Chun-hui Chang

Recent fear is resistant to extinction

In some individuals, fearful experiences (e.g., combat) yield persistent and debilitating psychological disturbances, including posttraumatic stress disorder (PTSD). Early intervention (e.g., debriefing) after psychological trauma is widely practiced and argued to be an effective strategy for limiting subsequent psychopathology, although there has been considerable debate on this point. Here we show in an animal model of traumatic fear that early intervention shortly after an aversive experience yields poor long-term fear reduction. Extinction trials administered minutes after aversive fear conditioning in rats suppressed fear acutely, but fear suppression was not maintained the next day. In contrast, delivering extinction trials 1 day after fear conditioning produced an enduring suppression of fear memory. We further show that the recent experience of an aversive event, not the timing of the extinction intervention per se, inhibits the development of long-term fear extinction. These results reveal that the level of fear present at the time of intervention is a critical factor in the efficacy of extinction. Importantly, our work suggests that early intervention may not yield optimal outcomes in reducing posttraumatic stress, particularly after severe trauma.

Single-Unit Activity in the Medial Prefrontal Cortex during Immediate and Delayed Extinction of Fear in Rats

Delivering extinction trials minutes after fear conditioning yields only a short-term fear suppression that fully recovers the following day. Because extinction has been reported to increase CS-evoked spike firing and spontaneous bursting in the infralimbic (IL) division of the medial prefrontal cortex (mPFC), we explored the possibility that this immediate extinction deficit is related to altered mPFC function. Single-units were simultaneously recorded in rats from neurons in IL and the prelimbic (PrL) division of the mPFC during an extinction session conducted 10 minutes (immediate) or 24 hours (delayed) after auditory fear conditioning. In contrast to previous reports, IL neurons exhibited CS-evoked responses early in extinction training in both immediate and delayed conditions and these responses decreased in magnitude over the course of extinction training. During the retention test, CS-evoked firing in IL was significantly greater in animals that failed to acquire extinction. Spontaneous bursting during the extinction and test sessions was also different in the immediate and delayed groups. There were no group differences in PrL activity during extinction or retention testing. Alterations in both spontaneous and CS-evoked neuronal activity in the IL may contribute to the immediate extinction deficit.

Early extinction after fear conditioning yields a context-independent and short-term suppression of conditional freezing in rats.

Extinction of Pavlovian fear conditioning in rats is a useful model for therapeutic interventions in humans with anxiety disorders. Recently, we found that delivering extinction trials soon (15 min) after fear conditioning yields a short-term suppression of fear, but little long-term extinction. Here, we explored the possible mechanisms underlying this deficit by assessing the suppression of fear to a CS immediately after extinction training (Experiment 1) and the context specificity of fear after both immediate and delayed extinction training (Experiment 2). We also examined the time course of the immediate extinction deficit (Experiment 3). Our results indicate that immediate extinction produces a short-lived and context-independent suppression of conditional freezing. Deficits in long-term extinction were apparent even when the extinction trials were given up to 6 h after conditioning. Moreover, this deficit was not due to different retention intervals that might have influenced the degree of spontaneous recovery after immediate and delayed extinction (Experiment 4). These results suggest that fear suppression under immediate extinction may be due to a short-term, context-independent habituation process, rather than extinction per se. Long-term extinction memory only develops when extinction training occurs at least six hours after conditioning.

Medial prefrontal cortex activation facilitates re-extinction of fear in rats

It has been suggested that reduced infralimbic (IL) cortical activity contributes to impairments of fear extinction. We therefore explored whether pharmacological activation of the IL would facilitate extinction under conditions it normally fails (i.e., immediate extinction). Rats received auditory fear conditioning 1 h before extinction training. Immediately prior to extinction, rats received microinfusions into the IL of the GABA(A) receptor antagonist, picrotoxin, or the NMDA receptor partial agonist, D-cycloserine. Although neither drug facilitated extinction, they both facilitated the subsequent re-extinction of fear when animals were trained in a drug-free state, suggesting that activating the IL primes behavioral extinction.

Strain difference in the effect of infralimbic cortex lesions on fear extinction in rats.

