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Deletion of murine astrocytic vesicular nucleotide transporter increases anxiety and depressive-like behavior and attenuates motivation for reward

Molecular Psychiatry (2024)Cite this article

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Abstract

Astrocytes are multi-functional glial cells in the central nervous system that play critical roles in modulation of metabolism, extracellular ion and neurotransmitter levels, and synaptic plasticity. Astrocyte-derived signaling molecules mediate many of these modulatory functions of astrocytes, including vesicular release of ATP. In the present study, we used a unique genetic mouse model to investigate the functional significance of astrocytic exocytosis of ATP. Using primary cultured astrocytes, we show that loss of vesicular nucleotide transporter (Vnut), a primary transporter responsible for loading cytosolic ATP into the secretory vesicles, dramatically reduces ATP loading into secretory lysosomes and ATP release, without any change in the molecular machinery of exocytosis or total intracellular ATP content. Deletion of astrocytic Vnut in adult mice leads to increased anxiety, depressive-like behaviors, and decreased motivation for reward, especially in females, without significant impact on food intake, systemic glucose metabolism, cognition, or sociability. These behavioral alterations are associated with significant decreases in the basal extracellular dopamine levels in the nucleus accumbens. Likewise, ex vivo brain slices from these mice show a strong trend toward a reduction in evoked dopamine release in the nucleus accumbens. Mechanistically, the reduced dopamine signaling we observed is likely due to an increased expression of monoamine oxidases. Together, these data demonstrate a key modulatory role of astrocytic exocytosis of ATP in anxiety, depressive-like behavior, and motivation for reward, by regulating the mesolimbic dopamine circuitry.

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Fig. 1: Vnut deletion in primary astrocytes does not cause major changes in the expression of signature astrocyte marker genes.
Fig. 2: Loss of Vnut impairs ATP loading into secretory lysosomes and ATP release in primary astrocytes.
Fig. 3: Loss of Vnut in astrocytes in adult mice shows minor effects on the expression of astrocyte marker genes, as well as genes involved in exocytosis and lysosomes.
Fig. 4: Loss of Vnut in astrocytes in adult mice does not affect systemic glucose metabolism and insulin sensitivity.
Fig. 5: Astrocyte-specific Vnut KO female mice display increased anxiety and depressive-like behavior.
Fig. 6: Astrocytic Vnut in the nucleus accumbens is a critical mediator for depressive-like behavior in female mice in response to inescapable stress.
Fig. 7: The effects of astrocytic Vnut loss in adult female mice on evoked dopamine release in the nucleus accumbens.
Fig. 8: Loss of Vnut in Aldh1l1+ astrocytes increases depressive-like behavior and reduces motivation for reward in adult female mice.

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Data availability

The present study does not include any omics data to be deposited to the public repository. All the raw images and raw data will be provided upon request for research purpose only.

References

  1. Halassa MM, Fellin T, Takano H, Dong JH, Haydon PG. Synaptic islands defined by the territory of a single astrocyte. J Neurosci. 2007;27:6473–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Verkhratsky A, Nedergaard M. Physiology of Astroglia. Physiol Rev. 2018;98:239–389.

    Article  CAS  PubMed  Google Scholar 

  3. Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci. 2002;22:183–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Dringen R, Gebhardt R, Hamprecht B. Glycogen in astrocytes: possible function as lactate supply for neighboring cells. Brain Res. 1993;623:208–14.

    Article  CAS  PubMed  Google Scholar 

  5. Suh SW, Bergher JP, Anderson CM, Treadway JL, Fosgerau K, Swanson RA.Astrocyte glycogen sustains neuronal activity during hypoglycemia: studies with the glycogen phosphorylase inhibitor CP-316,819 ([R-R*,S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)pro pyl]-1H-indole-2-carboxamide).J Pharmacol Exp Ther.2007;321:45–50.

