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.aversive learning ͉ context ͉ fear conditioning ͉ memory retrieval ͉ stress T raumatic events such as military combat, motor vehicle accidents, or sexual assault can lead to debilitating psychological disturbances, including posttraumatic stress disorder (PTSD) (1). Although PTSD is estimated to develop in Ͻ10% of individuals experiencing trauma in the general population (2), it presents at significantly higher rates in individuals exposed to extremely traumatic events (such as combat). For example, rates of PTSD as high as 17% have been reported in military personnel 3-4 months after returning from combat (3). It is not surprising then that traumatic events exact an incredible toll on mental health, affecting millions of people worldwide (1-3).Because of the staggering costs and consequences of PTSD and other anxiety disorders, clinical interventions to reduce the long-term consequences of psychological trauma are essential. As a first line of defense against the development of mental illness in the aftermath of a traumatic event, it has been argued that early interventions (such as psychological debriefing) are critical to manage the stress response to trauma (4, 5). In a typical debriefing session, victims of a traumatic event are encouraged to talk about their experience in a supportive group setting, which presumably facilitates psychological recovery from the trauma. Although early intervention is intuitively reasonable, considerable work has challenged the efficacy of debriefing in curbing the development of PTSD after trauma (for review, see ref. 6). Moreover, little work has systematically examined whether early interventions, whatever form they take, are more effective than delayed interventions in reducing the incidence of psychopathology after tra...

Background Major depressive disorder (MDD) affects more than 15% of the population across their lifespan. In this study, we used the well-characterized unpredictable chronic mild stress (CMS) model of depression to examine this condition. Methods Sprague-Dawley rats were presented randomly with mild stressors for four weeks, with body weight and sucrose intake monitored weekly. Locomotor activity and elevated plus maze test/forced swim test were conducted on week 5; ventral tegmental area (VTA) dopamine (DA) neuron activity was assessed within a week after the behavioral test using three indices: DA neuron population activity (defined as the number of spontaneously firing DA neurons), mean firing rate, and percent burst firing (i.e., the proportion of action potentials occurring in bursts). Results Consistent with previous studies, we found that, compared to controls, rats that underwent the CMS procedure were slower in gaining body weight, and developed anxiety- and despair-like behavior. We now report a significant decrease in DA neuron population activity of CMS rats, and this decrease is restored by pharmacologically attenuating the activity of either the basolateral nucleus of the amygdala (BLA), or the ventral pallidum (VP). Moreover, pharmacological activation of the amygdala in non-stressed rats decreases DA neuron population activity similar to that with CMS, which is reversed by blocking the BLA-VP pathway. Conclusions The CMS rat depression model is associated with a BLA-VP-VTA inhibition of DA neuron activity. This information can provide insight into the circuitry underlying MDD and serve as a template for refining therapeutic approaches to this disorder.

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.

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. Pavlovian fear conditioning and extinction are important behav-ioral models for studying the brain mechanisms underlying the acquisition, storage, retrieval, and suppression of traumatic fear (LeDoux 2000; Maren 2001, 2005; Kim and Jung 2005). In this procedure, an emotionally neutral stimulus, such as a tone, is paired with an aversive stimulus (US), such as an electric foot shock. After a few tone-foot shock pairings, the previous neutral tone becomes a potent conditioned stimulus (CS) and acquires the ability to elicit fear responses, such as freezing (CR). However, with repeated presentations of the CS-alone, the previously acquired CR gradually subsides, a process called extinction (Davis et al. 2003; Maren and Quirk 2004; Kim and Jung 2005; Myers and Davis 2007). The behavioral processes and the underlying neural mechanisms of extinction have attracted extensive attention in contemporary research of learning and memory (Bouton et al. 2006). Indeed, it has been suggested that failure to extinguish fear may contribute to post-traumatic stress disorder (PTSD) (Bouton et al. 2001; Rothbaum and Davis 2003). To avoid the possible long-term consequences and costs of PTSD or other anxiety disorders, clinical interventions are essential. While early interventions may manage the stress response to trauma, their efficacy has been challenged, because the acute intense stress of the traumatic experience might actually exacerbate relapse of fear (McNally 2003; Rothbaum and Davis 2003; Gray and Litz 2005). Thus, it is essential to learn when these interventions generate the best long-term extinction of fear responses. In a recent study, we demonstrated that delivering extincti...