Parallel circuits from the bed nuclei of stria terminalis to the lateral hypothalamus drive opposing emotional states

Abstract

Lateral hypothalamus (LH) neurons containing the neuropeptide hypocretin (HCRT; orexin) modulate affective components of arousal, but their relevant synaptic inputs remain poorly defined. Here we identified inputs onto LH neurons that originate from neuronal populations in the bed nuclei of stria terminalis (BNST; a heterogeneous region of extended amygdala). We characterized two non-overlapping LH-projecting GABAergic BNST subpopulations that express distinct neuropeptides (corticotropin-releasing factor, CRF, and cholecystokinin, CCK). To functionally interrogate BNST→LH circuitry, we used tools for monitoring and manipulating neural activity with cell-type-specific resolution in freely behaving mice. We found that Crf-BNST and Cck-BNST neurons respectively provide abundant and sparse inputs onto Hcrt-LH neurons, display discrete physiological responses to salient stimuli, drive opposite emotionally valenced behaviors, and receive different proportions of inputs from upstream networks. Together, our data provide an advanced model for how parallel BNST→LH pathways promote divergent emotional states via connectivity patterns of genetically defined, circuit-specific neuronal subpopulations.

Ultra-sparse connectivity within the lateral hypothalamus

“…We have found with multi-neuron whole cell recordings that the LH does not contain neocortical-like densely connected microcircuits (Figure 1,2). This is in line with the many optogenetically non-connected neurons in this study (Figure 3A,C) and previous studies (Ferrari et al, 2018;Kosse and Burdakov, 2019), as well as the orders of magnitude stronger inputs arising from optogenetically activated long-range sources of input to LH (Giardino et al, 2018;González et al, 2016a). Although we can qualitatively reconcile existing literature on LH intra-connectivity, our findings diverge quantitatively from some published optogenetic datasets: Firstly, we found VGAT-cre à orexin neuron optogenetic connections only in 2/24 cases while Ferrari and colleagues found them in 71/116 cases (Ferrari et al, 2018).…”

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

“…A recent study showed that BNST neurons that project to the LHA can be further subdivided by the expression of the neuropeptidergic genes corticotropinreleasing hormone (Crh BNSTàLHA ) and cholecystokinin (Cck BNSTàLHA ). These neurons show an increase in average calcium activity specific to a rewarding (female mouse urine) or aversive odorant (TMT), respectively (Giardino et al, 2018). Furthermore, chemogenetic activation of Vgat expressing neurons within the BNST increases anxiety-like behavior and leads to activation of the locus coeruleus (LC) (Mazzone et al, 2018).…”

“…The BNST is composed of various subnuclei that have unique molecular and functional identities (Giardino et al, 2018;Gungor and Paré, 2016). Therefore, we first assessed the distribution of Pnoc-expressing neurons across the BNST.…”

“…Historically, the role of the BNST in physiological arousal has been largely overlooked, although this region is involved in a variety of motivational states. For instance, recent neurocircuit studies in mice have highlighted the role of BNST in reward and aversion (Giardino et al, 2018;Jennings et al, 2013aJennings et al, , 2013bKim et al, 2013), fear and anxiety-like behaviors (Crowley et al, 2016;Duvarci et al, 2009;Kim et al, 2013;Marcinkiewcz et al, 2016;Walker et al, 2009), and social preference and aversion (Goodson and Wang, 2006;Lei et al, 2010;Newman Sarah Winans, 2006). Further, previous studies have identified how subsets of BNST neurons expressing certain marker genes such as corticotrophinreleasing hormone (Crh BNST ), protein kinase C δ (Pkcδ BNST ), and somatostatin (Som BNST ) drive motivated behaviors (Kash et al, 2015;Koob and Heinrichs, 1999;Lebow and Chen, 2016;Tovote et al, 2015).…”

Neurons in the ventral striatopallidal complex modulate lateral hypothalamic orexin/hypocretin neuron activity: Implications for reward-seeking

“…Importantly, recent work supports a broadened role for these neurons in general arousal-related behaviors, including avoidance to aversive stimuli (Viviani et al, 2014). For example, orexin cell activity is strongly increased by negatively valanced emotional stimuli such as predator odor (Giardino et al, 2018). There is also a large literature linking the orexin system with drug motivated behavior, including stress-and cue-evoked drug-seeking as well as the behavioral and physiological syndrome associated with opiate withdrawal (Georgescu et al, 2003).…”