van den Pol, A. N. Neuropeptide transmission in brain circuits. Neuron 76, 98â115 (2012).
Andermann, M. L. & Lowell, B. B. Toward a wiring diagram understanding of appetite control. Neuron 95, 757â778 (2017).
Cowley, M. A. et al. Integration of npy, agrp, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24, 155â163 (1999).
Garfield, A. S. et al. A neural basis for melanocortin-4 receptor-regulated appetite. Nat. Neurosci. 18, 863â871 (2015).
Krashes, M. J., Lowell, B. B. & Garfield, A. S. Melanocortin-4 receptor-regulated energy homeostasis. Nat. Neurosci. 19, 206â219 (2016).
Cone, R. D. Anatomy and regulation of the central melanocortin system. Nat. Neurosci. 8, 571â578 (2005).
Chen, Y., Lin, Y.-C., Kuo, T.-W. & Knight, Z. A. Sensory detection of food rapidly modulates arcuate feeding circuits. Cell 160, 829â841 (2015).
Mandelblat-Cerf, Y. et al. Arcuate hypothalamic AgRP and putative POMC neurons show opposite changes in spiking across multiple timescales. eLife 4, e07122 (2015).
Deem, J. D., Faber, C. L. & Morton, G. J. AgRP neurons: regulators of feeding, energy expenditure, and behavior. FEBS J. 289, 2362â2381 (2022).
Krashes, M. J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424â1428 (2011).
Aponte, Y., Atasoy, D. & Sternson, S. M. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat. Neurosci. 14, 351â355 (2011).
Mercer, A. J., Hentges, S. T., Meshul, C. K. & Low, M. J. Unraveling the central proopiomelanocortin neural circuits. Front. Neurosci. 7, 19 (2013).
Beutler, L. R. et al. Dynamics of gut-brain communication underlying hunger. Neuron 96, 461â475 (2017).
Betley, J. N. et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 521, 180â185 (2015).
Alhadeff, A. L. et al. Natural and drug rewards engage distinct pathways that converge on coordinated hypothalamic and reward circuits. Neuron 103, 891â908 (2019).
Goldstein, N. et al. Hypothalamic detection of macronutrients via multiple gut-brain pathways. Cell Metab. 33, 676â687 (2021).
Gantz, I. et al. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J. Biol. Chem. 268, 15174â15179 (1993).
Mountjoy, K. G., Robbins, L. S., Mortrud, M. T. & Cone, R. D. The cloning of a family of genes that encode the melanocortin receptors. Science 257, 1248â1251 (1992).
Wahlestedt, C., Regunathan, S. & Reis, D. J. Identification of cultured cells selectively expressing Y1-, Y2-, or Y3-type receptors for neuropeptide Y/peptide YY. Life Sci. 50, PL7âPL12 (1992).
Loos, R. J. F. & Yeo, G. S. H. The genetics of obesity: from discovery to biology. Nat. Rev. Genet. 23, 120â133 (2022).
Balthasar, N. et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123, 493â505 (2005).
Shah, B. P. et al. MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus. Proc. Natl Acad. Sci. USA 111, 13193â13198 (2014).
Zhang, S. X. et al. Hypothalamic dopamine neurons motivate mating through persistent cAMP signalling. Nature 597, 245â249 (2021).
Atasoy, D. et al. A genetically specified connectomics approach applied to long-range feeding regulatory circuits. Nat. Neurosci. 17, 1830â1839 (2014).
Jan, L. Y. & Jan, Y. N. Peptidergic synaptic transmission in sympathetic ganglia of the frog. J. Physiol. 327, 219â246 (1982).
Xiong, H. et al. Probing neuropeptide volume transmission in vivo by simultaneous near-infrared light-triggered release and optical sensing. Angew. Chem. Int. Ed. 61, e202206122 (2022).
Landgraf, R. & Neumann, I. D. Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front. Neuroendocrinol. 25, 150â176 (2004).
Qian, T. et al. A genetically encoded sensor measures temporal oxytocin release from different neuronal compartments. Nat. Biotechnol. https://doi.org/10.1038/s41587-022-01561-2 (2023).
Mountjoy, K. G., Mortrud, M. T., Low, M. J., Simerly, R. B. & Cone, R. D. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8, 1298â1308 (1994).
Chen, M. et al. Gsα deficiency in the paraventricular nucleus of the hypothalamus partially contributes to obesity associated with Gsα mutations. Endocrinology 153, 4256â4265 (2012).
Podyma, B. et al. The stimulatory G protein Gsα is required in melanocortin 4 receptor-expressing cells for normal energy balance, thermogenesis, and glucose metabolism. J. Biol. Chem. 293, 10993â11005 (2018).
Ghamari-Langroudi, M. et al. G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons. Nature 520, 94â98 (2015).
Lotta, L. A. et al. Human gain-of-function MC4R variants show signaling bias and protect against obesity. Cell 177, 597â607 (2019).
Li, Y. Q. et al. Gq/11α and Gsα mediate distinct physiological responses to central melanocortins. J. Clin. Invest. 126, 40â49 (2016).
