Anxiety disorders are frequently long-lasting and debilitating for more than 40 million American adults. Although stressor exposure plays an important role in the etiology of some anxiety disorders, the mechanisms by which exposure to stressful stimuli alters central circuits that mediate anxietylike emotional behavior are still unknown. Substantial evidence has implicated regions of the central extended amygdala, including the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA) as critical structures mediating fear-and anxiety-like behavior in both humans and animals. These areas organize coordinated fear-and anxiety-like behavioral responses as well as peripheral stress responding to threats via direct and indirect projections to the paraventricular nucleus of the hypothalamus (PVN) and brainstem regions (Walker et al., 2003;Ulrich-Lai and Herman, 2009;Walker et al., 2009). In particular, the BNST has been argued to mediate these central and peripheral responses when the perceived threat is of long duration (Waddell et al., 2006) and/or when the anxiety-like response is sustained (Walker and Davis, 2008); hence, the BNST may mediate pathological anxiety-like states that result from exposure to chronic stress. Indeed, chronic stress paradigms result in enhanced BNST neuroplasticity that has been associated with pathological anxiety-like states (Vyas et al., 2003;Pego et al., 2008). Here we review evidence that suggests that pituitary adenylate cyclase activating polypeptide (PACAP) and corticotropin-releasing hormone (CRH) work together to modulate BNST function and increase anxiety-like behavior. Moreover, we have shown that BNST PACAP as well as its cognate PAC1 receptor are substantially upregulated following chronic stress, particularly in the BNST oval nucleus where PACAP-containing neurons closely interact with CRH-containing neurons (Kozicz et al., 1997;Hammack et al., 2009). We describe how interactions between PACAP and CRH in the BNST may mediate stress-associated behaviors, including anorexia and anxiety-like behavior. These studies have the potential to define specific mechanisms underlying anxiety disorders, and may provide important therapeutic strategies for stress-and anxiety-management.

Stress is a precipitating factor for anxiety-related disorders, which are among the leading forms of psychiatric illness and impairment in the modern world. Rodent-based behavioral tests and models are widely used to understand the mechanisms by which stress triggers anxiety-related behaviors and to identify new treatments for anxiety-related disorders. Although substantial progress has been made and many of the key neural circuits and molecular pathways mediating stress responsiveness have been characterized, these advances have thus far failed to translate into fundamentally new treatments that are safer and more efficacious in humans. The purpose of this article is to describe methods that have been historically used for this type of research and to highlight new approaches that align with recent conceptualizations of disease symptomatology and that may ultimately prove to be more fruitful in facilitating the development of improved therapeutics.

Exposure to traumatic events can increase the risk for major depressive disorder (MDD) as well as posttraumatic stress disorder (PTSD), and pharmacological treatments for these disorders often involve the modulation of serotonergic (5-HT) systems. Several behavioral paradigms in rodents produce changes in behavior that resemble symptoms of MDD and these behavioral changes are sensitive to antidepressant treatments. Here we review two animal models in which MDD-like behavioral changes are elicited by exposure to an acute traumatic event during adulthood, learned helplessness (LH) and conditioned defeat. In LH, exposure of rats to inescapable, but not escapable, tailshock produces a constellation of behavioral changes that include deficits in fight/flight responding and enhanced anxiety-like behavior. In conditioned defeat, exposure of Syrian hamsters to a social defeat by a more aggressive animal leads to a loss of territorial aggression and an increase in submissive and defensive behaviors in subsequent encounters with non-aggressive conspecifics. Investigations into the neural substrates that control LH and conditioned defeat revealed that increased 5-HT activity in the dorsal raphe nucleus (DRN) is critical for both models. Other key brain regions that regulate the acquisition and/or expression of behavior in these two paradigms include the basolateral amygdala (BLA), central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). In this review, we compare and contrast the role of each of these neural structures in mediating LH and conditioned defeat, and discuss the relevance of these data in developing a better understanding of the mechanisms underlying trauma-related depression.

Recent gene association studies have implicated pituitary adenylate cyclase-activating peptide (PACAP) systems in several psychiatric disorders associated with stressor exposure, and we have argued that many of the behavioral consequences of repeated stressor exposure may depend on the expression of PACAP in the bed nucleus of the stria terminalis (BNST). One behavioral consequence of the activation of stress systems can be anorexia and subsequent weight loss, and both the activation of central PACAP systems as well as neuronal activity in the BNST have also been associated with anorexic states in rodents. Hence, we investigated the regulation of food and water intake and weight loss following BNST PACAP infusion. BNST PACAP38 dose-dependently decreased body weight, as well as food and water intake in the first 24 h following infusion. Because different BNST subregions differentially regulate stress responding, we further examined the effects of PACAP38 in either the anterior or posterior BNST. Anterior BNST PACAP38 infusion did not alter weight gain, whereas posterior PACAP38 infusion resulted in weight loss. PACAP38 infused into the lateral ventricles did not alter weight, suggesting that the effects of BNST-infused PACAP were not mediated by leakage into the ventricular system. These data suggest that PACAP receptor activation in posterior BNST subregions can produce anorexia and weight loss, and corroborate growing data implicating central PACAP activation in mediating the consequences of stressor exposure.