Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety
Introduction
The last several decades have seen enormous growth in our understanding of the neurobiological basis of fear. Much of this understanding is based on results from animal studies in which the ability of experimental manipulations (e.g., a brain lesion or drug injection) to modify an animal's response to conditioned fear stimuli (e.g., stimuli that predict shock) is evaluated. Because anxiety disorders may reflect dysregulation in the neural fear systems engaged by these tasks, it is hoped that the results from these studies will advance an understanding of clinical anxiety and will help guide the development of biologically based therapies for their treatment.
Results from these studies have identified the basolateral amygdala (defined here as the amygdala subdivision consisting of the lateral, basolateral, and basomedial amygdala nuclei) as a key player in fear and fear-learning. For example, lesions and pre-test infusions into the basolateral amygdala of compounds that disrupt basolateral amygdala function dramatically reduce, and in many cases abolish altogether, behavioral and autonomic responses to conditioned fear stimuli (cf., Davis, 2000, Fendt and Fanselow, 1999, LeDoux, 2000). Identification of the basolateral amygdala's crucial role in fear-related behaviors has provided a starting point for delineating more completely the neural circuitry that regulates fear and anxiety. Immediately downstream from the basolateral amygdala are two structures of particular interest—the central nucleus of the amygdala and the bed nucleus of the stria terminalis (see Fig. 1). These structures are interesting because they project, in turn, to a common set of target areas—areas that are thought, individually, to mediate the specific signs and symptoms of fear and to act collectively to produce an integrated fear response. This arrangement is depicted schematically in Fig. 2.
In the following sections, we will focus on the role of the bed nucleus of the stria terminalis. Because the bed nucleus of the stria terminalis and central nucleus of the amygdala are anatomically, neurochemically, cytoarchitectonically, and embryologically related (cf., Alheid et al., 1995), we will highlight, wherever possible, the functional similarities and differences between these two structures as suggested by various experimental outcomes, and will attempt to integrate these data into a coherent theory of bed nucleus of the stria terminalis versus central nucleus of the amygdala function as it relates to fear, stress, and anxiety.
Section snippets
Acute fear responses to shock-predicting stimuli (fear-potentiated startle and freezing)
In our laboratory, fear is studied using the potentiated startle paradigm. In this procedure, initially developed by Brown et al. (1951), rats receive pairings of an initially neutral, soon-to-be conditioned stimulus (CS—e.g., a tone or light) and an aversive unconditioned stimulus (US—in almost all cases a footshock). Rats are later tested for fear to the CS by presenting them with a series of startle-eliciting noise bursts. Some of these noise bursts are presented in the presence of the
CRH-enhanced startle
In 1986, Swerdlow et al. reported that infusions of corticotropin releasing hormone (CRH) into the lateral cerebral ventricle markedly increased the amplitude of the acoustic startle response in rats. Consistent with the view that these increases reflected anxiety, the benzodiazepine anxiolytic, chlordiazepoxide, reduced startle amplitude in CRH-treated rats but not in rats whose startle amplitude had been increased by the non-anxiogenic agents strychnine and amphetamine.