    Article  CAS  PubMed  Google Scholar 

  6. Brown AM, Ransom BR. Astrocyte glycogen and brain energy metabolism. Glia. 2007;55:1263–71.

    Article  PubMed  Google Scholar 

  7. Anderson CM, Swanson RA. Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia. 2000;32:1–14.

    Article  CAS  PubMed  Google Scholar 

  8. Danbolt NC. Glutamate uptake. Prog Neurobiol. 2001;65:1–105.

    Article  CAS  PubMed  Google Scholar 

  9. Su ZZ, Leszczyniecka M, Kang DC, Sarkar D, Chao W, Volsky DJ, et al. Insights into glutamate transport regulation in human astrocytes: cloning of the promoter for excitatory amino acid transporter 2 (EAAT2). Proc Natl Acad Sci USA. 2003;100:1955–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC. Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci. 1995;15:1835–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Muthukumar AK, Stork T, Freeman MR. Activity-dependent regulation of astrocyte GAT levels during synaptogenesis. Nat Neurosci. 2014;17:1340–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li K, Li J, Zheng J, Qin S. Reactive astrocytes in neurodegenerative diseases. Aging Dis. 2019;10:664–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Burda JE, Bernstein AM, Sofroniew MV. Astrocyte roles in traumatic brain injury. Exp Neurol. 2016;275:305–15.

    Article  CAS  PubMed  Google Scholar 

  14. Rossi DJ, Brady JD, Mohr C. Astrocyte metabolism and signaling during brain ischemia. Nat Neurosci. 2007;10:1377–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. 2017;46:957–67.

    Article  CAS  PubMed  Google Scholar 

  16. Haydon PG, Carmignoto G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev. 2006;86:1009–31.

    Article  CAS  PubMed  Google Scholar 

  17. Araque A, Carmignoto G, Haydon PG, Oliet SH, Robitaille R, Volterra A. Gliotransmitters travel in time and space. Neuron. 2014;81:728–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Di Castro MA, Chuquet J, Liaudet N, Bhaukaurally K, Santello M, Bouvier D, et al. Local Ca2+ detection and modulation of synaptic release by astrocytes. Nat Neurosci. 2011;14:1276–84.

    Article  PubMed  Google Scholar 

  19. Habbas S, Santello M, Becker D, Stubbe H, Zappia G, Liaudet N, et al. Neuroinflammatory TNFalpha impairs memory via astrocyte signaling. Cell. 2015;163:1730–41.

    Article  CAS  PubMed  Google Scholar 

  20. Jourdain P, Bergersen LH, Bhaukaurally K, Bezzi P, Santello M, Domercq M, et al. Glutamate exocytosis from astrocytes controls synaptic strength. Nat Neurosci. 2007;10:331–9.

    Article  CAS  PubMed  Google Scholar 

  21. Lalo U, Palygin O, Rasooli-Nejad S, Andrew J, Haydon PG, Pankratov Y. Exocytosis of ATP from astrocytes modulates phasic and tonic inhibition in the neocortex. PLoS Biol. 2014;12:e1001747.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Cai W, Xue C, Sakaguchi M, Konishi M, Shirazian A, Ferris HA, et al. Insulin regulates astrocyte gliotransmission and modulates behavior. J Clin Investig. 2018;128:2914–26.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lalo U, Palygin O, Verkhratsky A, Grant SG, Pankratov Y. ATP from synaptic terminals and astrocytes regulates NMDA receptors and synaptic plasticity through PSD-95 multi-protein complex. Sci Rep. 2016;6:33609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, et al. Astrocytic purinergic signaling coordinates synaptic networks. Science. 2005;310:113–6.

    Article  CAS  PubMed  Google Scholar 

  25. Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, et al. Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med. 2013;19:773–7.

    Article  CAS  PubMed  Google Scholar 

  26. Kim JG, Suyama S, Koch M, Jin S, Argente-Arizon P, Argente J, et al. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nat Neurosci. 2014;17:908–10.

    Article  CAS  PubMed  Google Scholar 

  27. Papouin T, Dunphy JM, Tolman M, Dineley KT, Haydon PG. Septal cholinergic neuromodulation tunes the astrocyte-dependent gating of hippocampal NMDA receptors to wakefulness. Neuron. 2017;94:840–54.e847.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Suzuki A, Stern SA, Bozdagi O, Huntley GW, Walker RH, Magistretti PJ, et al. Astrocyte-neuron lactate transport is required for long-term memory formation. Cell. 2011;144:810–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bennett MV, Contreras JE, Bukauskas FF, Saez JC. New roles for astrocytes: gap junction hemichannels have something to communicate. Trends Neurosci. 2003;26:610–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hamilton NB, Attwell D. Do astrocytes really exocytose neurotransmitters? Nat Rev Neurosci. 2010;11:227–38.

