Habituation and extinction of fear recruit overlapping forebrain structures.

Establishing the neurocircuitry involved in inhibiting fear is important for understanding and treating anxiety disorders. To date, extinction procedures have been predominately used to examine the inhibition of learned fear, where fear is reduced to a conditioned stimulus (CS) by presenting it in the absence of the unconditioned stimulus (US). However, learned fear can also be reduced by habituation procedures where the US is presented in the absence of the CS. Here we used expression of the activity marker c-Fos in rats to compare the recruitment of several forebrain structures following fear habituation and extinction. Following fear conditioning where a tone CS was paired with a loud noise US, fear was then reduced the following day by either presentation of the CS or US alone (i.e. CS extinction or US habituation, respectively). This extinction and habituation training recruited several common structures, including infralimbic cortex, basolateral amygdala, midline thalamus and medial hypothalamus (orexin neurons). Moreover, this overlap was shared when examining the neural correlates of the expression of habituation and extinction, with common recruitment of infralimbic cortex and midline thalamus. However, there were also important differences. Specifically, acquisition of habituation was associated with greater recruitment of prelimbic cortex whereas expression of habituation was associated with greater recruitment of paraventricular thalamus. There was also less recruitment of central amygdala for habituation compared to extinction in the retention phase. These findings indicate that largely overlapping neurocircuitries underlie habituation and fear extinction and imply common mechanisms for reducing fear across different inhibitory treatments.

Pharmacological enhancement of fear reduction: preclinical models.

Anxiety disorders have a high prevalence, and despite the substantial advances in the psychological treatment of anxiety, relapse is still a common problem. One approach to improving existing psychological treatments for anxiety has been to develop pharmacological agents that can be used to enhance the processes underlying exposure therapy, which is the most commonly used and empirically validated psychological treatment for anxiety during which individuals are taught to appropriately inhibit fear. Animal models of exposure therapy, particularly fear extinction, have proved to be a very useful way of examining the neural and molecular correlates of fear inhibition, which has in turn led to the identification of numerous drugs that enhance these processes in rats. Several of these drugs have subsequently been tested as novel pharmacological adjuncts to exposure therapy in humans with a range of anxiety disorders. The purpose of this review is to outline the key animal models of exposure therapy and to describe how these have been used to develop potential pharmacological adjuncts for anxiety disorders. Drugs that are currently in clinical use, as well as those currently in the preclinical stages of investigation, are described.

Fibroblast growth factor-2 enhances extinction and reduces renewal of conditioned fear.

Anxiety disorders are increasingly prevalent in society; hence, there is a need to improve on existing treatments for such disorders. Fibroblast growth factor-2 (FGF2), a mitogen that is involved in brain development and regeneration, has been shown to both facilitate long-term extinction of fear and reduce stress-precipitated relapse in rats. Extinction is the laboratory analog of exposure-based therapies in humans. In this study, we continued to investigate the clinical potential of FGF2 as a pharmacological enhancer of extinction by examining its effect on renewal, a common type of relapse. In all experiments, rats were trained to fear a white noise-conditioned stimulus, and then this learned fear was extinguished the following day. Rats received systemic injections of FGF2 or vehicle immediately after extinction training. At test, on the day after extinction training, levels of freezing elicited by the white noise in either the extinction context or the original training context were measured. FGF2-treated rats showed less renewal of fear when tested in the original training context than did vehicle-treated rats. This pattern occurred even when vehicle rats were given double the amount of extinction training, and when FGF2-treated rats were given equivalent exposure to the extinction context. These results show that FGF2 facilitates long-term extinction and attenuates relapse, and thus highlight its potential as a novel pharmacological adjunct to exposure therapy.

D-cycloserine facilitates extinction the first time but not the second time: an examination of the role of NMDA across the course of repeated extinction sessions.

Extinction of learned fear is facilitated by the partial NMDA agonist D-cycloserine (DCS). However, some studies suggest that the involvement of NMDA in learning differs depending on whether learning is for the first or second time. The current study aimed to extend these findings by examining the role of NMDA in extinction for the first and the second time. Specifically, the present series of experiments used Pavlovian fear conditioning and extinction paradigms to compare the effect of DCS on extinction of fear to a light CS the first and second time around. As found previously, DCS facilitated extinction of learned fear (Experiment 1). A novel finding, however, was that DCS did not facilitate the re-extinction of fear to this same CS following retraining (Experiments 2A and 2B). Finally, it was demonstrated that the transition from NMDA-dependent to NMDA-independent extinction was stimulus specific (Experiment 3). That is, rats were first trained to fear a CS (light); this fear was then extinguished. Following this, rats were then retrained to fear the same CS (light) or a new CS (white noise). When given a second extinction session, DCS was found to facilitate extinction of the new CS but not the original CS. The results of this series of experiments suggest that the role of NMDA in extinction depends on whether extinction is new learning (first extinction) or retrieval of a previous extinction memory (re-extinction).

