Extended amygdala-parabrachial circuits alter threat assessment to regulate feeding

Abstract

29An animal's evolutionary success depends on the ability to seek and consume foods while 30 avoiding environmental threats. However, how evolutionarily conserved threat detection circuits 31 modulate feeding is unknown. In mammals, feeding and threat assessment are strongly 32 influenced by the parabrachial nucleus (PBN), a structure that responds to threats and inhibits 33 feeding. Here, we report that the PBN receives dense inputs from the bed nucleus of the stria 34 terminalis (BNST), an extended amygdala structure that encodes affective information. Using a 35 series of complementary approaches, we identify opposing BNST-PBN circuits that modulate a 36 genetically-defined population of PBN neurons to control feeding. This previously unrecognized 37 neural circuit integrates threat assessment with the intrinsic drive to eat. 38 39 Keywords: extended amygdala; bed nucleus of the stria terminalis; parabrachial nucleus; 40 feeding; threat assessment; anxiety; motivation 41 Main text: 42 43 Introduction 44All animals must successfully seek and consume food while avoiding environmental 45 threats to survive. The internal state of an animal directly impacts the expression of risky 46 behaviors, such as exploring a dangerous environment to obtain rewards and maintain 47 homeostasis. Animals must adaptively prioritize certain behaviors to appropriately respond to their 48 internal state (Alhadeff et al., 2018; Burnett et al., 2016). While many studies have explored the 49 interaction of metabolic need states with behavior, how mammals integrate affective-threat 50 assessment with internal need states remains largely unknown. 51Several recent reports have found that in mammals, food consumption and threat 52 assessment are heavily influenced by the parabrachial nucleus (PBN), a pontine structure that 53 integrates visceral and sensory information to encode metabolic needs (Campos et al., 2016(Campos et al., , 54 2018 Carter et al., 2013; Essner et al., 2017; Han et al., 2015; Mu et al., 2017; Roman et al., 55 2016; Ryan et al., 2017; Zséli et al., 2016). The amygdala and extended amygdala are 56 evolutionarily conserved brain regions that encode and integrate valence, stress, and threat to 57 alter behavioral states. Anatomical data suggest that the PBN receives input from several regions 58 that may encode affective information, including the bed nucleus of the stria terminalis (BNST), a 59 structure in the extended amygdala (Douglass et al., 2017; Kim et al., 2013; Mazzone et al., 2018; 60 Zséli et al., 2016). However, the neural circuit mechanisms that underlie the integration of an 61 animal's own motivation to eat with internal affective states regarding environmental threats are 62 still unknown. Here, we identified two previously unknown afferents from distinct populations 63 within the BNST to the PBN that underlie the complex integration of threat-assessment and 64 feeding signals to modulate PBN activity and ultimately regulate state-dependent feeding. 65 66 67 Results 68 Anatomical and Molecular...

Parabrachial opioidergic projections to preoptic hypothalamus mediate behavioral and physiological thermal defenses

“…Although a functional division in the PBN is plausible, our results (particularly based on Pdyn expression) suggest that this conclusion warrants further study using high resolution approaches. It is also important to note that we recently observed that modulation of Pdyn PBN neurons can replicate behavioral effects that were once attributed solely to CGRP neurons in the PBN, and while these two populations are genetically distinct, similar behavioral effects were observed ( Bhatti et al, 2020 ). Interestingly, Yang et al observe hyperthermia in response activation of VGLUT2+ PBN neurons in some animals but with activation VGLUT2 PBN→POA projecting cells raising questions for future study about hypothermia activated PBN neurons and what their projection targets are.…”

Functional Dissection of Glutamatergic and GABAergic Neurons in the Bed Nucleus of the Stria Terminalis

“…Another study that showed the opposing roles of these populations focused on their projections to the parabrachial nucleus (PB), a small pontine structure that has been implicated in a number of functions including feeding ( Kim et al, 2020 ; Palmiter, 2018 ). In this study, optogenetic stimulation of the axon terminals of BNST Vglut2 neurons in the PB suppressed feeding in food-deprived mice, induced place avoidance, supported negative reinforcement of an operant behavior to turn off the stimulation, and increased anxiety-like behavior ( Bhatti et al, 2020 ). In contrast, stimulating the terminals of BNST Vgat neurons increased food intake in ad libitum fed mice, induced place preference, supported positive reinforcement of an operant task to turn on the stimulation, had an anxiolytic effect, and suppressed freezing responses to a learned auditory threat signal.…”

“…Notably, while the activation of both the BNST Vgat -PB and vBNST Vgat -VTA projections supported place preference and reduced anxiety-like behaviors, only the activation of the former increased feeding behavior ( Bhatti et al, 2020 ; Jennings et al, 2013a ). Furthermore, a separate study showed that optogenetic stimulation of the projection from the anterior dorsal part of the BNST (adBNST, mostly composed of GABAergic neurons) to the VTA supports place preference, but does not affect anxiety-like behavior ( Kim et al, 2013 ).…”

“…The anterior and dorsal parts of the BNST are mostly comprised of GABAergic neurons, while the posterior and ventral parts of the BNST contain significant numbers of both glutamatergic and GABAergic neurons ( Poulin et al, 2009 ). To target glutamatergic or GABAergic BNST subpopulations, most studies used the Vglut2 or Vgat gene (that encodes vesicular glutamate transporter 2 or vesicular GABA transporter, respectively) as the genetic marker, respectively ( Bhatti et al, 2020 ; Jennings et al, 2013a ; 2013b ), while some used Gad2 (encoding 65 kDa isoform of glutamic acid decarboxylase) to gain genetic access to GABAergic BNST neurons ( Hao et al, 2019 ). Specifically, these studies used knock-in mouse lines expressing a bacterial recombinase Cre under the promoter of Vglut2 , Vgat , or Gad2 in combination with viral tools that allow Cre-dependent expression of optogenetic or chemogenetic tools or fluorescent calcium indicators.…”

“…At the same time, these studies have also clearly demonstrated the functional heterogeneity within each population. This heterogeneity was revealed by single-unit recordings ( Jennings et al, 2013b ) and projection-specific activity recordings and manipulations ( Bhatti et al, 2020 ; Hao et al, 2019 ; Jennings et al, 2013a ). Recent studies targeting subpopulations of GABAergic BNST neurons also reinforce this notion.…”