Lutas, A., Fernando, K., Zhang, S. X., Sambangi, A. & Andermann, M. L. History-dependent dopamine release increases cAMP levels in most basal amygdala glutamatergic neurons to control learning. Cell Rep. 38, 110297 (2022).
Chen, Y. et al. Sustained NPY signaling enables AgRP neurons to drive feeding. eLife 8, e46348 (2019).
Betley, J. N., Cao, Z. F. H., Ritola, K. D. & Sternson, S. M. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155, 1337â1350 (2013).
Nguyen, A. D. et al. Y1 and Y5 receptors are both required for the regulation of food intake and energy homeostasis in mice. PLoS ONE 7, e40191 (2012).
Haskell-Luevano, C. & Monck, E. K. Agouti-related protein functions as an inverse agonist at a constitutively active brain melanocortin-4 receptor. Regul. Pept. 99, 1â7 (2001).
Krashes, M. J., Shah, B. P., Koda, S. & Lowell, B. B. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab. 18, 588â595 (2013).
Takahashi, K. A. & Cone, R. D. Fasting induces a large, leptin-dependent increase in the intrinsic action potential frequency of orexigenic arcuate nucleus neuropeptide Y/agouti-related protein neurons. Endocrinology 146, 1043â1047 (2005).
Cowley, M. A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480â484 (2001).
Chen, S.-R. et al. Ghrelin receptors mediate ghrelin-induced excitation of agouti-related protein/neuropeptide Y but not pro-opiomelanocortin neurons. J. Neurochem. 142, 512â520 (2017).
He, Z. et al. Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise. Mol. Metab. 18, 107â119 (2018).
De Solis, A. J. et al. Reciprocal activity of AgRP and POMC neurons governs coordinated control of feeding and metabolism. Nat. Metab. 6, 473â493 (2024).
Biglari, N. et al. Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting. Nat. Neurosci. 24, 913â929 (2021).
Fenselau, H. et al. A rapidly acting glutamatergic ARCâPVH satiety circuit postsynaptically regulated by α-MSH. Nat. Neurosci. 20, 42â51 (2017).
Li, C. et al. Defined paraventricular hypothalamic populations exhibit differential responses to food contingent on caloric state. Cell Metab. 29, 681â694 (2019).
Thornquist, S. C., Pitsch, M. J., Auth, C. S. & Crickmore, M. A. Biochemical evidence accumulates across neurons to drive a network-level eruption. Mol. Cell 81, 675â690 (2021).
Alvarado, J. S. et al. Transient cAMP production drives rapid and sustained spiking in brainstem parabrachial neurons to suppress feeding. Neuron 112, 1416â1425 (2024).
Huganir, R. L. & Nicoll, R. A. AMPARs and synaptic plasticity: the last 25 years. Neuron 80, 704â717 (2013).
Knabbe, J., Nassal, J. P., Verhage, M. & Kuner, T. Secretory vesicle trafficking in awake and anaesthetized mice: differential speeds in axons versus synapses. J. Physiol. 596, 3759â3773 (2018).
Hawton, K. et al. Slow down: behavioural and physiological effects of reducing eating rate. Nutrients 11, 50 (2018).
Hollopeter, G., Erickson, J. C., Seeley, R. J., Marsh, D. J. & Palmiter, R. D. Response of neuropeptide Y-deficient mice to feeding effectors. Regul. Pept. 75â76, 383â389 (1998).
Marsh, D. J., Hollopeter, G., Kafer, K. E. & Palmiter, R. D. Role of the Y5 neuropeptide Y receptor in feeding and obesity. Nat. Med. 4, 718â721 (1998).
Collet, T.-H. et al. Evaluation of a melanocortin-4 receptor (MC4R) agonist (setmelanotide) in MC4R deficiency. Mol. Metab. 6, 1321â1329 (2017).
Sadana, R. & Dessauer, C. W. Physiological roles for G protein-regulated adenylyl cyclase isoforms: insights from knockout and overexpression studies. Neurosignals 17, 5â22 (2009).
Yang, Y., Atasoy, D., Su, H. H. & Sternson, S. M. Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992â1003 (2011).
Spangler, S. M. & Bruchas, M. R. Optogenetic approaches for dissecting neuromodulation and GPCR signaling in neural circuits. Curr. Opin. Pharmacol. 32, 56â70 (2017).
Turner, A. J., Matsas, R. & Kenny, A. J. Are there neuropeptide-specific peptidases? Biochem. Pharmacol. 34, 1347â1356 (1985).
Chen, Y., Lin, Y.-C., Zimmerman, C. A., Essner, R. A. & Knight, Z. A. Hunger neurons drive feeding through a sustained, positive reinforcement signal. eLife 5, e18640 (2016).
Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 488, 172â177 (2012).
Lutas, A. et al. State-specific gating of salient cues by midbrain dopaminergic input to basal amygdala. Nat. Neurosci. 22, 1820â1833 (2019).
Singh, U. et al. Neuroanatomical organization and functional roles of PVN MC4R pathways in physiological and behavioral regulations. Mol. Metab. 55, 101401 (2022).
