Central Amygdala Prepronociceptin-Expressing Neurons Mediate Palatable Food Consumption and Reward

Hardaway, J. Andrew; Halladay, Lindsay R.; Mazzone, Christopher M.; Pati, Dipanwita; Bloodgood, Daniel W.; Kim, Michelle; Jensen, Jennifer R.; DiBerto, Jeffrey F.; Boyt, Kristen M.; Shiddapur, Ami; Erfani, Ava; Hon, Olivia J.; Neira, Sofia; Stanhope, Christina M; Sugam, Jonathan A.; Saddoris, Michael P.; Tipton, Greg; McElligott, Zoé A.; Jhou, Thomas C.; Stuber, Garret D.; Bruchas, Michael R.; Bulik, Cynthia M.; Holmes, Andrew; Kash, Thomas L.

doi:10.1016/j.neuron.2019.03.037

Cited by 106 publications

(92 citation statements)

References 53 publications

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“…PNOC encodes a preproprotein that is proteolytically processed to generate the nociceptin neuropeptide, which opposes the effects of hypocretin to reduce arousal and spontaneous activity in zebrafish 30 , 31 . The colocalization of daytime napping with BMI at this locus is consistent with known pleiotropic effects of PNOC in feeding behavior 32 (pp = 0.84; Supplementary Table 8 ). The known 33 missense variant in PATJ [rs12140153; G1543V; G allele frequency 0.90] has a stronger association with daytime napping than any previously studied sleep phenotypes (Supplementary Data 4 ), and is likely a shared causal variant with daytime sleepiness, chronotype, and with BMI (pp = 0.81 and pp = 0.99; Supplementary Tables 7 and 8 ).…”

Section: Resultssupporting

confidence: 82%

Genetic determinants of daytime napping and effects on cardiometabolic health

et al. 2021

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Daytime napping is a common, heritable behavior, but its genetic basis and causal relationship with cardiometabolic health remain unclear. Here, we perform a genome-wide association study of self-reported daytime napping in the UK Biobank (n = 452,633) and identify 123 loci of which 61 replicate in the 23andMe research cohort (n = 541,333). Findings include missense variants in established drug targets for sleep disorders (HCRTR1, HCRTR2), genes with roles in arousal (TRPC6, PNOC), and genes suggesting an obesity-hypersomnolence pathway (PNOC, PATJ). Association signals are concordant with accelerometer-measured daytime inactivity duration and 33 loci colocalize with loci for other sleep phenotypes. Cluster analysis identifies three distinct clusters of nap-promoting mechanisms with heterogeneous associations with cardiometabolic outcomes. Mendelian randomization shows potential causal links between more frequent daytime napping and higher blood pressure and waist circumference.

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Section: Resultssupporting

confidence: 82%

Genetic determinants of daytime napping and effects on cardiometabolic health

et al. 2021

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“…BNST vGLUT2 -PBN neurons are enriched in Adcyap1 , which encodes the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP), previously identified as a major regulator of stress responses in the BNST ( 30 , 31 ), including in contexts of addiction and posttraumatic stress disorder ( 32 , 33 ). Both BNST vGAT -PBN and BNST vGLUT2 -PBN neurons express calcitonin receptor ( Calcr ), recently associated with the regulation of feeding ( 34 , 35 ), and nociceptin ( Pnoc ), linked to motivated behaviors including feeding ( 24 , 36 – 38 ). We further validated these RNA sequencing (RNA-seq) findings by performing fluorescent in situ hybridization experiments, which revealed coexpression of Tac2 , Sstr3 , and Calcr with vGAT and Adcyap1 with vGLUT2 neurons within the BNST (fig.…”

Section: Resultsmentioning

confidence: 99%

Extended amygdala-parabrachial circuits alter threat assessment and regulate feeding

et al. 2021

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An animal’s evolutionary success depends on the ability to seek and consume foods while avoiding environmental threats. However, how evolutionarily conserved threat detection circuits modulate feeding is unknown. In mammals, feeding and threat assessment are strongly influenced by the parabrachial nucleus (PBN), a structure that responds to threats and inhibits feeding. Here, we report that the PBN receives dense inputs from two discrete neuronal populations in the bed nucleus of the stria terminalis (BNST), an extended amygdala structure that encodes affective information. Using a series of complementary approaches, we identify opposing BNST-PBN circuits that modulate neuropeptide-expressing PBN neurons to control feeding and affective states. These previously unrecognized neural circuits thus serve as potential nodes of neural circuitry critical for the integration of threat information with the intrinsic drive to feed.

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“…Nociceptin is likely to have additional roles in feeding behavior, as its administration into the BNST prevents corticotropin-releasing hormone–induced stress and anorexia (51). In addition, nociceptin-expressing neurons in the central amygdala (CeA) promote the intake of highly palatable food but not normal chow, and nociceptin-expressing neurons in the ventral tegmental area (VTA) are also involved in reward behavior (53, 54). Intriguingly, CeA nociceptin–expressing neurons project to the ventral aBNST to alter reward and anxiety but not food intake.…”

Section: Discussionmentioning

confidence: 99%

Extrahypothalamic GABAergic nociceptin–expressing neurons regulate AgRP neuron activity to control feeding behavior

Smith¹,

Choudhury²,

Glegola³

et al. 2019

Journal of Clinical Investigation

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Arcuate nucleus agouti–related peptide (AgRP) neurons play a central role in feeding and are under complex regulation by both homeostatic hormonal and nutrient signals and hypothalamic neuronal pathways. Feeding may also be influenced by environmental cues, sensory inputs, and other behaviors, implying the involvement of higher brain regions. However, whether such pathways modulate feeding through direct synaptic control of AgRP neuron activity is unknown. Here, we show that nociceptin-expressing neurons in the anterior bed nuclei of the stria terminalis (aBNST) make direct GABAergic inputs onto AgRP neurons. We found that activation of these neurons inhibited AgRP neurons and feeding. The activity of these neurons increased upon food availability, and their ablation resulted in obesity. Furthermore, these neurons received afferent inputs from a range of upstream brain regions as well as hypothalamic nuclei. Therefore, aBNST GABAergic nociceptin neurons may act as a gateway to feeding behavior by connecting AgRP neurons to both homeostatic and nonhomeostatic neuronal inputs.

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Central Amygdala Prepronociceptin-Expressing Neurons Mediate Palatable Food Consumption and Reward

Abstract: Highlights d Pnoc CeA neurons are activated following palatable food consumption d Pnoc CeA neurons promote palatable food consumption specifically d Pnoc CeA neuronal projections in the CeA, vBNST, PBN, and NTS promote reward

Cited by 106 publications

References 53 publications

Genetic determinants of daytime napping and effects on cardiometabolic health

Genetic determinants of daytime napping and effects on cardiometabolic health

Extended amygdala-parabrachial circuits alter threat assessment and regulate feeding

Extrahypothalamic GABAergic nociceptin–expressing neurons regulate AgRP neuron activity to control feeding behavior

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