Role of the Hippocampus, the Bed Nucleus of the Stria Terminalis, and the Amygdala in the Excitatory Effect of Corticotropin-Releasing Hormone on the Acoustic Startle Reflex

Abstract

Previously, we demonstrated that transection of the fimbria/ fornix blocked the excitatory effect of corticotropin-releasing hormone (CRH) on startle (CRH-enhanced startle), suggesting that the hippocampus and its efferent target areas that communicate via the fimbria may be critically involved in CRHenhanced startle. The bed nucleus of the stria terminalis (BNST) receives direct projections from the ventral hippocampus via the fimbria/fornix. Therefore, the role of the ventral hippocampus, the BNST, and the amygdala in CRH-enhanced startle was investigated. NMDA lesions of the BNST completely blocked CRH-enhanced startle, whereas chemical lesions of the ventral hippocampus and the amygdala failed to block CRH-enhanced startle. However, the same amygdala-lesioned animals showed a complete blockade of fear-potentiated startle, a conditioned fear response sensitive to manipulations of the amygdala. In contrast, BNST-lesioned rats had normal fear-potentiated startle. This indicates a double dissociation between the BNST and the amygdala in two different paradigms that enhance startle amplitude. Microinfusions of CRH into the BNST, but not into the ventral hippocampus, mimicked intracerebroventricular CRH effects. Furthermore, infusion of a CRH antagonist into the BNST blocked CRH-enhanced startle in a dose-dependent manner. Control studies showed that this blockade did not result from either leakage of the antagonist into the ventricular system or a local anesthetic effect caused by infusion of the antagonist into the BNST. The present studies strongly suggest that CRH in the CSF can activate the BNST, which could lead to activation of brainstem and hypothalamic BNST target areas involved in anxiety and stress responses. Key words: bed nucleus of the stria terminalis (BNST ); amygdala; hippocampus; corticotropin-releasing hormone (CRH); startle; anxiety; fearIntracerebroventricular inf usion of corticotropin-releasing hormone (CRH) elicits a constellation of behavioral, physiological, and endocrinological changes similar to those produced by natural stressors (cf. Dunn and Berridge, 1990). Thus far, however, the exact anatomical sites responsible for these behavioral and physiological actions of CRH after intracerebroventricular administration have not been identified. As part of an effort to delineate the neural circuitry underlying intracerebroventricular CRH effects, recently we investigated a possible involvement of the septum, using increased acoustic startle amplitude after CRH (CRH-enhanced startle) as a behavioral measure (Lee and Davis, 1997). Electrolytic lesions of the whole septum and the medial septum, but not the lateral septum, blocked CRH-enhanced startle. However, fiber-sparing chemical lesions of the medial septum failed to block CRH-enhanced startle, suggesting that the blockade seen with electrolytic lesions was probably caused by damage to fibers of passage, presumably the fornix. Supporting this conclusion, f unctional lesions of the fornix induced by knife cuts of the fimbria /fornix complete...

Models and mechanisms of anxiety: evidence from startle studies

“…Chemical lesions of the BNST, but not lesions of the amygdala or of the ventral hippocampus, prevent CRH-enhanced startle (Lee and Davis 1997). Infusion of CRH in the BNST, but not in the amygdala mimics the ICV CRH effect (Liang et al 1992) and infusion of the CRH-receptor antagonist alpha-helical CRH in the BNST blocks CRH-enhanced startle (Lee and Davis 1997). These results implicate the BNST rather than amygdala as the primary source for the anxiogenic effect of CRH on startle, pointing to a selective role of CRH in the BNST as a potential mechanism for anxiety states.…”

CRH: The link between hormonal-, metabolic- and behavioral responses to stress

“…The role of the extended amygdala in fear and anxiety is well established (Davis 1992, Davis et al 1994, Lee & Davis 1997, Merali et al 2003, Schulkin et al 1998. It has been shown that infusion of CRH into the BNST and amygdala provokes number of fear-related behavioral responses in a CRH1R receptor dependent manner (Lee & Davis 1997, Shepard et al 2000.…”

“…It has been shown that infusion of CRH into the BNST and amygdala provokes number of fear-related behavioral responses in a CRH1R receptor dependent manner (Lee & Davis 1997, Shepard et al 2000.…”

“…CeA projections to the periaqueductal gray are responsible for freezing (LeDoux 1995), while efferents to the nucleus reticularis pontis caudalis facilitate startle response to stress (Lee & Davis 1997, Rosen et al 1991. Chronic CORT treatment elevates CRH mRNA in the CeA, increases fear, enhance learning and memory consolidation, however, does not potentiate innate fear responses (Rosen et al 2008).…”

Increased expression level of corticotropin-releasing hormone in the amygdala and in the hypothalamus in rats exposed to chronic unpredictable mild stress

“…It is of interest that HPA-axis becomes activated during stimulation of rat amygdala, along with an increase in the level of corticosterone in serum and symptoms that are similar to those observed during stress response, such as freezing [30] . CRH administration in a chemical lesion of the amygdala failed to induce the behavioral effects [31] . Furthermore, application of a CRH antagonist in the amygdala could significantly reduce the response to repeated stress [33] .…”