Fear extinction in rats: Implications for human brain imaging and anxiety disorders
Introduction
Pavlovian fear conditioning has been an influential animal model for the study of anxiety disorders (Buchel and Dolan, 2000, Myers and Davis, 2002, Sullivan et al., 2003, Charney, 2004). After repeated pairing of a conditioned stimulus (CS, usually a tone or light) with an unconditioned stimulus (US, usually a footshock), the CS comes to elicit conditioned fear responses such as freezing, increased startle reflexes, autonomic changes, analgesia, and behavioral response suppression (Helmstetter and Bellgowan, 1993, Davis, 1997, Fendt and Fanselow, 1999, LeDoux, 2000). Conditioned fear responses can be extinguished by repeatedly presenting the CS without the US (Pavlov, 1927, Rescorla and Heth, 1975). In certain respects, fear conditioning resembles PTSD (Pitman, 1997, Hamner et al., 1999). For example, a soldier in combat may associate the sound of a helicopter with a severe traumatic event. Years after the war, the sound of the helicopter will continue to induce conditioned fear responses in those veterans who developed PTSD. In PTSD, re-exposure to stimuli associated with the trauma evokes inappropriate fear responses that become disabling and can have devastating consequences on the lives of PTSD sufferers (Pitman et al., 2001, Bremner, 2003).
Exposure therapies used as treatments for anxiety disorders incorporate extinction procedures (Foa, 2000, Rothbaum and Davis, 2003). As with fear extinction in rats, patients with PTSD are exposed to the trauma-associated, conditioned stimuli in the absence of any negative reinforcement (Wald and Taylor, 2003, Taylor et al., 2003). After several sessions of exposure therapy, the majority of patients learn to inhibit their fear responses (Taylor et al., 2003). However, some patients with anxiety disorders fail to respond to exposure therapy (Foa, 2000, van Minnen et al., 2002), suggesting a deficit in extinction learning. Therefore, understanding the neural mechanisms of fear extinction in animals may be fundamental to elucidating the pathophysiology of anxiety disorders, such as PTSD, and could enhance our understanding of the mechanism of action underlying extinction-based therapies (e.g. see Rauch et al., 2003a). In the present review, after briefly outlining what is currently known about the neural mechanisms of fear conditioning, we discuss in detail the involvement of the rat medial prefrontal cortex (mPFC) in the long-term retention and expression of extinction memory. We also consider the homology of prefrontal areas in rats and primates. We then discuss the implications of findings from rat studies of fear extinction with respect to human brain imaging and anxiety disorders. Finally, the potential use of new techniques for the treatment of anxiety disorders in the context of the animal data on fear extinction is considered.
Section snippets
Neural circuitry of conditioned fear acquisition
A large body of evidence from rodent studies indicates that the amygdala plays a critical role in the acquisition and expression of conditioned fear (Helmstetter, 1992, Fendt and Fanselow, 1999, LeDoux, 2000, Davis and Whalen, 2001, Maren and Quirk, 2004). Fear conditioning to a tone CS potentiates medial geniculate inputs to the lateral nucleus of the amygdala (Quirk et al., 1995, Rogan et al., 1997, Malkani and Rosen, 2000, Bauer et al., 2002), which then excites central nucleus neurons (
Extinction as new learning
Pavlov was the first to suggest that extinction does not erase conditioning, based on his observation that extinguished responses spontaneously recovered with the passage of time (Pavlov, 1927). Subsequent studies have confirmed this for conditioned fear; extinguished freezing to a tone CS spontaneously recovers to full strength (Rescorla, 2001, Quirk, 2002), can be reinstated by unsignaled shocks (Rescorla and Heth, 1975, Bouton and Bolles, 1979) or renewed by placing the animal in a context
Fear extinction in humans
The role of the human vmPFC in the inhibition of inappropriate emotional responses is well documented in the literature (Bechara et al., 1999, Manes et al., 2002, Clark et al., 2003). A recent fMRI study showed that humans with high levels of anxiety (due to the expectancy of threat-related stimuli) showed reduced mPFC activity (Bishop et al., 2004). Together with the rodent data, this suggests that the human vmPFC may be required for inhibition of fear responses following extinction.
Most
Are prefrontal areas homologous in rats and primates?
The nomenclature for the various medial prefrontal regions in the rat differs from that in the primate brain, most likely due to the fact that the prefrontal cortex is more developed in the latter, especially in humans. For example, Brodmann's areas 25 and 32 in the human brain are commonly referred to as subcallosal (SC) and rostral anterior cingulate cortex (rACC), respectively; whereas in the rat, A. 25 and A. 32 are referred to as IL and PL cortices. Even in the rat brain, the same PFC
Prefrontal cortex and PTSD: deficient extinction?
The current neurocircuitry model of PTSD hypothesizes hyper-responsiveness within the amygdala to threat-related stimuli, with inadequate top-down governance by the vmPFC (Rauch et al., 1998, Pitman et al., 2001, Villarreal and King, 2001, Bremner, 2003, Charney, 2004). This model is supported by converging evidence from multiple laboratories. Patients with PTSD exhibit exaggerated amygdala responses when viewing masked-fearful faces (Rauch et al., 2000) and during the processing of auditory
Testing the extinction hypothesis of PTSD
The fact that PTSD subjects show decreased activity in prefrontal areas hypothesized to be involved in extinction retention (based on rodent data) implies deficient extinction retention circuits in the pathophysiology of PTSD. Therefore, it would be timely to combine state of the art imaging techniques with a novel extinction paradigm in order to characterize the neural circuits of fear extinction in healthy humans, and then apply such a paradigm to the study of subjects with PTSD and matched,
Prefrontal cortex and amygdala in PTSD: where is the pathology?
Whereas most studies of PTSD suggest deficient top-down control of the amygdala by the vmPFC, one recent report on the functional connectivity of the mPFC and the amygdala in PTSD implied an excessive “bottom-up” influence of the amygdala over the mPFC (Gilboa et al., 2004), This suggests that the primary pathology in PTSD might be located in the amygdala. This proposition is consistent with the findings of Rauch et al. (2000) showing amygdala hyperactivity in PTSD subjects in response to the
Stimulation of prefrontal cortex in PTSD: could it facilitate extinction memory?
Whether anxiety disorders stem from too much “bottom-up” amygdala activation or too little “top-down” inhibitory control, facilitation of mPFC activity might be effective in controlling an overactive amygdala. The effectiveness of IL stimulation in reducing conditioned fear responses in rats raises the intriguing possibility of using an analogous approach to ameliorating symptoms in patients with anxiety disorders such as PTSD. Deep brain stimulation (DBS) has been used in the treatment of OCD
Concluding remarks
PTSD is a disorder that is characterized by the pathological acquisition, expression, and persistence of learned fear associations. A fuller understanding of the rat and human networks that mediate extinction may be essential to elucidating the pathophysiology of PTSD as well as the mechanism of action of certain extinction-based therapies. Rat studies identifying the brain regions involved in extinction retention will guide hypotheses regarding regions of interest in future neuroimaging
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