    Article  CAS  PubMed  Google Scholar 

  31. Sawada K, Echigo N, Juge N, Miyaji T, Otsuka M, Omote H, et al. Identification of a vesicular nucleotide transporter. Proc Natl Acad Sci USA. 2008;105:5683–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sakamoto S, Miyaji T, Hiasa M, Ichikawa R, Uematsu A, Iwatsuki K, et al. Impairment of vesicular ATP release affects glucose metabolism and increases insulin sensitivity. Sci Rep. 2014;4:6689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Masuda T, Ozono Y, Mikuriya S, Kohro Y, Tozaki-Saitoh H, Iwatsuki K, et al. Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain. Nat Commun. 2016;7:12529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kato Y, Ohsugi K, Fukuno Y, Iwatsuki K, Harada Y, Miyaji T. Vesicular nucleotide transporter is a molecular target of eicosapentaenoic acid for neuropathic and inflammatory pain treatment. Proc Natl Acad Sci USA. 2022;119:e2122158119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee EC, Yu D, Martinez de Velasco J, Tessarollo L, Swing DA, Court DL, et al. A highly efficient Escherichia coli-based chromosome engineering system adapted for recombinogenic targeting and subcloning of BAC DNA. Genomics. 2001;73:56–65.

    Article  CAS  PubMed  Google Scholar 

  36. Mazzone CM, Liang-Guallpa J, Li C, Wolcott NS, Boone MH, Southern M, et al. High-fat food biases hypothalamic and mesolimbic expression of consummatory drives. Nat Neurosci. 2020;23:1253–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Richardson NR, Roberts DC. Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods. 1996;66:1–11.

    Article  CAS  PubMed  Google Scholar 

  38. Garris PA, Ciolkowski EL, Pastore P, Wightman RM. Efflux of dopamine from the synaptic cleft in the nucleus accumbens of the rat brain. J Neurosci. 1994;14:6084–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Oya M, Kitaguchi T, Yanagihara Y, Numano R, Kakeyama M, Ikematsu K, et al. Vesicular nucleotide transporter is involved in ATP storage of secretory lysosomes in astrocytes. Biochem Biophys Res Commun. 2013;438:145–51.

    Article  CAS  PubMed  Google Scholar 

  40. Chao CC, Gutierrez-Vazquez C, Rothhammer V, Mayo L, Wheeler MA, Tjon EC, et al. Metabolic control of astrocyte pathogenic activity via cPLA2-MAVS. Cell. 2019;179:1483–98.e1422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Herrera Moro Chao D, Kirchner MK, Pham C, Foppen E, Denis RGP, Castel J, et al. Hypothalamic astrocytes control systemic glucose metabolism and energy balance. Cell Metab. 2022;34:1532–1547.e1536.

    Article  CAS  PubMed  Google Scholar 

  42. Garcia-Caceres C, Quarta C, Varela L, Gao Y, Gruber T, Legutko B, et al. Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell. 2016;166:867–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai HC, Finkelstein J, et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. 2013;493:537–41.

    Article  CAS  PubMed  Google Scholar 

  44. Nestler EJ, Carlezon WA Jr. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry. 2006;59:1151–9.

    Article  CAS  PubMed  Google Scholar 

  45. Belujon P, Grace AA. Dopamine system dysregulation in major depressive disorders. Int J Neuropsychopharmacol. 2017;20:1036–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Corkrum M, Covelo A, Lines J, Bellocchio L, Pisansky M, Loke K, et al. Dopamine-evoked synaptic regulation in the nucleus accumbens requires astrocyte activity. Neuron. 2020;105:1036–1047 e1035.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Srinivasan R, Lu TY, Chai H, Xu J, Huang BS, Golshani P, et al. New transgenic mouse lines for selectively targeting astrocytes and studying calcium signals in astrocyte processes in situ and in vivo. Neuron. 2016;92:1181–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cagniard B, Balsam PD, Brunner D, Zhuang X. Mice with chronically elevated dopamine exhibit enhanced motivation, but not learning, for a food reward. Neuropsychopharmacology. 2006;31:1362–70.

