Extended Amygdala Neuropeptide Circuitry of Emotional Arousal: Waking Up on the Wrong Side of the Bed Nuclei of Stria Terminalis

Abstract

Sleep is fundamental to life, and poor sleep quality is linked to the suboptimal function of the neural circuits that process and respond to emotional stimuli. Wakefulness (“arousal”) is chiefly regulated by circadian and homeostatic forces, but affective mood states also strongly impact the balance between sleep and wake. Considering the bidirectional relationships between sleep/wake changes and emotional dynamics, we use the term “emotional arousal” as a representative characteristic of the profound overlap between brain pathways that: (1) modulate wakefulness; (2) interpret emotional information; and (3) calibrate motivated behaviors. Interestingly, many emotional arousal circuits communicate using specialized signaling molecules called neuropeptides to broadly modify neural network activities. One major neuropeptide-enriched brain region that is critical for emotional processing and has been recently implicated in sleep regulation is the bed nuclei of stria terminalis (BNST), a core component of the extended amygdala (an anatomical term that also includes the central and medial amygdalae, nucleus accumbens shell, and transition zones betwixt). The BNST encompasses an astonishing diversity of cell types that differ across many features including spatial organization, molecular signature, biological sex and hormonal milieu, synaptic input, axonal output, neurophysiological communication mode, and functional role. Given this tremendous complexity, comprehensive elucidation of the BNST neuropeptide circuit mechanisms underlying emotional arousal presents an ambitious set of challenges. In this review, we describe how rigorous investigation of these unresolved questions may reveal key insights to enhancing psychiatric treatments and global psychological wellbeing.

Distinct Encoding of Reward and Aversion by Peptidergic BNST Inputs to the VTA

“…In the BNST projections to the VTA, we find that just over half of the neurons express some combination of two of the three neuropeptides, but again very few expressed all three. We also observed that nearly half of all the inputs to the VTA from the BNST do not express any of the three neuropeptides investigated here, suggesting that these neurons are likely to release other neuropeptides into the VTA, such as the endogenous opioids enkephalin, dynorphin, and nociceptin that are known to modulate neural activity in this region (Kash et al, 2015;Giardino and Pomrenze, 2021). Indeed, we previously identified a dynorphin-expressing BNST to VTA population that contributed to anxiety-like behavior, but not conditioned threat discrimination (Fellinger et al, 2021).…”

Prepronociceptin-expressing neurons in the extended amygdala signal darting away from an aversive odor

“…In addition, these results contrast with another study that showed that inactivation of BNST reduced TMT-induced fear-related behavior (Fendt et al, 2003). The BNST is composed of several genetically identifiable cell-types (Giardino and Pomrenze, 2021; Ortiz-Juza et al, 2021), therefore, one explanation for why our inactivation of one cell-type in the BNST did not reduce TMT fear-related behavior could be that a different cell-type is responsible for TMT induced fear-related behavior. Another possible explanation for our finding could be that bulk inhibition of Pnoc BNST neurons is not selective enough to modulate behavior.…”

“…The bed nucleus of the stria terminalis (BNST) is a genetically diverse hub of the extended amygdala (Giardino and Pomrenze, 2021; Ortiz-Juza et al, 2021), and is strongly implicated in human psychopathologies defined by alterations in arousal and motivational states (Straube et al, 2007; Walker et al, 2009; Yassa et al, 2012). Recently, we identified that the activity of a subpopulation of prepronociceptin -expressing neurons within the BNST ( Pnoc BNST neurons) directly correlates with rapid changes in physiological arousal (observed by increases in pupillary size) when mice are presented with motivationally salient predator and food odors (Rodriguez-Romaguera et al, 2020).…”

Whole-brain input mapping of the lateral versus medial anterodorsal bed nucleus of the stria terminalis in the mouse

“…Recent studies showed that the alBNST mediates stress-induced anxiety-like behavior through the CRH neural network coordinating with CeA ( Pomrenze et al, 2019 ; Yamauchi et al, 2018 ). The functional distinctions between the lateral and medial adBNST appear to go beyond stress and anxiety because opposing roles in motivated states via specific responses to aversive and rewarding stimuli are shown for BNST CRH and CCK neurons, respectively ( Giardino et al, 2018 ; Giardino and Pomrenze, 2021 ). A specialized role in feeding regulation by PKC-δ neurons in the BNSTov is also reported ( Schnapp et al, 2022 ; Wang et al, 2019 ).…”