Role of bed nucleus of the stria terminalis and amygdala AMPA receptors in the development and expression of context conditioning and sensitization of startle by prior shock

Abstract

A core symptom of post-traumatic stress disorder is hyper-arousal—manifest in part by increases in the amplitude of the acoustic startle reflex. Gewirtz et al. (Prog Neuropsychopharmacol Biol Psychiatry 22:625–648, 1998) found that, in rats, persistent shock-induced startle increases were prevented by pre-test electrolytic lesions of the bed nucleus of the stria terminalis (BNST). We used reversible inactivation to determine if similar effects reflect actions on (a) BNST neurons themselves versus fibers-of-passage, (b) the development versus expression of such increases, and (c) associative fear versus non-associative sensitization. Twenty-four hours after the last of three shock sessions, startle was markedly enhanced when rats were tested in a non-shock context. These increases decayed over the course of several days. Decay was unaffected by context exposure, and elevated startle was restored when rats were tested for the first time in the original shock context. Thus, both associative and non-associative components could be measured under different conditions. Pre-test intra-BNST infusions of the AMPA receptor antagonist NBQX (3 μg/side) blocked the non-associative (as did infusions into the basolateral amygdala) but not the associative component, whereas pre-shock infusions disrupted both. NBQX did not affect baseline startle or shock reactivity. These results indicate that AMPA receptors in or very near to the BNST are critical for the expression and development of non-associative shock-induced startle sensitization, and also for context fear conditioning, but not context fear expression. More generally, they suggest that treatments targeting the BNST may be clinically useful for treating trauma-related hyper-arousal and perhaps for retarding its development.

CGRP antagonist infused into the bed nucleus of the stria terminalis impairs the acquisition and expression of context but not discretely cued fear

“…In other studies, effects of BNST manipulations on what appear to be shock-induced nonassociative sensitization have been reported (Gewirtz et al 1998;Davis and Walker 2013). To verify that the increases in startle that were disrupted by CGRP 8 -37 infusions reflected associative fear to the context rather than sensitization, other rats were trained and tested in the same or distinctively different chambers (Experiment 3).…”

“…The bed nucleus of the stria terminalis (BNST) has emerged as an integral component of the neural circuitry that regulates unconditioned anxiety (e.g., Fendt et al 2003Fendt et al , 2005bSink et al 2011;Gomes et al 2012;Xu et al 2012), various behavioral stress effects (Morilak et al 2003;Hammack et al 2004;Bangasser et al 2005;Roman et al 2012;Davis and Walker 2013), and certain types of conditioned fear responses (c.f., Walker et al 2009). As part of the "extended amygdala" (Alheid and Heimer 1988;Alheid et al 1995), the BNST has rich connections with other brain regions that have been classically associated with stress, fear, and anxiety.…”

Stress Modulation of Opposing Circuits in the Bed Nucleus of the Stria Terminalis

“…A growing body of evidence suggests that the bed nucleus of the stria terminalis (BNST) plays a crucial role in regulating trait anxiety as well as contextual fear memory formation (Davis and Walker, 2014;Duvarci et al, 2009;Fox et al, 2010;Hott et al, 2012;Kalin et al, 2005;Oler et al, 2009;Sink et al, 2013;Somerville et al, 2010;Straube et al, 2007;Sullivan et al, 2004;Walker and Davis, 2008;Yassa et al, 2012;Zimmerman and Maren, 2011). However, the BNST can be subdivided into at least 16 unique sub-regions and has been reported to be one of the most complex structures in the entire central nervous system (Bota et al, 2012;Dong and Swanson, 2004;Dong et al, 2001b;Ju et al, 1989;Larriva-Sahd, 2006).…”

The Human BNST: Functional Role in Anxiety and Addiction

“…Thus, mounting evidence now suggests that the amygdala mediates short-term, phasic responses to immediate threats, whereas the BNST mediates sustained responses to contextual, diffuse, and unpredictable threats. Recent studies have shown that the BNST also mediates hypervigilance and arousal (Davis et al, 2010), increased sensitization to the environment (Davis and Walker, 2013), and stress-enhanced learning (Bangasser and Shors, 2008), with recent optogenetics research further emphasizing the central role of the BNST in myriad stress and anxiety-related behaviors (Kim et al, 2013).…”