Fear extinction in rats: Implications for human brain imaging and anxiety disorders

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Abstract

Fear extinction is the decrease in conditioned fear responses that normally occurs when a conditioned stimulus (CS) is repeatedly presented in the absence of the aversive unconditioned stimulus (US). Extinction does not erase the initial CS–US association, but is thought to form a new memory. After extinction training, extinction memory competes with conditioning memory for control of fear expression. Deficits in fear extinction are thought to contribute to post-traumatic stress disorder (PTSD). Herein, we review studies performed in rats showing that the medial prefrontal cortex plays a critical role in the retention and expression of extinction memory. We also review human studies indicating that prefrontal areas homologous to those critical for extinction in rats are structurally and functionally deficient in patients with PTSD. We then discuss how findings from rat studies may allow us to: (1) develop new fear extinction paradigms in humans, (2) make specific predictions as to the location of extinction-related areas in humans, and (3) improve current extinction-based behavioral therapies for 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

References (151)

  • H. Fischer et al.

    Brain habituation during repeated exposure to fearful and neutral faces: a functional MRI study

    Brain Research Bulletin

    (2003)
  • A. Gilboa et al.

    Functional connectivity of the prefrontal cortex and the amygdala in posttraumatic stress disorder

    Biological Psychiatry

    (2004)
  • F.J. Helmstetter et al.

    Lesions of the amygdala block conditional hypoalgesia on the tail flick test

    Brain Research

    (1993)
  • T. Hendler et al.

    Sensing the invisible: differential sensitivity of visual cortex and amygdala to traumatic context

    Neuroimage

    (2003)
  • K.C. Koenen et al.

    Measures of prefrontal system dysfunction in posttraumatic stress disorder

    Brain Cognition

    (2001)
  • K.S. LaBar et al.

    Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study

    Neuron

    (1998)
  • R.A. Lanius et al.

    Brain activation during script-driven imagery induced dissociative responses in PTSD: a functional magnetic resonance imaging investigation

    Biological Psychiatry

    (2002)
  • I. Liberzon et al.

    Brain activation in PTSD in response to trauma-related stimuli

    Biological Psychiatry

    (1999)
  • S. Malkani et al.

    Specific induction of early growth response gene 1 in the lateral nucleus of the amygdala following contextual fear conditioning in rats

    Neuroscience

    (2000)
  • A.J. McDonald

    Cortical pathways to the mammalian amygdala

    Progress in Neurobiology

    (1998)
  • A.J. McDonald et al.

    Projections of the medial and lateral prefrontal cortices to the amygdala: a Phaseolus vulgaris leucoagglutinin study in the rat

    Neuroscience

    (1996)
  • M.A. Morgan et al.

    Extinction of emotional learning: contribution of medial prefrontal cortex

    Neuroscience Letters

    (1993)
  • M.A. Morgan et al.

    Ventral medial prefrontal cortex and emotional perseveration: the memory for prior extinction training

    Behavioural Brain Research

    (2003)
  • B.A. Morrow et al.

    The role of mesoprefrontal dopamine neurons in the acquisition and expression of conditioned fear in the rat

    Neuroscience

    (1999)
  • K.M. Myers et al.

    Behavioral and neural analysis of extinction

    Neuron

    (2002)
  • B. Nuttin et al.

    Deep brain stimulation for psychiatric disorders

    Neurosurgery Clinics of North America

    (2003)
  • X. An et al.

    Prefrontal cortical projections to longitudinal columns in the midbrain periaqueductal gray in macaque monkeys

    Journal of Comparative Neurology

    (1998)
  • J.L. Armony et al.

    Modulation of auditory neural responses by a visual context in human fear conditioning

    Neuroreport

    (2001)
  • H. Barbas et al.

    Diverse thalamic projections to the prefrontal cortex in the rhesus monkey

    Journal of Comparative Neurology

    (1991)
  • D. Barrett et al.

    Metabolic mapping of mouse brain activity after extinction of a conditioned emotional response

    Journal of Neuroscience

    (2003)
  • E.P. Bauer et al.

    NMDA receptors and L-type voltage-gated calcium channels contribute to long-term potentiation and different components of fear memory formation in the lateral amygdala

    Journal of Neuroscience

    (2002)
  • A. Bechara et al.

    Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making

    Journal of Neuroscience

    (1999)
  • A. Bechara et al.

    Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans

    Science

    (1995)
  • A. Benazzouz et al.

    Intraoperative microrecordings of the subthalamic nucleus in Parkinson's disease

    Movement Disorders

    (2002)
  • S. Bishop et al.

    Prefrontal cortical function and anxiety: controlling attention to threat-related stimuli

    Nature Neuroscience

    (2004)
  • M.E. Bouton

    Context, time, and memory retrieval in the interference paradigms of Pavlovian learning

    Psychological Bulletin

    (1993)
  • M.E. Bouton et al.

    Role of conditioned contextual stimuli in reinstatement of extinguished fear

    Journal of Experimental Psychology-Animal Behavior Processes

    (1979)
  • M.E. Bouton et al.

    Contextual control of the extinction of conditioned fear: tests for the associative value of the context

    Journal of Experimental Psychology-Animal Behavior Processes

    (1983)
  • J.D. Bremner

    Functional neuroanatomical correlates of traumatic stress revisited 7 years later, this time with data

    Psychopharmacological Bulletin

    (2003)
  • J.D. Bremner et al.

    Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder

    American Journal of Psychiatry

    (1999)
  • C. Buchel et al.

    Amygdala-hippocampal involvement in human aversive trace conditioning revealed through event-related functional magnetic resonance imaging

    Journal of Neuroscience

    (1999)
  • S.T. Carmichael et al.

    Limbic connections of the orbital and medial prefrontal cortex in macaque monkeys

    Journal of Comparative Neurology

    (1995)
  • S.T. Carmichael et al.

    Connectional networks within the orbital and medial prefrontal cortex of macaque monkeys

    Journal of Comparative Neurology

    (1996)
  • D.S. Charney

    Psychobiological mechanisms of resilience and vulnerability: implications for successful adaptation to extreme stress

    American Journal of Psychiatry

    (2004)
  • D.T. Cheng et al.

    Functional MRI of human amygdala activity during Pavlovian fear conditioning: stimulus processing versus response expression

    Behavioral Neuroscience

    (2003)
  • H. Cohen et al.

    Repetitive transcranial magnetic stimulation of the right dorsolateral prefrontal cortex in posttraumatic stress disorder: a double-blind, placebo-controlled study

    American Journal of Psychiatry

    (2004)
  • D.R. Collins et al.

    Reciprocal changes in the firing probability of lateral and central medial amygdala neurons

    Journal of Neuroscience

    (1999)
  • F. Conde et al.

    Afferent connections of the medial frontal cortex of the rat. II. Cortical and subcortical afferents

    Journal of Comparative Neurology

    (1995)
  • M. Davis

    Neurobiology of fear responses: the role of the amygdala

    Journal of Neuropsychiatry and Clinical Neuroscience

    (1997)
  • M. Davis et al.

    The amygdala: vigilance and emotion

    Molecular Psychiatry

    (2001)
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