Prepronociceptin expressing neurons in the extended amygdala encode and promote rapid arousal responses to motivationally salient stimuli

Abstract

Motivational states are complex and consist of cognitive, emotional, and physiological components controlled by a network across multiple brain regions. An integral component of this neural circuitry is the bed nucleus of the stria terminalis (BNST). Here, we identified a subpopulation of neurons within BNST expressing the gene prepronociceptin (Pnoc BNST ), that can modulate the rapid changes in physiological arousal that occur upon exposure to stimuli with motivational salience. Using in vivo two-photon calcium imaging we found that excitatory responses from individual Pnoc BNST neurons directly corresponded with rapid increases in pupillary size and occurred upon exposure to both aversive and rewarding odors. Furthermore, optogenetic activation of these neurons increased pupillary size, but did not alter approach/avoidance or locomotor behaviors. These findings suggest that excitatory responses in Pnoc BNST neurons encode rapid arousal responses irrespective of tested behaviors. Further histological, electrophysiological, and single-cell RNA sequencing data revealed that Pnoc BNST neurons are composed of genetically and anatomically identifiable subpopulations that can be further investigated. Taken together, our findings demonstrate a key role for a Pnoc BNST neuronal ensemble in encoding the rapid arousal responses that are triggered by motivational stimuli.

Corticotropin-Releasing Factor Neurons in the Bed Nucleus of the Stria Terminalis Differentially Influence Pain Processing and Modulation in Male and Female Mice

“…Considering that salience is an important predictor of pain sensitivity and analgesic efficacy (Borsook et al, 2013), it is possible that alterations in the timing and synchrony of BNST CRF+ responses will change nociceptive detection and contribute to pain sensitivity in a sex-specific manner. This is an intriguing possibility given that BNST neurons expressing Crf or the prepronociceptin gene have been reported to exhibit in vivo responses to motivationally salient and aversive stimuli such as predator odor (Giardino et al, 2018;Rodriguez-Romaguera et al, 2020). These observations support prior conclusions that the BNST encodes for salient threats that may cause physical or emotional harm (Somerville et al, 2010;Borsook et al, 2013;Grupe et al, 2013;Avery et al, 2016;Hermann et al, 2016;Minami, 2019).…”

Coordination of social behaviors by the bed nucleus of the stria terminalis

“…The vast majority of BNST neurons release the inhibitory neurotransmitter GABA, form symmetric synapses, and express the vesicular GABA transporter (vGAT) (Kudo et al, 2012;Mazzone et al, 2018;Moffitt et al, 2018;Welch et al, 2019;Rodriguez-Romaguera et al, 2020). Thus, BNST outputs generally inhibit their target cells.…”

“…For example, one recent study that performed single-cell transcriptional profiling of BNST neurons reported that they can be divided into as many as 41 different transcriptional clusters (Welch et al, 2019). Another study suggested that BNST neurons can be divided into 11 distinct transcriptional clusters, and that expression of pre-pro-nociceptin, the precursor for the NC neuropeptide, is distributed across 4 of these 11 clusters (Rodriguez-Romaguera et al, 2020). These two studies likely identified differing numbers of BNST cell types because of the clustering analyses used.…”

“…Thus, BNST outputs generally inhibit their target cells. However, roughly onetenth of BNST neurons release glutamate, form asymmetric synapses, and express the vesicular glutamate transporter 2 (vGlut2) (Kudo et al, 2012;Moffitt et al, 2018;Welch et al, 2019;Rodriguez-Romaguera et al, 2020). Although there is also a small population of vesicular glutamate transporter 3 (vGlut3)-expressing neurons in the BNST, these neurons form symmetric synapses, express enzymes necessary for GABA production, and release GABA (Kudo et al, 2012;Welch et al, 2019).…”