Abstract
Engineered neurobiological tools for the manipulation of cellular activity, such as chemogenetics and optogenetics, have become a cornerstone of modern neuroscience research. These tools are invaluable for the interrogation of the central control of metabolism as they provide a direct means to establish a causal relationship between brain activity and biological processes at the cellular, tissue and organismal levels. The utility of these methods has grown substantially due to advances in cellular-targeting strategies, alongside improvements in the resolution and potency of such tools. Furthermore, the potential to recapitulate endogenous cellular signalling has been enriched by insights into the molecular signatures and activity dynamics of discrete brain cell types. However, each modulatory tool has a specific set of advantages and limitations; therefore, tool selection and suitability are of paramount importance to optimally interrogate the cellular and circuit-based underpinnings of metabolic outcomes within the organism. Here, we describe the key principles and uses of engineered neurobiological tools. We also highlight inspiring applications and outline critical considerations to be made when using these tools within the field of metabolism research. We contend that the appropriate application of these biotechnological advances will enable the delineation of the central circuitry regulating systemic metabolism with unprecedented potential.
Key points
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Neurobiological tools facilitate the probing of the interaction between discrete cell populations of the brain and systemic metabolism with unprecedented potential.
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Chemogenetic and optogenetic tools have different properties, which enables their complementary use to optimize the testing of the necessity and sufficiency of metabolic neural circuitry.
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The relative advantages and drawbacks of chemogenetic and optogenetic tools are important considerations as they dictate the ideal experimental conditions under which these tools should be used.
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The delineation and subsequent dissection of the complex neural circuitry underlying metabolism can leverage novel translational elements and pharmacological strategies for the treatment of metabolic diseases.
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References
Atasoy, D. & Sternson, S. M. Chemogenetic tools for causal cellular and neuronal biology. Physiol. Rev. 98, 391–418 (2018).
Roth, B. L. DREADDs for neuroscientists. Neuron 89, 683–694 (2016).
Deisseroth, K. Optogenetics: 10 years of microbial opsins in neuroscience. Nat. Neurosci. 18, 1213–1225 (2015).
Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012).
Fenselau, H. et al. A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH. Nat. Neurosci. 20, 42–51 (2017).
Krashes, M. J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424–1428 (2011).
Zhang, X. & van den Pol, A. N. Hypothalamic arcuate nucleus tyrosine hydroxylase neurons play orexigenic role in energy homeostasis. Nat. Neurosci. 19, 1341–1347 (2016).
Steculorum, S. M. et al. AgRP Neurons control systemic insulin sensitivity via myostatin expression in brown adipose tissue. Cell 165, 125–138 (2016).
Garfield, A. S. et al. A parabrachial-hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia. Cell Metab. 20, 1030–1037 (2014).
Flak, J. N. et al. Ventromedial hypothalamic nucleus neuronal subset regulates blood glucose independently of insulin. J. Clin. Invest. 130, 2943–2952 (2020).
Myers, M. G. Jr, Affinati, A. H., Richardson, N. & Schwartz, M. W. Central nervous system regulation of organismal energy and glucose homeostasis. Nat. Metab. 3, 737–750 (2021).
Alcantara, I. C., Tapia, A. P. M., Aponte, Y. & Krashes, M. J. Acts of appetite: neural circuits governing the appetitive, consummatory, and terminating phases of feeding. Nat. Metab. 4, 836–847 (2022).
Steuernagel, L. et al. HypoMap-a unified single-cell gene expression atlas of the murine hypothalamus. Nat. Metab. 4, 1402–1419 (2022).
Schnütgen, F. et al. A directional strategy for monitoring Cre-mediated recombination at the cellular level in the mouse. Nat. Biotechnol. 21, 562–565 (2003).
Atasoy, D., Aponte, Y., Su, H. H. & Sternson, S. M. A FLEX switch targets Channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping. J. Neurosci. 28, 7025–7030 (2008).
Quadros, R. M. et al. Easi-CRISPR: a robust method for one-step generation of mice carrying conditional and insertion alleles using long ssDNA donors and CRISPR ribonucleoproteins. Genome Biol. 18, 92 (2017).