The ontogeny of fear-potentiated startle: effects of earlier-acquired fear memories.

Research has shown that learned fear emerges in a response-specific sequence. For example, freezing is observed at a younger age than is potentiated startle (P. Hunt & B. A. Campbell, 1997). The present study shows that the age at which a specific learned fear response emerges is influenced by the animal's early experiences. Specifically, fear potentiation of startle emerges earlier in development if the rat is given prior fear conditioning to a different stimulus. Some constraints of this "facilitation" effect are determined in follow-up experiments. This facilitation effect may provide a novel way of testing the development of the neural circuits underlying learned fear.

A developmental dissociation of context and GABA effects on extinguished fear in rats.

Although extinction has attracted considerable attention in recent years, there has been very little empirical work on extinction during development. Using Pavlovian fear conditioning, the authors provide evidence for developmental differences in extinction. Specifically, Postnatal Day (PND) 23 rats exhibited recovery of an extinguished freezing response to an auditory conditioned stimulus when tested in a context different from that in which extinction occurred (i.e., renewal) or when injected with the gamma-amino butyric acid (GABA) inverse agonist FG7142 prior to test. In contrast, PND 16 rats failed to exhibit either of these effects, although a subsequent experiment demonstrated that FG7142 alleviated spontaneous forgetting in PND 16 rats. Taken together, it appears that there are fundamental differences in the processes involved in extinction across development.

Loss of emotional experience after traumatic brain injury: findings with the startle probe procedure.

The authors used affective modulation of the eyeblink startle response to examine the impact of traumatic brain injury (TBI) on emotional reactions to pictures. Participants were 13 individuals with severe TBI and 24 controls. Participants were presented with pictures that differed in affective valence (e.g., mutilated bodies, erotic couples, and household objects) while the eyeblink startle response to an acoustic probe was measured. Startle amplitude was used to assess valence of emotional response, and startle latency was used to index interest in the pictures. Subjective ratings of the affect and arousal elicited by the various pictures were also obtained. TBI impaired startle potentiation to unpleasant pictures but not startle attenuation to pleasant pictures. Further, subjective ratings indicated that TBI participants found unpleasant pictures less arousing than did controls. The results are consistent with recent evidence of differential impairment in negative versus positive emotions after TBI and are discussed in relation to 2 competing explanations of startle modulation.

Temporary inactivation of the perirhinal cortex by muscimol injections block acquisition and expression of fear-potentiated startle.

The present study examined the role of the perirhinal cortex (PRh) in aversive information processing and emotional learning. Specifically, we studied the effects of temporary inactivation of the PRh on acquisition and expression of conditioned fear as measured by fear-potentiated startle in rats, as well as on shock sensitization of startle. Temporary inactivation of the PRh was induced by local injections of the GABAA agonist muscimol (0.0, 1.1, 2.2, 4.4 nmol/0.5 micro L). Muscimol injections into the PRh blocked both the expression and acquisition of fear-potentiated startle, as well as shock sensitization of startle. Shock sensitivity was not affected by muscimol injections, indicating that the observed blockade of acquisition and shock sensitization was not caused by a disruption in the perception of shock. Taken together, the present data show that the PRh is critical for the processing of aversive information and is necessary for the expression of emotional learning.

High illumination levels potentiate the acoustic startle response in preweanling rats.

Fear potentiation of the acoustic startle response (FPS) by aversive conditioned stimuli does not emerge in rats until Postnatal Day (P)23 (see P. S. Hunt & B. A. Campbell, 1997). However, the present study found that when presented with an unconditioned fear-eliciting stimulus, rats younger than P23 display FPS. Specifically, high illumination levels were found to enhance startle amplitudes in rats aged 18 and 25 days, but not 14 days. Furthermore, the light-enhanced startle observed in P18 rats was prevented by a systemic injection of the noradrenergic beta-receptor antagonist propranolol. These data suggest that conditioned and unconditioned FPS have different ontogenetic trajectories, and thereby provide support for the idea that learned and unlearned fear are subserved by dissociable neural systems.