    Article  CAS  PubMed  Google Scholar 

  49. Bromberg-Martin ES, Matsumoto M, Hikosaka O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron. 2010;68:815–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang Z, Chen G, Zhou W, Song A, Xu T, Luo Q, et al. Regulated ATP release from astrocytes through lysosome exocytosis. Nat Cell Biol. 2007;9:945–53.

    Article  CAS  PubMed  Google Scholar 

  51. Jun M, Xiaolong Q, Chaojuan Y, Ruiyuan P, Shukun W, Junbing W, et al. Calhm2 governs astrocytic ATP releasing in the development of depression-like behaviors. Mol Psychiatry. 2018;23:1091.

    Article  CAS  PubMed  Google Scholar 

  52. Anselmi F, Hernandez VH, Crispino G, Seydel A, Ortolano S, Roper SD, et al. ATP release through connexin hemichannels and gap junction transfer of second messengers propagate Ca2+ signals across the inner ear. Proc Natl Acad Sci USA. 2008;105:18770–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhang YX, Yamashita H, Ohshita T, Sawamoto N, Nakamura S. ATP increases extracellular dopamine level through stimulation of P2Y purinoceptors in the rat striatum. Brain Res. 1995;691:205–12.

    Article  CAS  PubMed  Google Scholar 

  54. Robson SC, Sevigny J, Zimmermann H. The E-NTPDase family of ectonucleotidases: Structure function relationships and pathophysiological significance. Purinergic Signal. 2006;2:409–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Heuts DP, Weissenborn MJ, Olkhov RV, Shaw AM, Gummadova J, Levy C, et al. Crystal structure of a soluble form of human CD73 with ecto-5’-nucleotidase activity. Chembiochem. 2012;13:2384–91.

    Article  CAS  PubMed  Google Scholar 

  56. Cui QQ, Hu ZL, Hu YL, Chen X, Wang J, Mao L, et al. Hippocampal CD39/ENTPD1 promotes mouse depression-like behavior through hydrolyzing extracellular ATP. EMBO Rep. 2020;21:e47857.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Halassa MM, Florian C, Fellin T, Munoz JR, Lee SY, Abel T, et al. Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron. 2009;61:213–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Augusto E, Goncalves FQ, Real JE, Silva HB, Pochmann D, Silva TS, et al. Increased ATP release and CD73-mediated adenosine A(2A) receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction. Neurobiol Dis. 2021;157:105441.

    Article  CAS  PubMed  Google Scholar 

  59. Dias L, Pochmann D, Lemos C, Silva HB, Real JI, Goncalves FQ, et al. Increased synaptic ATP release and CD73-mediated formation of extracellular adenosine in the control of behavioral and electrophysiological modifications caused by chronic stress. ACS Chem Neurosci. 2023;14:1299–309.

    Article  CAS  PubMed  Google Scholar 

  60. Roberts BM, Lambert E, Livesey JA, Wu Z, Li Y, Cragg SJ. Dopamine release in nucleus accumbens is under tonic inhibition by adenosine A(1) receptors regulated by astrocytic ENT1 and dysregulated by ethanol. J Neurosci. 2022;42:1738–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Schubert V, Bouvier D, Volterra A. SNARE protein expression in synaptic terminals and astrocytes in the adult hippocampus: a comparative analysis. Glia. 2011;59:1472–88.

    Article  PubMed  Google Scholar 

  62. Rao SK, Huynh C, Proux-Gillardeaux V, Galli T, Andrews NW. Identification of SNAREs involved in synaptotagmin VII-regulated lysosomal exocytosis. J Biol Chem. 2004;279:20471–9.

    Article  CAS  PubMed  Google Scholar 

  63. Tao-Cheng JH, Pham A, Yang Y, Winters CA, Gallant PE, Reese TS. Syntaxin 4 is concentrated on plasma membrane of astrocytes. Neuroscience. 2015;286:264–71.

    Article  CAS  PubMed  Google Scholar 

  64. Verderio C, Cagnoli C, Bergami M, Francolini M, Schenk U, Colombo A, et al. TI-VAMP/VAMP7 is the SNARE of secretory lysosomes contributing to ATP secretion from astrocytes. Biol Cell. 2012;104:213–28.