Miura, H., Quadros, R. M., Gurumurthy, C. B. & Ohtsuka, M. Easi-CRISPR for creating knock-in and conditional knockout mouse models using long ssDNA donors. Nat. Protoc. 13, 195–215 (2018).
Nectow, A. R. & Nestler, E. J. Viral tools for neuroscience. Nat. Rev. Neurosci. 21, 669–681 (2020).
Madisen, L. et al. A toolbox of Cre-dependent optogenetic transgenic mice for light-induced activation and silencing. Nat. Neurosci. 15, 793–802 (2012).
Fenno, L. E. et al. Targeting cells with single vectors using multiple-feature Boolean logic. Nat. Methods 11, 763–772 (2014).
Fenno, L. E. et al. Comprehensive dual- and triple-feature intersectional single-vector delivery of diverse functional payloads to cells of behaving mammals. Neuron 107, 836–853 (2020).
Ludwig, M. Q. et al. A genetic map of the mouse dorsal vagal complex and its role in obesity. Nat. Metab. 3, 530–545 (2021).
Bai, L. et al. Genetic identification of vagal sensory neurons that control feeding. Cell 179, 1129–1143 (2019).
Zhang, Q. et al. Food-induced dopamine signaling in AgRP neurons promotes feeding. Cell Rep. 41, 111718 (2022).
Kamm, G. B. et al. A synaptic temperature sensor for body cooling. Neuron 109, 3283–3297 (2021).
Li, L. et al. Delineating a serotonin 1B receptor circuit for appetite suppression in mice. J. Exp. Med. 219, e20212307 (2022).
Sciolino, N. R. et al. Recombinase-dependent mouse lines for chemogenetic activation of genetically defined cell types. Cell Rep. 15, 2563–2573 (2016).
Madisen, L. et al. Transgenic mice for intersectional targeting of neural sensors and effectors with high specificity and performance. Neuron 85, 942–958 (2015).
Gaziano, I. et al. Dopamine-inhibited POMCDrd2+ neurons in the ARC acutely regulate feeding and body temperature. JCI Insight 7, e162753 (2022).
Biglari, N. et al. Functionally distinct POMC-expressing neuron subpopulations in hypothalamus revealed by intersectional targeting. Nat. Neurosci. 24, 913–929 (2021).
Borgmann, D. et al. Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism. Cell Metab. 33, 1466–1482 (2021).
Bai, L. et al. Enteroendocrine cell types that drive food reward and aversion. eLife 11, e74964 (2022).
Hayashi, M. et al. Enteroendocrine cell lineages that differentially control feeding and gut motility. eLife 12, e78512 (2023).
Ferrari, L. L., Ogbeide-Latario, O. E., Gompf, H. S. & Anaclet, C. Validation of DREADD agonists and administration route in a murine model of sleep enhancement. J. Neurosci. Methods 380, 109679 (2022).
Vardy, E. et al. A new DREADD facilitates the multiplexed chemogenetic interrogation of behavior. Neuron 86, 936–946 (2015).
Lynagh, T. & Lynch, J. W. An improved ivermectin-activated chloride channel receptor for inhibiting electrical activity in defined neuronal populations. J. Biol. Chem. 285, 14890–14897 (2010).
Magnus, C. J. et al. Ultrapotent chemogenetics for research and potential clinical applications. Science 364, eaav5282 (2019).
Magnus, C. J. et al. Chemical and genetic engineering of selective ion channel-ligand interactions. Science 333, 1292–1296 (2011).
Gantz, S. C., Ortiz, M. M., Belilos, A. J. & Moussawi, K. Excitation of medium spiny neurons by ‘inhibitory’ ultrapotent chemogenetics via shifts in chloride reversal potential. eLife 10, e64241 (2021).
Dodd, G. T. et al. Insulin regulates POMC neuronal plasticity to control glucose metabolism. eLife 7, e38704 (2018).
Üner, A. G. et al. Role of POMC and AgRP neuronal activities on glycaemia in mice. Sci. Rep. 9, 13068 (2019).
