Early work stressed the differing involvement of the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) in the genesis of fear versus anxiety, respectively. In 2009, Walker, Miles, and Davis proposed a model of amygdala-BNST interactions to explain these functional differences. This model became extremely influential and now guides a new wave of studies on the role of BNST in humans. Here, we consider evidence for and against this model, in the process highlighting central principles of BNST organization. This analysis leads us to conclude that BNST's influence is not limited to the generation of anxiety-like responses to diffuse threats, but that it also shapes the impact of discrete threatening stimuli. It is likely that BNST-CeA interactions are involved in modulating responses to such threats. In addition, whereas current views emphasize the contributions of the anterolateral BNST region in anxiety, accumulating data indicate that the anteromedial and anteroventral regions also play a critical role. The presence of multiple functional subregions within the small volume of BNST raises significant technical obstacles for functional imaging studies in humans.

The basomedial amygdala (BM) influences the ventromedial nucleus of the hypothalamus (VMH) through direct glutamatergic projections as well as indirectly, through the anterior part of the bed nucleus of the stria terminalis (BNSTa). However, BM and BNSTa axons end in a segregated fashion in VMH. BM projects to the core of VMH, where VMH’s projection cells are located, whereas BNSTa projects to the shell of VMH, where GABAergic cells that inhibit core neurons are concentrated. However, the consequences of this dual regulation of VMH by BM and BNSTa are unknown. To study this question, we recorded the responses of VMH’s shell and core neurons to the optogenetic activation of BM or BNSTa inputs in transgenic mice that selectively express Cre-recombinase in glutamatergic or GABAergic neurons. Glutamatergic BM inputs fired most core neurons but elicited no response in GABAergic shell neurons. Following BM infusions of AAV-EF1α-DIO-hChR2-mCherry in Vgat-ires-Cre-Ai6 mice, no anterograde labeling was observed in the VMH, suggesting that GABAergic BM neurons do not project to the VMH. In contrast, BNSTa sent mostly GABAergic projections that inhibited both shell and core neurons. However, BNSTa-evoked IPSPs had a higher amplitude in shell neurons. Since we also found that activation of GABAergic shell neurons causes an inhibition of core neurons, these results suggest that depending on the firing rate of shell neurons, BNSTa inputs could elicit a net inhibition or disinhibition of core neurons. Thus, the dual regulation of VMH by BM and BNSTa imparts flexibility to this regulator of defensive and social behaviors.

study of the projections from the bed nucleus of the stria terminalis to the central amygdala. J Neurophysiol 114: 2903-2911. First published September 23, 2015 doi:10.1152/jn.00677.2015.-It has been proposed that the central amygdala (CeA), particularly its medial sector (CeM), generates brief fear responses to discrete conditioned cues, whereas the bed nucleus of the stria terminalis (BNST) promotes long-lasting, anxiety-like states in response to more diffuse contingencies. Although it is believed that BNST-CeA interactions determine the transition between short-and long-duration responses, the nature of these interactions remains unknown. To shed light on this question, we used a double viral strategy to drive the expression of channelrhodopsin (ChR2) in BNST cells that project to CeA. Next, using patch-clamp recordings in vitro, we investigated the connectivity of infected cells to noninfected cells in BNST and compared the influence of BNST axons on neurons in the medial and lateral (CeL) parts of CeA. CeA-projecting BNST cells were concentrated in the anterolateral (AL) and anteroventral (AV) sectors of BNST. Dense plexuses of BNST axons were observed throughout CeA. In CeA and BNST, light-evoked excitatory postsynaptic potentials accounted for a minority of responses (0 -9% of tested cells); inhibition prevailed. The incidence of inhibitory responses was higher in CeM than in CeL (66% and 43% of tested cells, respectively). Within BNST, the connections from CeA-projecting to non-CeA-targeting cells varied as a function of the BNST sector: 50% vs. 9% of tested cells exhibited light-evoked responses in BNST-AL vs. BNST-AV, respectively. Overall, these results suggest that via its projection to CeA, BNST exerts an inhibitory influence over cued fear and that BNST neurons projecting to CeA form contrasting connections in different BNST subnuclei.

The bed nucleus of the stria terminalis (BNST) is thought to generate anxiety-like states via its projections to autonomic and neuroendocrine regulatory structures of the brain. However, because most BNST cells are GABAergic, they are expected to inhibit target neurons. In contrast with this, infusion of calcitonin gene-related peptide (CGRP) into BNST was reported to potentiate anxiety while activating BNST targets. The present study aimed to shed light on this paradox. The CGRP innervation of BNST originates in the pontine parabrachial nucleus and targets its anterolateral sector (BNST-AL). Thus, we investigated the effects of CGRP on BNST-AL neurons using patch recordings in vitro in male rats. CGRP did not alter the passive properties of BNST-AL cells but increased the amplitude of IPSPs evoked by stimulation of the stria terminalis (ST). However, IPSP paired-pulse ratios were unchanged by CGRP, and there was no correlation between IPSP potentiation and variance, suggesting that CGRP acts postsynaptically. Consistent with this, CGRP hyperpolarized the GABA-A reversal of BNST-AL cells. These results indicate that CGRP increases ST-evoked GABA-A IPSPs and hyperpolarizes their reversal potential through a postsynaptic change in Cl Ϫ homeostasis. Overall, our findings suggest that CGRP potentiates anxiety-like behaviors and increases neural activity in BNST targets, by inhibiting BNST-AL cells, supporting the conclusion that BNST-AL exerts anxiolytic effects.

The response-signal speed-accuracy trade-off (SAT) procedure was used to provide an in-depth investigation of the impact of aging on the dynamics of short-term memory retrieval. Young and older adults studied sequentially presented 3-item lists, immediately followed by a recognition probe. Analyses of composite list and serial position SAT functions found no differences in overall accuracy, but indicated slower retrieval speed for older adults. Analysis of false alarms to recent negatives (lures from the previous study list) revealed no differences in the timing or magnitude of early false alarms that are thought to reflect familiarity-based judgments. However, onset and accrual of recollective processing required for resolving interference was slower for older adults. These findings suggest that older adults have a selective impairment on controlled and recollective retrieval operations, and further specify this impairment to arise primarily from delayed onset of cognitive control potentially coupled with reduced availability of recollective information.