The Central Nucleus of the Amygdala and Corticotropin-Releasing Factor: Insights into Contextual Fear Memory

Abstract

The central nucleus of the amygdala (CeA) has been traditionally viewed in fear conditioning to serve as an output neural center that transfers conditioned information formed in the basolateral amygdala to brain structures that generate emotional responses. Recent studies suggest that the CeA may also be involved in fear memory consolidation. In addition, corticotropin-releasing factor systems were shown to facilitate memory consolidation in the amygdala, which contains a high density of CRF immunoreactive cell bodies and fibers in the lateral part of the CeA (CeAl). However, the involvement of CeA CRF in contextual fear conditioning remains poorly understood. Therefore, we first conducted a series of studies using fiber-sparing lesion and reversible inactivation methods to assess the general role of the CeA in contextual fear. We then used identical training and testing procedures to compare and evaluate the specific function of CeA CRF using CRF antisense oligonucleotides (CRF ASO). Rats microinjected with ibotenic acid, muscimol, or a CRF ASO into the CeA before contextual fear conditioning showed typical levels of freezing during acquisition training but exhibited significant reductions in contextual freezing in a retention test 48 h later. Furthermore, CeA inactivation induced by either muscimol or CRF ASO administration immediately before retention testing did not impair freezing, suggesting that the previously observed retention deficits were caused by inhibition of consolidation rather than fear expression. Collectively, our results suggest CeA involvement in the consolidation of contextual fear memory and specifically implicate CeA CRF as an important mediator.

The Ventral Striatopallidum and Extended Amygdala in Huntington Disease

“…Functionally, the central nucleus is involved in mediating the behavioral and physiological responses associated with fear and anxiety, it modulates hormonal responses to stress and plays an important role in learning Pavlovian conditioning (Kalin et al, 2004;Liubashina et al, 2000). It has recently been proposed, that while the central nucleus of the amygdala is involved in acute fear responses, the bed nucleus of the stria terminalis is more related to anxiety responses (Pitts et al, 2009). The lateral bed nucleus of the stria terminalis is a heterogeneous cell continuum expanding from the internal capsule on the medial side to the nucleus accumbens rostrally, it borders the caudate nucleus dorsally and reaches the IPAC at its caudal end.…”

Contextual conditioning in rats as an animal model for generalized anxiety disorder

“…On the other hand, several studies provide evidence for a role of CRF in contextual conditioning (Deak, Nguyen, Ehrlich, Watkins, Spencer, Maier et al, 1999;Hubbard, Nakashima, Lee, & Takahashi, 2007;Ohmura, Yamaguchi, Izumi, Matsumoto, & Yoshioka, 2008;Pitts, Todorovic, Blank, & Takahashi, 2009). To clarify this apparent discrepancy between GAD and CC, further CRF studies in patients are needed.…”

GABA and NMDA receptors in CRF neurons have opposing effects in fear acquisition and anxiety in central amygdala vs. bed nucleus of the stria terminalis

“…In fact, other studies have found that CeA infusion of a CRF antagonist prior to contextual fear conditioning (Swiergiel et al, 1993) or CRF antisense at different time points after contextual fear conditioning (Pitts et al, 2009; Pitts and Takahashi, 2011) is effective at modulating fear memory. The lack of effectiveness of CRF receptor antagonists in the CeA in some studies may be partially explained by the relative expression of CRF receptors in the BLA compared to the CeA.…”