Duncan, A. et al. Habenular TCF7L2 links nicotine addiction to diabetes. Nature 574, 372–377 (2019).
Carter, M. E., Soden, M. E., Zweifel, L. S. & Palmiter, R. D. Genetic identification of a neural circuit that suppresses appetite. Nature 503, 111–114 (2013).
Ewbank, S. N. et al. Chronic Gq AgRP neurons does not cause obesity. Proc. Natl Acad. Sci. USA 117, 20874–20880 (2020).
Sabatini, P. V. et al. GFRAL-expressing neurons suppress food intake via aversive pathways. Proc. Natl Acad. Sci. USA 118, e2021357118 (2021).
Dodd, G. T. et al. Leptin and insulin act on POMC neurons to promote the browning of white fat. Cell 160, 88–104 (2015).
Claes, M., De Groef, L. & Moons, L. The DREADDful hurdles and opportunities of the chronic chemogenetic toolbox. Cells 11, 1110 (2022).
Jendryka, M. et al. Pharmacokinetic and pharmacodynamic actions of clozapine-N-oxide, clozapine, and compound 21 in DREADD-based chemogenetics in mice. Sci. Rep. 9, 4522 (2019).
Kong, D. et al. GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell 151, 645–657 (2012).
Zhang, K. X. et al. Violet-light suppression of thermogenesis by opsin 5 hypothalamic neurons. Nature 585, 420–425 (2020).
Ye, H. et al. An estrogen-sensitive hypothalamus-midbrain neural circuit controls thermogenesis and physical activity. Sci. Adv. 8, eabk0185 (2022).
Nakamura, Y. et al. Prostaglandin EP3 receptor-expressing preoptic neurons bidirectionally control body temperature via tonic GABAergic signaling. Sci. Adv. 8, eadd5463 (2022).
Yu, S. et al. Glutamatergic preoptic area neurons that express leptin receptors drive temperature-dependent body weight homeostasis. J. Neurosci. 36, 5034–5046 (2016).
Hrvatin, S. et al. Neurons that regulate mouse torpor. Nature 583, 115–121 (2020).
Takahashi, T. M. et al. A discrete neuronal circuit induces a hibernation-like state in rodents. Nature 583, 109–114 (2020).
Nakajima, K.-i et al. Gs-coupled GPCR signalling in AgRP neurons triggers sustained increase in food intake. Nat. Commun. 7, 10268 (2016).
Durkee, C. A. et al. Gi/o protein-coupled receptors inhibit neurons but activate astrocytes and stimulate gliotransmission. Glia 67, 1076–1093 (2019).
Vaidyanathan, T. V., Collard, M., Yokoyama, S., Reitman, M. E. & Poskanzer, K. E. Cortical astrocytes independently regulate sleep depth and duration via separate GPCR pathways. eLife 10, e63329 (2021).
Chai, H. et al. Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron 95, 531–549 (2017).
Nagai, J. et al. Hyperactivity with disrupted attention by activation of an astrocyte synaptogenic cue. Cell 177, 1280–1292 (2019).
Van Den Herrewegen, Y. et al. Side-by-side comparison of the effects of Gq- and Gi-DREADD-mediated astrocyte modulation on intracellular calcium dynamics and synaptic plasticity in the hippocampal CA1. Mol. Brain 14, 144 (2021).
Goutaudier, R., Coizet, V., Carcenac, C. & Carnicella, S. Compound 21, a two-edged sword with both DREADD-selective and off-target outcomes in rats. PLoS One 15, e0238156 (2020).
Traut, J. et al. Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice. eLife 12, e84740 (2023).
MacLaren, D. A. et al. Clozapine N-oxide administration produces behavioral effects in long-evans rats: implications for designing DREADD experiments. eNeuro 3, eneuro.0219-16.2016 (2016).
Gomez, J. L. et al. Chemogenetics revealed: DREADD occupancy and activation via converted clozapine. Science 357, 503–507 (2017).
Wiegert, J. S., Mahn, M., Prigge, M., Printz, Y. & Yizhar, O. Silencing neurons: tools, applications, and experimental constraints. Neuron 95, 504–529 (2017).
Emiliani, V. et al. Optogenetics for light control of biological systems. Nat. Rev. Methods Prim. 2, 55 (2022).
Stujenske, J. M., Spellman, T. & Gordon, J. A. Modeling the spatiotemporal dynamics of light and heat propagation for in vivo optogenetics. Cell Rep. 12, 525–534 (2015).
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).
Chen, Y. et al. Sustained NPY signaling enables AgRP neurons to drive feeding. eLife 8, e46348 (2019).
Zhang, X. & van den Pol, A. N. Rapid binge-like eating and body weight gain driven by zona incerta GABA neuron activation. Science 356, 853–859 (2017).
Kwon, E. et al. Optogenetic stimulation of the liver-projecting melanocortinergic pathway promotes hepatic glucose production. Nat. Commun. 11, 6295 (2020).
Meek, T. H. et al. Functional identification of a neurocircuit regulating blood glucose. Proc. Natl Acad. Sci. USA 113, E2073–E2082 (2016).
Garfield, A. S. et al. A neural basis for melanocortin-4 receptor-regulated appetite. Nat. Neurosci. 18, 863–871 (2015).
Jennings, J. H., Rizzi, G., Stamatakis, A. M., Ung, R. L. & Stuber, G. D. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science 341, 1517–1521 (2013).
D’Agostino, G. et al. Appetite controlled by a cholecystokinin nucleus of the solitary tract to hypothalamus neurocircuit. eLife 5, e12225 (2016).
Gong, R., Xu, S., Hermundstad, A., Yu, Y. & Sternson, S. M. Hindbrain double-negative feedback mediates palatability-guided food and water consumption. Cell 182, 1589–1605 (2020).
Sciolino, N. R. et al. Natural locus coeruleus dynamics during feeding. Sci. Adv. 8, eabn9134 (2022).
Chen, Y., Lin, Y.-C., Kuo, T.-W. & Knight, Z. A. Sensory detection of food rapidly modulates arcuate feeding circuits. Cell 160, 829–841 (2015).
Betley, J. N. et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 521, 180–185 (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).
Zhao, Z.-D. et al. A hypothalamic circuit that controls body temperature. Proc. Natl Acad. Sci. USA 114, 2042–2047 (2017).
Kataoka, N., Shima, Y., Nakajima, K. & Nakamura, K. A central master driver of psychosocial stress responses in the rat. Science 367, 1105–1112 (2020).
Kim, W. S. et al. Organ-specific, multimodal, wireless optoelectronics for high-throughput phenotyping of peripheral neural pathways. Nat. Commun. 12, 157 (2021).
Yang, Y. et al. Wireless multilateral devices for optogenetic studies of individual and social behaviors. Nat. Neurosci. 24, 1035–1045 (2021).
Tajima, K. et al. Wireless optogenetics protects against obesity via stimulation of non-canonical fat thermogenesis. Nat. Commun. 11, 1730 (2020).
Stuber, G. D. et al. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature 475, 377–380 (2011).
Stachniak, T. J., Ghosh, A. & Sternson, S. M. Chemogenetic synaptic silencing of neural circuits localizes a hypothalamus→midbrain pathway for feeding behavior. Neuron 82, 797–808 (2014).
Raimondo, J. V., Kay, L., Ellender, T. J. & Akerman, C. J. Optogenetic silencing strategies differ in their effects on inhibitory synaptic transmission. Nat. Neurosci. 15, 1102–1104 (2012).
Mahn, M., Prigge, M., Ron, S., Levy, R. & Yizhar, O. Biophysical constraints of optogenetic inhibition at presynaptic terminals. Nat. Neurosci. 19, 554–556 (2016).
Copits, B. A. et al. A photoswitchable GPCR-based opsin for presynaptic inhibition. Neuron 109, 1791–1809 (2021).
Mahn, M. et al. Efficient optogenetic silencing of neurotransmitter release with a mosquito rhodopsin. Neuron 109, 1621–1635 (2021).
Owen, S. F., Liu, M. H. & Kreitzer, A. C. Thermal constraints on in vivo optogenetic manipulations. Nat. Neurosci. 22, 1061–1065 (2019).
