Progress in Neuro-Psychopharmacology and Biological Psychiatry
Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like responses
Section snippets
CRF-enhanced versus fear-potentiated startle
In 1986, Swerdlow et al. (1986) reported that CRF infusions into the lateral cerebral ventricle markedly increased startle amplitude in rats and that these increases were prevented by pretreatment with the anxiolytic compound chlordiazepoxide. This “CRF-enhanced startle” effect was later replicated in our own laboratory by Liang et al. (1992b) who reported large dose-dependent startle increases that began approximately 30 min after the infusion had ended and which grew steadily over the course
Light-enhanced versus fear-potentiated startle
During the same time that the BNST's involvement in CRF-enhanced startle was being characterized, we were also evaluating the effect on startle of testing rats in illuminated versus darkened test cages. We found that rats tested in illuminated test cages show higher-amplitude startle responses than rats tested in the dark (Walker and Davis, 1997a) and that this effect was disrupted by several anxiolytic compounds (Walker and Davis, 1997a, Walker and Davis, 2002a; and see also de Jongh et al.,
CRF mediation of BNST-dependent light-enhanced startle but not CeA-dependent fear-potentiated startle
The involvement of the BNST in both CRF- and light-enhanced, but not fear-potentiated startle, suggests that light-enhanced startle, and perhaps BNST-dependent responses more generally, might be especially sensitive to CRF receptor blockade. Indeed, de Jongh et al. (2003) reported that i.c.v. infusions of the CRF-R1/2 antagonist αhCRF had no effect on fear-potentiated startle to a 3.7-s light, but non-monotonically disrupted light-enhanced startle, significantly disrupting it at an intermediate
Two hypotheses for the differential involvement of the BNST and CeA in fear-potentiated versus CRF- and light-enhanced startle
Given the many similarities between fear-potentiated and light-enhanced startle – i.e., both use increased startle as a behavioral measure and light as a stimulus to produce this effect – their differential susceptibility to CeA versus BNST inactivation and to CRF-R1 blockade is perhaps surprising. These similarities are also quite useful however in that they greatly constrain the range of possible interpretations for the dissociations just noted. We previously suggested that there are two
Preferential involvement of CRF in sustained versus phasic threat responses
As noted above, we believe that CRF receptors participate preferentially in BNST as opposed to CeA-dependent responses. As such, we have also compared the effect of CRF-R1 blockade (oral administration) on short- versus long-duration startle increases to conditioned fear stimuli. Data are shown for two experiments, one comparing the effect of the selective CRF-R1 antagonist GSK876008 on startle increases to a short (3.7 s) versus long-duration (8 min) low-frequency-filtered 72-dB white-noise CS
CeA influences on BNSTL function: a special role for CeAL?
A possible role for CeAL in sustained fear was briefly alluded to in the preceding section and will be discussed in more detail here. In fact, the lateral subdivision of the CeA is distinct from the medial subdivision in a number of key respects, including cell morphology (McDonald, 1982), neurochemical content (Cassell et al., 1986, Sun and Cassell, 1993, Wray and Hoffman, 1983), and intrinsic (c.f., Jolkkonen and Pitkanen, 1998) as well as extrinsic connectivity (c.f., Pitkanen, 2000, Sah et
Results from behavioral occlusion studies support the view that phasic and sustained startle increases are mediated by independent systems
The findings reviewed above, obtained primarily from lesion and inactivation studies, strongly suggest that phasic and sustained startle increases, and perhaps phasic and sustained threat responses more generally, are mediated by different neural systems. Although the results from lesion and inactivation studies have contributed greatly to our current understanding of brain–behavior relationships, they can also lead to false conclusions when taken in isolation (e.g., due to distant or
Findings from context conditioning studies also implicate the BNST and CRF in sustained but not short-duration threat responses
Because context is also a long-duration stimulus, which evokes long-duration responses, we would expect that those responses would be similarly vulnerable to BNST lesions/inactivation and to CRF receptor blockade. In fact, Gray et al. (1993) found many years ago that pre-training excitotoxic BNST lesions disrupt ACTH and corticosterone responses to a shock-paired context. This was later replicated by Sullivan et al. (2004) who reported that post-training electrolytic BNST lesions also disrupted
BNST involvement in shock-dependent non-associative startle increases
To evaluate the possibility that a partial contribution of the BNST to phasic fear had been missed in earlier experiments due to ceiling effects, Gewirtz et al. (1998) trained and tested sham- and BNST-lesioned rats using a slow-acquisition repeated-test procedure which allowed for an evaluation of lesion effects over the entire course of conditioning (i.e., on weak fear responses which appear early in conditioning as well as stronger responses which occur later). On each of 20 days, rats
A specific neural circuit for sustained fear
The results reviewed above suggest to us a particular relationship between the BLA and the BNSTL, and a particular role for CRF (see Fig. 15). Particularly influential to our thinking are results from an unpublished experiment in which we found that bilateral intra-BLA infusions of an NBQX/muscimol (3 μg/0.1 μg) cocktail completely blocked CRF (1 μg, i.c.v.) — enhanced startle (Fig. 16). As noted earlier, CRF does not increase startle when infused into the BLA (Liang et al., 1992a), so we do
Does BNST plasticity mediate stress-induced anxiety?
As discussed earlier, the standard model of fear conditioning suggests that conditioning-related plasticity occurs in the BLA, and that the CeA serves as a more-or-less passive relay to various other brain areas that mediate the specific signs and symptoms of fear. A revisionist view suggests that the CeA may play a more active role, perhaps being a site of plasticity itself (c.f., Pare et al., 2004). Consistent with this latter view is the finding that intra-CeA infusions of the protein
Direct evidence of stress-related plasticity in the BNST
The behavioral results reviewed above provide direct evidence for a critical involvement of the BNST in stress-induced plasticity, but only indirect evidence that such plasticity occurs in the BNST itself. Clearly however, the BNST is capable of such plasticity. In one of the first such demonstrations, Vyas et al. (2003) showed that chronic restraint stress (2-h day/10 days) led to significant changes in dendritic morphology in the BNST, with increases being observed for the number of dendritic
Summary, conclusions, and possible clinical relevance
A few short years ago, it was possible to author a review on the BNST's involvement in stress and anxiety that was both comprehensive and concise. That this has become increasingly difficult is testimony to the ever-growing body of relevant findings and interest in this area. We have focused here on those findings most directly relevant to our hypothesis that the BNST plays a special role in longer-duration, sustained, anxiety-like responses and CeAM in shorter-duration fear responses. As the
Disclosures
Dr. Walker and Ms. Miles have no financial relationships to disclose. During the last three years Dr. Davis received research support from Astra-Zeneca Pharmaceuticals to study compounds on sustained fear. Dr. Davis also received honoraria from Astra-Zeneca Pharmaceuticals, Lundbeck Research, and Sepracor, Inc. for lectures related to phasic and sustained fear-potentiated startle.
Acknowledgements
This research was supported by NIMH grants MH069056, MH47840, MH57250, and MH59906 (MD), the Science and Technology Center (The Center for Behavioral Neuroscience of the National Science Foundation under Agreement No. IBN-9876754), a NARSAD Young Investigator award (DLW), and The American Psychological Association Diversity Program in Neuroscience Predoctoral Fellowship 5T32 MH18882 (LM). None of the authors have competing interests related to the research described herein. Principles of
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