The infralimbic division of the medial prefrontal cortex (IL) has been implicated in the consolidation and retention of extinction memories. However, the effects of IL lesions on the retention of extinction memory are inconsistent. In the present experiments, we examined whether rat strain influences the effects of IL lesions on extinction. In Experiment 1, Sprague-Dawley (SD) or Long-Evans (LE) rats received a standard auditory fear conditioning procedure, which was followed by an extinction session; freezing served as the index of conditional fear. Our results reveal that focal IL lesions impair the retention of extinction in SD, but not LE rats. In addition to the strain difference in sensitivity to IL lesions, LE rats exhibited significantly higher levels of contextual fear before the outset of extinction training than SD rats. In a second experiment we thus examined whether contextual fear influenced the sensitivity of extinction to IL lesions in LE rats. LE rats received the same conditioning as in Experiment 1, and then were either merely exposed to a novel context or administered unsignaled shocks in that context, followed by extinction and test sessions. Our results reveal that LE rats with IL lesions showed normal extinction regardless of the levels of contextual fear manifest before extinction. Thus, we conclude that rat strain is an important variable that influences the role of infralimbic cortex in fear extinction.

Fear extinction in rodents

Pavlovian conditioning paradigms have become important model systems for understanding the neuroscience of behavior. In particular, studies of the extinction of Pavlovian fear responses are yielding important information about the neural substrates of anxiety disorders, such as phobias and post‐traumatic stress disorder (PTSD) in humans. These studies are germane to understanding the neural mechanisms underlying behavioral interventions that suppress fear, including exposure therapy in anxiety disorders. This unit describes detailed behavioral protocols for examining the nature and properties of fear extinction in laboratory rodents. Curr. Protoc. Neurosci. 47:8.23.1‐8.23.17.

Inhibitory avoidance learning altered ensemble activity of amygdaloid neurons in rats

In this study, we examined single‐unit activity in the amygdala before and after a rat had acquired an inhibitory avoidance task. Long‐Evans rats with microwires chronically implanted into the central nucleus (CeA) or basolateral complex (BLC) of the amygdala were acclimatized to the apparatus of a step‐through inhibitory avoidance task for three sessions. On the fourth session, rats in the experimental group received an inescapable footshock (3 mA, 1 s) as they stepped from the lit side into the dark side of the task apparatus, whereas rats in the control group received the same amount of shock on a different apparatus. All rats were tested for retention in the task apparatus 1 day after shock training. The experimental rats showed better retention than the controls as they stayed longer in the lit side. Ensemble unit activities were recorded in the amygdala nuclei from the indwelling wire bundles during the acclimation and test sessions. The data collected from well‐isolated amygdala units showed that neuronal discharge habituated from the first to the third acclimation session. In the test session, the experimental group, but not the control group, showed elevated firing rates in the CeA or BLC neurons located on either side of the brain. These findings provide the first piece of evidence showing that learning of an inhibitory avoidance task leads to an increase in amygdala neuronal discharges during a retention test.

Bidirectional changes in the intrinsic excitability of infralimbic neurons reflect a possible regulatory role in the acquisition and extinction of Pavlovian conditioned fear.

Although being able to recall highly fear-arousing events can be adaptive in certain contexts, it is also advantageous to be able to inhibit these responses. Pavlovian fear extinction occurs when a conditioned stimulus is repeatedly presented in the absence of the unconditioned stimulus, which

Involvement of the Amygdala in Two Different Forms of the Inhibitory Avoidance Task

The amygdala has been implicated in either mediating or modulating affective memory formation. To evaluate these two views, female Long-Evan rats received lesions of the amygdala central nucleus (CEA) or basolateral complex (BLC) and were trained on the step-through and step-down inhibitory avoidance tasks. Both responses learned under an inescapable procedure were impaired by CEA or BLC lesions, whereas those learned under an escapable procedure were impaired only by BLC lesions, suggesting that learning the two different tasks relied on the same amygdala circuit, but deploying different coping strategies engaged different circuits. To further address the issue, CEA and BLC ensemble activities were recorded in retention tests of an escapable step-down task and an inescapable step-through task. For both tasks, repeated exposure to a training apparatus caused habituation of neuronal firing, and training led to increased firing activities in both the CEA and BLC. Some neurons were highly reactive in one task, and others highly reactive in both. These data suggest that CEA and BLC neurons may be involved in processing both specific and general information inherent in inhibitory avoidance tasks and that the amygdala may play both modulating and mediating roles for different aspects of affective memory.