Reinoß, P. et al. Hypothalamic Pomc neurons innervate the spinal cord and modulate the excitability of premotor circuits. Curr. Biol. 30, 4579–4593 (2020).
Grzelka, K. et al. A synaptic amplifier of hunger for regaining body weight in the hypothalamus. Cell Metab. 35, 770–785 (2023).
Mahn, M. et al. High-efficiency optogenetic silencing with soma-targeted anion-conducting channelrhodopsins. Nat. Commun. 9, 4125 (2018).
Feketa, V. V., Nikolaev, Y. A., Merriman, D. K., Bagriantsev, S. N. & Gracheva, E. O. CNGA3 acts as a cold sensor in hypothalamic neurons. eLife 9, e55370 (2020).
Jeong, J. H. et al. Activation of temperature-sensitive TRPV1-like receptors in ARC POMC neurons reduces food intake. PLoS Biol. 16, e2004399 (2018).
Zhou, Q. et al. Hypothalamic warm-sensitive neurons require TRPC4 channel for detecting internal warmth and regulating body temperature in mice. Neuron 111, 387–404 (2023).
Yang, Y. et al. Induction of a torpor-like hypothermic and hypometabolic state in rodents by ultrasound. Nat. Metab. 5, 789–803 (2023).
Cheng, W. et al. NTS Prlh overcomes orexigenic stimuli and ameliorates dietary and genetic forms of obesity. Nat. Commun. 12, 5175 (2021).
Kim, J. C. et al. Linking genetically defined neurons to behavior through a broadly applicable silencing allele. Neuron 63, 305–315 (2009).
Slezak, M. et al. Relevance of exocytotic glutamate release from retinal glia. Neuron 74, 504–516 (2012).
Yang, C. F. et al. Sexually dimorphic neurons in the ventromedial hypothalamus govern mating in both sexes and aggression in males. Cell 153, 896–909 (2013).
Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat. Methods 2, 419–426 (2005).
Zhan, C. et al. Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J. Neurosci. 33, 3624–3632 (2013).
Li, M. M. et al. The paraventricular hypothalamus regulates satiety and prevents obesity via two genetically distinct circuits. Neuron 102, 653–667 (2019).
Campos, C. A. et al. Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. Nat. Neurosci. 20, 934–942 (2017).
Li, H. et al. The melanocortin action is biased toward protection from weight loss in mice. Nat. Commun. 14, 2200 (2023).
Zhu, C. et al. Profound and redundant functions of arcuate neurons in obesity development. Nat. Metab. 2, 763–774 (2020).
Petreanu, L., Huber, D., Sobczyk, A. & Svoboda, K. Channelrhodopsin-2-assisted circuit mapping of long-range callosal projections. Nat. Neurosci. 10, 663–668 (2007).
Krashes, M. J. et al. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507, 238–242 (2014).
Garfield, A. S. et al. Dynamic GABAergic afferent modulation of AgRP neurons. Nat. Neurosci. 19, 1628–1635 (2016).
Hanno, Y., Nakahira, M., Jishage, K.-I., Noda, T. & Yoshihara, Y. Tracking mouse visual pathways with WGA transgene. Eur. J. Neurosci. 18, 2910–2914 (2003).
He, Y. et al. 5-HT recruits distinct neurocircuits to inhibit hunger-driven and non-hunger-driven feeding. Mol. Psychiatry 26, 7211–7224 (2021).
Wang, C. et al. AgRP neurons trigger long-term potentiation and facilitate food seeking. Transl. Psychiatry 11, 11 (2021).
Li, Y. et al. TLR4 in POMC neurons regulates thermogenesis in a sex-dependent manner. J. Lipid Res. 64, 100368 (2023).
Gradinaru, V. et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154–165 (2010).
Alhadeff, A. L. et al. A neural circuit for the suppression of pain by a competing need state. Cell 173, 140–152 (2018).
Berrios, J. et al. Food cue regulation of AGRP hunger neurons guides learning. Nature 595, 695–700 (2021).