McHugh, T. J. et al. Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 317, 94â99 (2007).
Tong, Q., Ye, C. P., Jones, J. E., Elmquist, J. K. & Lowell, B. B. Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat. Neurosci. 11, 998â1000 (2008).
Iyengar, S., Li, D. L. & Simmons, R. M. A. Characterization of neuropeptide Y-induced feeding in mice: do Y1âY6 receptor subtypes mediate feeding? J. Pharmacol. Exp. Ther. 289, 1031â1040 (1999).
Lecklin, A. et al. Receptor subtypes Y1 and Y5 mediate neuropeptide Y induced feeding in the guinea-pig. Br. J. Pharmacol. 135, 2029â2037 (2002).
Criscione, L. et al. Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor. J. Clin. Invest. 102, 2136â2145 (1998).
Rossi, M. et al. A C-terminal fragment of agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 139, 4428â4431 (1998).
Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J. & Cone, R. D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165â168 (1997).
Millington, G. W. M. The role of proopiomelanocortin (POMC) neurons in feeding behaviour. Nutr. Metab. 4, 18 (2007).
Tung, Y. L., Piper, S. J., Yeung, D., OâRahilly, S. & Coll, A. P. A comparative study of the central effects of specific POMC-derived melanocortin peptides on food intake and body weight in Pomc null mice. Endocrinology 147, 5940â5947 (2006).
Hentges, S. T., Otero-Corchon, V., Pennock, R. L., King, C. M. & Low, M. J. Proopiomelanocortin expression in both GABA and glutamate neurons. J. Neurosci. 29, 13684â13690 (2009).
Livneh, Y. et al. Homeostatic circuits selectively gate food cue responses in insular cortex. Nature 546, 611â616 (2017).
Burgess, C. R. et al. Hunger-dependent enhancement of food cue responses in mouse postrhinal cortex and lateral amygdala. Neuron 91, 1154â1169 (2016).
Zhan, C. et al. Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J. Neurosci. 33, 3624â3632 (2013).
Wei, Q. et al. Uneven balance of power between hypothalamic peptidergic neurons in the control of feeding. Proc. Natl Acad. Sci. 115, E9489âE9498 (2018).
Mina, A. I. et al. CalR: a web-based analysis tool for indirect calorimetry experiments. Cell Metab. 28, 656â666 (2018).
Pachitariu, M. & Stringer, C. Cellpose 2.0: how to train your own model. Nat. Methods 19, 1634â1641 (2022).
Wang, H. et al. A tool kit of highly selective and sensitive genetically encoded neuropeptide sensors. Science 382, eabq8173 (2023).
Garfield, A. S. et al. Dynamic GABAergic afferent modulation of AgRP neurons. Nat. Neurosci. 19, 1628â1635 (2016).
Yasuda, R. Imaging spatiotemporal dynamics of neuronal signaling using fluorescence resonance energy transfer and fluorescence lifetime imaging microscopy. Curr. Opin. Neurobiol. 16, 551â561 (2006).
Massengill, C. I. et al. Sensitive genetically encoded sensors for population and subcellular imaging of cAMP in vivo. Nat. Methods 19, 1461â1471 (2022).
Bernard, A. et al. MRAP2 regulates energy homeostasis by promoting primary cilia localization of MC4R. JCI Insight 8, e155900 (2023).
Tewson, P. H., Martinka, S., Shaner, N. C., Hughes, T. E. & Quinn, A. M. New DAG and cAMP sensors optimized for live-cell assays in automated laboratories. J. Biomol. Screen. 21, 298â305 (2016).
Zhang, S. X., Miner, L. E., Boutros, C. L., Rogulja, D. & Crickmore, M. A. Motivation, perception, and chance converge to make a binary decision. Neuron 99, 376â388 (2018).
Korn, H. & Faber, D. S. Quantal analysis and synaptic efficacy in the CNS. Trends Neurosci. 14, 439â445 (1991).
Goutte, C. & Gaussier, E. in Advances in Information Retrieval (eds Losada, D. E. & Fernández-Luna, J. M.) 345â359 (Springer, 2005); https://doi.org/10.1007/978-3-540-31865-1_25.
Bock, A. et al. Optical mapping of cAMP signaling at the nanometer scale. Cell 182, 1519â1530 (2020).
Anton, S. E. et al. Receptor-associated independent cAMP nanodomains mediate spatiotemporal specificity of GPCR signaling. Cell https://doi.org/10.1016/j.cell.2022.02.011 (2022).
Zaccolo, M., Zerio, A. & Lobo, M. J. Subcellular organization of the camp signaling pathway. Pharmacol. Rev. 73, 278â309 (2021).
Bacskai, B. J. et al. Spatially resolved dynamics of cAMP and protein kinase A subunits in aplysia sensory neurons. Science 260, 222â226 (1993).
Fuxe, K. et al. On the role of volume transmission and receptorâreceptor interactions in social behaviour: focus on central catecholamine and oxytocin neurons. Brain Res. 1476, 119â131 (2012).
Klapoetke, N. C. et al. Independent optical excitation of distinct neural populations. Nat. Methods 11, 338â346 (2014).
