and major paradigms for investigating sensorimotor gating systems in humans and rodents in a similar fashion. PPI deficits are observed not only in patients with schizophrenia, but also in patients with anxiety disorders. Previous studies have shown that PPI in rats can be enhanced by auditory fear conditioning. In this study, we evaluated the effects of contextual fear conditioning (FC) for six times a day and fear extinction (FE) for seven days on PPI in mice. C57BL/6J mice (male, 8–12 weeks) were divided into three groups; no-FC (control), FC and FC + FE. We measured PPI at the following three time points, (1) baseline before FC, (2) after FC, and (3) after FE. The results showed that PPI was increased after FC. Moreover, the enhanced PPI following FC was observed even after FE with decreased freezing behaviors. These results suggested contextual fear conditioning could enhance acoustic PPI, and that contextual fear extinction could decrease freezing behaviors, but not acoustic PPI. © 2009 Elsevier Inc. All rights reserved. 1. Introduction Prepulse inhibition (PPI) of the acoustic startle reflex, used in the current study, is an established paradigm for the assessment of sensorimotor gating systems. PPI reflects the regulation of sensory input by filtering out irrelevant or distracting signals, and PPI is defined as a substantial reduction of the amplitude of the startle reflex that occurs when a prepulse is presented 30–500 ms prior to the startling stimulus. PPI are disturbed in schizophrenia (Swerdlow et al., 1994; Braff et al., 2001; Geyer et al., 2002). Interestingly, PPI deficits were also reported in patients with anxiety disorders, including posttraumatic stress disorder (PTSD) (Grillon et al., 1996), panic disorder (Ludewig et al, 2002) and obsessive–compulsive disorder (Hoenig et al., 2005). The paradigm of fear conditioning and extinction in rodents has been considered as a valuable animal model for studying anxiety disorders such as PTSD. Fear conditioning to either a cue or a context represents a form of associative learning involving the formation of linkages between a neutral stimulus and a stimulus with innate behavioral significance (Sanders et al., 2002). As a conditioned stimulus (CS) such as a contextual or a tone and an aversive unconditioned stimulus (US) such as an electric footshock are repeatedly and consistently paired, CS alone begins to elicit a freezing behavior in anticipation of US presentation. Fear extinction refers to the repeated presentations of the CS in the absence of the US previously paired. It has been hypothesized that extinction does not erase the original fear memory (a previously established CS–US association) but forms a new memory of safety that inhibits fear expression (a newly established CS–no US association) (Myers and Davis, 2007). Even a completely extinguished fear can be recovered spontaneously after the passage of time or “reinstated” by the presentations of the US alone or renewed by placing the animal in a different context. Extinction might be labile and weak, compared with fear conditioning itself. Understanding the neural mechanisms of fear extinction is important for the treatment of patients with anxiety disorders. Cognitive behavior therapy including exposure to fear- eliciting cues in a safe setting is based on mechanisms of fear extinction. It is widely used today and remains one of the most effective therapies for pathological anxiety including PTSD, panic disorder, phobias and obsessive–compulsive disorder (Sotres-Bayon et al., 2006). In general, two types of conditioning that are typically employed are cued and contextual conditioning (Curzon et al., 2009). In this study, we focused on contextual but not auditory (cued) fear conditioning. Contextual fear conditioning is the most basic of the conditioning procedures. It involves taking an animal and placing it in Progress in Neuro-Psychopharmacology & Biological Psychiatry 34 (2010) 183–188 Abbreviations: ASR, Acoustic startle reactivity; CS, Conditioned stimulus; FC, Fear conditioning; FE, Fear extinction; PPI, Prepulse inhibition; PTSD, Posttraumatic stress disorder; US, Unconditioned stimulus. ⁎ Corresponding author. Tel.: +81 43 226 2027; fax: +81 43 226 2028. E-mail address: eiji@faculty.chiba-u.jp (E. Shimizu). 0278-5846/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2009.10.023 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp