Table 1.
This table summarizes the results of those studies that have directly compared (i.e., within the same study) the effect of (A) CRF receptor antagonists, (B) BNST inactivation, or (C) CeA inactivation on phasic versus sustained duration fear responses. Direct comparisons between the effects of different manipulations on the same response – either (D) phasic or (E) sustained are also shown. In some (shaded cells) but not all cases, these alternate comparisons are made using data which appear earlier in the table.
The comparisons consistently show that CRF receptor antagonists and BNST manipulations disrupt sustained but not phasic fear, whereas CeA manipulations often have the opposite effect. Interpretation of the effect of CeA manipulations is complicated by several factors. First, electrolytic CeA lesions would most likely transect BLA-to-BNST projections such that disruptive effects on sustained fear would be predicted based on the hypothesis outlined in this chapter. Second, sustained startle increases produced by CRF administration are thought to act directly on BNST neurons (with no involvement of the CeA) whereas sustained fear responses produced by environmental stimuli may involve release into the BNST of CRF from CeAL terminals. Thus, even though CRF- and sustained threat-induced startle increases are both of long duration, a differential involvement of the CeA is predicted due to the different origin of CRF in these paradigms. Third, studies showing that AMPA receptor antagonist infusions into the CeA do not disrupt sustained fear should be interpreted with caution insofar as sustained threat signals may activate relevant CeA neurons (i.e., those in the lateral subdivision) through non-AMPA (e.g., peptide) receptors. Even with these caveats however, the data are fairly consistent in suggesting a special role for the CRF and the BNST in sustained fear, and a negligible or at least different role for the CeA in phasic fear.
| A. Effect of CRF receptor antagonists on Short- vs. Long-Duration Fear Response | ||
|---|---|---|
| Study and Treatment | Effect on Phasic Fear | Effect on Sustained Fear |
| Walker et al. (2008) | FPS to 3.7-sec visual CS not disrupted | Light-Enhanced Startle (20 min exposure |
| to bright light) non-monotonically | ||
| Oral administration of the | blocked | |
| CRF-R1 antagonist | ||
| GSK876008 | Startle increases evoked by sustained | |
| exposure to shock-paired context non- | ||
| monotonically blocked | ||
| De Jongh et al. (2006) | FPS to 3.7-sec visual CS not disrupted | Light-Enhanced Startle (20 min exposure |
| to bright light) non-monotonically | ||
| i.c.v. infusion of the non | disrupted | |
| selective CRF antagonist | ||
| α-helical CRF | ||
| Walker, Miles, and Davis | FPS to 3.7-sec clicker CS not | FPS to 8-min clicker CS blocked |
| (unpublished) | disrupted | |
| FPS to 8-min filtered noise CS blocked | ||
| Oral administration of the | FPS to 3.7-sec filtered noise CS not | |
| CRF-R1 antagonist | disrupted | |
| GSK876008 | ||
| B. Effect of BNST Disruption on Short- vs. Long-Duration Fear Response | ||
|---|---|---|
| Study and Treatment | Effect on Phasic Fear | Effect on Sustained Fear |
| Gewirtz et al. (1998) | FPS to 3.7-sec visual CS not disrupted | Long-lasting sensitization of startle by |
| repeated footshocks across multiple days | ||
| Electrolytic lesion | blocked | |
| Lee and Davis (1997) | FPS to 3.7-sec visual CS not disrupted | CRF-enhanced startle blocked |
| Excitotoxic lesion | ||
| Waddell et al. (2006) | Conditioned Suppression to 60-sec CS | Conditioned Suppression to 10-min CS |
| not disrupted | blocked | |
| Excitotoxic lesion | ||
| Sullivan et al. (2004) | Freezing to 20-sec CS not blocked | Freezing to context CS blocked |
| Corticosterone response to 20-sec CS | Corticosterone response to context CS | |
| Electrolytic lesions | not disrupted | blocked |
| Walker and Davis (1997b) | Light-enhanced startle (20 min | Light-enhanced startle (20 min stimulus |
| stimulus duration) not disrupted | duration) disrupted (AMPAr antagonist | |
| AMPA receptor antagonist | (AMPAr antagonist infusion) | infusion) |
| infusion | ||
| C. Effect of CeA Disruption on Short- vs. Long-Duration Fear Response | ||
|---|---|---|
| Study and Treatment | Effect on Phasic Fear | Effect on Sustained Fear |
| Lee and Davis (1997) | FPS to 3.7-sec visual CS blocked | CRF-enhanced startle not disrupted |
| (excitotoxic lesion) | (excitotoxic lesion) | |
| Excitotoxic lesion | ||
| Sullivan et al. (2004) | Freezing to 20-sec CS blocked |
Freezing to context CS blocked |
| Electrolytic lesions | Corticosterone response to 20-sec CS | Corticosterone response to context CS |
| blocked | blocked | |
| Walker and Davis (1997b) | FPS to 3.7-sec visual CS blocked | Light-enhanced startle (20 min stimulus |
| duration) not disrupted | ||
| AMPA receptor antagonist | ||
| infusions | ||
| D. Effect on Phasic Fear Responses of CeA vs BNST Manipulations | ||
|---|---|---|
| Study and Treatment | Study and Treatment | Effect of BNST Manipulations |
| Hitchcock and Davis (1991) | FPS to 3.7-sec visual CS blocked | FPS to 3.7-sec visual CS not disrupted |
| Electrolytic (For CeA, | ||
| unilateral combined with | ||
| contralateral transection of | ||
| ventro-amygdalafugal | ||
| pathway; for BNST, | ||
| bilateral) | ||
| Lee and Davis (1997) | FPS to 3.7-sec visual CS blocked | FPS to 3.7-sec visual CS not disrupted |
| Excitotoxic lesion | ||
| Sullivan et al. (2004) | Freezing to 20-sec tone CS blocked | Freezing to 20-sec CS not disrupted |
| Electrolytic lesions | Corticosterone response to context CS | Corticosterone response to 20-sec CS |
| blocked | not disrupted | |
| Walker and Davis (1997b) | FPS to 3.7-sec visual CS blocked | FPS to 3.7-sec visual CS blocked |
| AMPA receptor antagonist | ||
| infusions | ||
| E. Effect on Sustained Fear Responses of CeA vs BNST Manipulations | ||
|---|---|---|
| Study and Treatment | Effect of CeA Manipulations | Effect of CeA Manipulations |
| Lee and Davis (1997) | CRF-enhanced startle not disrupted | CRF-enhanced startle disrupted |
| Excitotoxic lesion | ||
| Sullivan et al. (2004) | Freezing to context CS blocked | Freezing to context CS blocked |
| Electrolytic lesions | Corticosterone response to context CS | Corticosterone response to context CS |
| blocked | blocked | |
| Walker and Davis (1997b) | Light-enhanced startle (20 min | Light-enhanced startle (20 min stimulus |
| stimulus duration) not disrupted | duration) blocked | |
| AMPA receptor antagonist | ||
| infusions | ||
| Walker and Davis | FPS to 8-min filtered-noise CS not | FPS to 8-min filtered-noise enhanced |
| (unpublished observations) | disrupted | during 1st half of CS and blocked |
| during 2nd half minutes | ||
| AMPA receptor antagonist | ||
| infusions | ||