Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like responses

Abstract

The medial division of the central nucleus of the amygdala (CeA M ) and the lateral division of the bed nucleus of the stria terminalis (BNST L ) are closely related. Both receive projections from the basolateral amygdala (BLA) and both project to brain areas that mediate fear-influenced behaviors. In contrast to CeA M however, initial attempts to implicate the BNST in conditioned fear responses were largely unsuccessful. More recent studies have shown that the BNST does participate in some types of anxiety and stress responses. Here, we review evidence suggesting that the CeA M and BNST L are functionally complementary, with CeA M mediating short-but not long-duration threat responses (i.e., phasic fear) and BNST L mediating long-but not short-duration responses (sustained fear or 'anxiety'). We also review findings implicating the stress-related peptide corticotropin-releasing factor (CRF) in sustained but not phasic threat responses, and attempt to integrate these findings into a neural circuit model which accounts for these and related observations. Keywords anxiety; startle; amygdala; bed nucleus of the stria terminalis; corticotropin releasing factor A now-familiar and widely-adopted neural circuit model of fear places the amygdala in center stage and assigns different functions to different amygdala subdivisions (Fig. 1). Thus, the basolateral group (BLA) screens incoming sensory information for threat cues and, if such cues are detected, passes this information on to the central nucleus of the amygdala's medial subdivision (CeA M ), which mediates threat responses by way of its many projections to areas that mediate specific fear-influenced behaviors (c.f., Davis, 1992;Fanselow and LeDoux, 1999;Maren, 2001;Pare et al., 2004).In the following pages, we review evidence suggesting that this model is incomplete, and should be expanded to include the bed nucleus of the stria terminalis (specifically, it's lateral subdivision -BNST L ). In fact, by many criteria, the CeA and BNST are closely related (Alheid © 2009 Elsevier Inc. All rights reserved.Correspondence should be addressed to: David L. Walker, Emory University School of Medicine, 954 Gatewood Road NE, Yerkes Neurosci Bldg -Rm 5214, Atlanta, GA 30329, Ph: (404) Fax: (404) 727-8070, dlwalke@emory.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptProg Neuropsychopharmacol Biol Psychiatry. Author manuscript; available in PMC 2010 November 13. Published in final edited form as:Prog Neuropsychopharmacol Biol Psychiatry. Alheid and Heimer, 1988;Johnston, 1923). Of par...

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing

“…In contrast, anxious apprehension can be associated with defensive behaviors during the exposure to less specific and less predictable threats (sustained fear/anxiety). Animal models that are differentiating phasic and sustained fear 63 suggest that corticotropin-releasing factor CRF might be involved only in the latter, mainly by acting on the bed nucleus of the stria terminalis (BNST), the core brain region in mediating sustained fear (for reviews see [63][64][65] ). There is evidence that CRH-dependent BNST activation during anxiety states is mediated by CRHR1 activation.…”

“…There is evidence that CRH-dependent BNST activation during anxiety states is mediated by CRHR1 activation. For example, in rats, administration of a Crhr1-specific antagonist blocked defensive behaviors during laboratory models of sustained, but not phasic fear 65 .…”

Phasic and Sustained Fear are Pharmacologically Dissociable in Rats

“…The search for such compounds (ie, drugs that reduce sustained startle increases) may be aided by evidence that sustained fear, including fear responses to static contexts, is especially dependent on the BNST (eg, Walker and Davis, 1997b;Hammack et al, 2004;Sullivan et al, 2004;Waddell et al, 2006), whereas phasic fear responses are more dependent on the medial division of the CeA (cf, Walker et al, 2009b). Evidence supporting this view is derived primarily from lesion and inactivation studies, but is consistent with the results of unit recording and imaging studies in rats (Quirk et al, 1995) and human beings (Phelps et al, 2001), which have indicated only a transient activation of the amygdala by threat stimuli, but perhaps a more sustained activation of the BNST, the latter which may be exaggerated in subjects with high trait anxiety (Somerville et al, 2010).…”

Cannabidiol as a Potential Treatment for Anxiety Disorders

“…Microinjection of CBD into the DPAG produced anxiolytic effects in the EPM, VGC, and ETM that were partially mediated by activation of 5-HT 1A Rs but not by CB 1 Rs [65,68]. The bed nucleus of the stria terminalis (BNST) serves as a principal output structure of the amygdaloid complex to coordinate sustained fear responses, relevant to anxiety [93]. Anxiolytic effects of CBD in the EPM and VCT occurred upon microinjection into the BNST, where they depended on 5-HT 1A R activation [79], and also upon microinjection into the central nucleus of the amygdala [78].…”