Xu, L. et al. An H2R-dependent medial septum histaminergic circuit mediates feeding behavior. Curr. Biol. 32, 1937–1948 (2022).
Kennedy, A. et al. Stimulus-specific hypothalamic encoding of a persistent defensive state. Nature 586, 730–734 (2020).
Berndt, A. et al. High-efficiency channelrhodopsins for fast neuronal stimulation at low light levels. Proc. Natl Acad. Sci. USA 108, 7595–7600 (2011).
Murakoshi, H. et al. Kinetics of endogenous CaMKII required for synaptic plasticity revealed by optogenetic kinase inhibitor. Neuron 94, 37–47 (2017).
Anderson, K. A. et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 7, 377–388 (2008).
Gruber, T. et al. Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension. Cell Metab. 33, 1155–1170 (2021).
Porniece Kumar, M. et al. Insulin signalling in tanycytes gates hypothalamic insulin uptake and regulation of AgRP neuron activity. Nat. Metab. 3, 1662–1679 (2021).
Wiedemann, S. J. et al. The cephalic phase of insulin release is modulated by IL-1β. Cell Metab. 34, 991–1003 (2022).
Herrera Moro Chao, D. et al. Hypothalamic astrocytes control systemic glucose metabolism and energy balance. Cell Metab. 34, 1532–1547 (2022).
Könner, A. C. et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 5, 438–449 (2007).
Chen, W. et al. Nutrient-sensing AgRP neurons relay control of liver autophagy during energy deprivation. Cell Metab. 35, 786–806 (2023).
Wu, Z., Lin, D. & Li, Y. Pushing the frontiers: tools for monitoring neurotransmitters and neuromodulators. Nat. Rev. Neurosci. 23, 257–274 (2022).
Zeng, W. et al. Sympathetic neuro-adipose connections mediate leptin-driven lipolysis. Cell 163, 84–94 (2015).
Buchanan, K. L. et al. The preference for sugar over sweetener depends on a gut sensor cell. Nat. Neurosci. 25, 191–200 (2022).
Kaelberer, M. M. et al. A gut-brain neural circuit for nutrient sensory transduction. Science 361, eaat5236 (2018).
Dutton, A. & Dyball, R. E. Phasic firing enhances vasopressin release from the rat neurohypophysis. J. Physiol. 290, 433–440 (1979).
Cazalis, M., Dayanithi, G. & Nordmann, J. J. The role of patterned burst and interburst interval on the excitation-coupling mechanism in the isolated rat neural lobe. J. Physiol. 369, 45–60 (1985).
Schöne, C., Apergis-Schoute, J., Sakurai, T., Adamantidis, A. & Burdakov, D. Coreleased orexin and glutamate evoke nonredundant spike outputs and computations in histamine neurons. Cell Rep. 7, 697–704 (2014).
Liu, J. J., Tsien, R. W. & Pang, Z. P. Hypothalamic melanin-concentrating hormone regulates hippocampus-dorsolateral septum activity. Nat. Neurosci. 25, 61–71 (2022).
Jang, H. J. et al. Distinct roles of parvalbumin and somatostatin interneurons in gating the synchronization of spike times in the neocortex. Sci. Adv. 6, eaay5333 (2020).
Yoshida, K. et al. Opposing ventral striatal medium spiny neuron activities shaped by striatal parvalbumin-expressing interneurons during goal-directed behaviors. Cell Rep. 31, 107829 (2020).
Acknowledgements
We thank Marielle Minère, Thomas Wunderlich and Sophie Steculorum (Max Planck Institute for Metabolism Research) for helpful discussions and comments on the manuscript. H.F. has received funding from the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Programme (grant agreement ID 851778), research funds through collaboration agreements with Novo Nordisk (Denmark), and funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; grant IDs 409551513 and 505389599) and within the Excellence Initiative by German Federal and State Governments (CECAD).
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Mirabella, P.N., Fenselau, H. Advanced neurobiological tools to interrogate metabolism. Nat Rev Endocrinol 19, 639–654 (2023). https://doi.org/10.1038/s41574-023-00885-6
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DOI: https://doi.org/10.1038/s41574-023-00885-6