CRH-enhanced startle
Light-enhanced startle
In 1997, Walker and Davis described a new animal model of anxiety termed light-enhanced startle (Walker and Davis, 1997a). In this paradigm, startle amplitude is measured during two consecutive test phases, each lasting 20 min. During the first phase, rats are tested in the dark. During the second phase, rats are tested again in the dark or, alternatively, in the presence of bright light. Startle amplitude increases from phase I to phase II during dark→light test sessions but not during
Long-term sensitization of the acoustic startle response by repeated footshock
In the fear-potentiated startle experiments described earlier, rats were tested at the completion of fear conditioning, typically after 20 CS-shock pairings. In these experiments, pre-test manipulations of the bed nucleus of the stria terminalis (i.e., lesions or NBQX infusions) did not disrupt fear-potentiated startle. It is possible, however, that an involvement of the bed nucleus of the stria terminalis in fear-potentiated startle might be evident earlier in training, when conditioned fear
What does the bed nucleus of the stria terminalis do? A provisional hypothesis based on results from fear conditioning and acoustic startle studies
Is there a common element to the paradigms in which bed nucleus of the stria terminalis manipulations interfere with behavior? An early hypothesis was that the bed nucleus of the stria terminalis mediates unconditioned fear responses, whereas the central nucleus of the amygdala mediates conditioned fear responses (Walker and Davis, 1997b). The hypothesis recently received additional support from Fendt et al. (2002) who examined unconditioned freezing responses to an 11-min presentation of the
Further evidence for the independence of anxiety (bed nucleus of the stria terminalis) and fear (central nucleus of the amygdala) systems
The view that fear and anxiety are mediated by independent systems is also supported by recent findings in which we evaluated the effect on startle of separate or combined presentations of stimuli whose influence on startle is mediated via either the central nucleus of the amygdala or bed nucleus of the stria terminalis (Walker and Davis, 2002b). In one experiment, the potentiating effect on startle of two different conditioned fear stimuli (i.e., a light and a tone) were evaluated (two central
Withdrawal
Based on evidence that (a) opiate withdrawal is associated with large increases in noradrenergic activity, (b) these increases play a role in the somatic and behavioral consequences of opiate withdrawal (cf., Maldonado, 1997), and (c) the bed nucleus of the stria terminalis receives an extremely rich input of noradrenergic fibers Brownstein et al., 1974, Kilts and Anderson, 1986, Aston-Jones et al. (1999) and Delfs et al. (2000) evaluated the role of noradrenergic innervation of the bed nucleus
Conditioned defeat
When a Syrian hamster is introduced into the home cage of a smaller Syrian hamster, agonistic encounters ensue in which the smaller hamster is typically defeated by the larger hamster (Potegal et al., 1993). Once defeated, hamsters will no longer defend their home cage, even when confronted with a smaller intruder that would not normally defeat the resident (Potegal et al., 1993). Overexpression within the basolateral amygdala of cAMP-response element binding protein (CREB) enhances the
Bed nucleus of the stria terminalis mediation of panic and other anxiety behaviors
Rats that receive chronic infusions into the dorsomedial hypothalamus of the GABA synthesis inhibitor, l-allylglycine, show behavioral (in the elevated plus-maze and social interaction paradigms) and autonomic (heart rate, respiratory rate, and blood pressure) responses to peripheral lactate infusions Shekhar and Keim, 2000, Shekhar et al., 1996 that are indicative of anxiety and that are not observed in untreated controls (i.e., rats without disinhibition of the dorsomedial hypothalamus). Rats
Sexual dimorphism in the bed nucleus of the stria terminalis
The bed nucleus of the stria terminalis is volumetrically and neurochemically sexually dimorphic. Several studies have demonstrated gender-related volumetric differences in bed nucleus of the stria terminalis subregions of both rats (Hines et al., 1992) and humans Allen and Gorski, 1990, Chung et al., 2002. Neurochemical differences have also been reported (cf., De Vries and Miller, 1998, Koolhaas et al., 1998, Stefanova and Ovtscharoff, 2000)—being particularly well documented with respect to
Conclusion
An involvement of the bed nucleus of the stria terminalis is evident in paradigms in which behavior is influenced by long-duration stimuli (e.g., CRH- or light-enhanced startle) and in paradigms that assess the persistent behavioral effects of even a brief stressor (e.g., long-term shock-dependent increases in baseline startle, conditioned defeat, the effects of inescapable shock in the learned helplessness model or on subsequent eyeblink conditioning). Despite behavioral outcomes that are
Acknowledgements
The authors research has been supported by National Institute of Mental Health Grants MH 47840, MH 57250, MH 58922, MH 52384, MH 59906, the Woodruff Foundation, the STC Program (The Center For Behavioral Neuroscience) of the National Science Foundation under Agreement No. IBN-9876754, and a Pfizer Postdoctoral Fellowship Award (KJR).
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