    Article  CAS  PubMed  Google Scholar 

  65. Geffken SJ, Moon S, Smith CO, Tang S, Lee HH, Lewis K, et al. Insulin and IGF-1 elicit robust transcriptional regulation to modulate autophagy in astrocytes. Mol Metab. 2022;66:101647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Chen W, Cai W, Hoover B, Kahn CR. Insulin action in the brain: cell types, circuits, and diseases. Trends Neurosci. 2022;45:384–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chen W, Huang Q, Lazdon EK, Gomes A, Wong M, Stephens E, et al. Loss of insulin signaling in astrocytes exacerbates Alzheimer-like phenotypes in a 5xFAD mouse model. Proc Natl Acad Sci USA. 2023;120:e2220684120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Stouffer MA, Woods CA, Patel JC, Lee CR, Witkovsky P, Bao L, et al. Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward. Nat Commun. 2015;6:8543.

    Article  CAS  PubMed  Google Scholar 

  69. Mancini M, Patel JC, Affinati AH, Witkovsky P, Rice ME. Leptin promotes striatal dopamine release via cholinergic interneurons and regionally distinct signaling pathways. J Neurosci. 2022;42:6668–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kleinridders A, Cai W, Cappellucci L, Ghazarian A, Collins WR, Vienberg SG, et al. Insulin resistance in brain alters dopamine turnover and causes behavioral disorders. Proc Natl Acad Sci USA. 2015;112:3463–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Requie LM, Gomez-Gonzalo M, Speggiorin M, Manago F, Melone M, Congiu M, et al. Astrocytes mediate long-lasting synaptic regulation of ventral tegmental area dopamine neurons. Nat Neurosci. 2022;25:1639–50.

    Article  CAS  PubMed  Google Scholar 

  72. Angelova PR, Iversen KZ, Teschemacher AG, Kasparov S, Gourine AV, Abramov AY. Signal transduction in astrocytes: localization and release of inorganic polyphosphate. Glia. 2018;66:2126–36.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Dinarvand P, Hassanian SM, Qureshi SH, Manithody C, Eissenberg JC, Yang L, et al. Polyphosphate amplifies proinflammatory responses of nuclear proteins through interaction with receptor for advanced glycation end products and P2Y1 purinergic receptor. Blood. 2014;123:935–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bezzi P, Gundersen V, Galbete JL, Seifert G, Steinhauser C, Pilati E, et al. Astrocytes contain a vesicular compartment that is competent for regulated exocytosis of glutamate. Nat Neurosci. 2004;7:613–20.

    Article  CAS  PubMed  Google Scholar 

  75. de Ceglia R, Ledonne A, Litvin DG, Lind BL, Carriero G, Latagliata EC, et al. Specialized astrocytes mediate glutamatergic gliotransmission in the CNS. Nature. 2023;622:120–9.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Cuellar-Santoyo AO, Ruiz-Rodriguez VM, Mares-Barbosa TB, Patron-Soberano A, Howe AG, Portales-Perez DP, et al. Revealing the contribution of astrocytes to glutamatergic neuronal transmission. Front Cell Neurosci. 2022;16:1037641.

    Article  CAS  PubMed  Google Scholar 

  77. Larsson M, Sawada K, Morland C, Hiasa M, Ormel L, Moriyama Y, et al. Functional and anatomical identification of a vesicular transporter mediating neuronal ATP release. Cereb Cortex. 2012;22:1203–14.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by NIH grants R01 MH125903 and R03 AG083363 (to W.C.) and the Programs in Pharmacology and Experimental Therapeutics and Pharmacology and Drug Development of the Tufts University Graduate School of Biomedical Sciences (E.N.P.). We thank Dr. Bradford Lowell’s laboratory at BIDMC, Harvard Medical School for the development and sharing of the Vnutf/f mice (P30 DK057521, P30 DK046200, R01 DK075632, R01 DK096010, R01 DK089044, and R01 DK071051, to B.B.L). A.E. is funded by an NIH grant R01 DK122167. The Imaging Center at the New York Institute of Technology provided important support.

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  1. Department of Molecular and Cellular Biochemistry, the Barnstable Brown Diabetes and Obesity Center, University of Kentucky College of Medicine, Lexington, KY, USA

    Qian Huang & Weikang Cai

  2. Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY, USA

    Qian Huang, Hiu Ham Lee, Bryan Volpe, Allen Li, Alyssa Lee, Sharon Tang, Chun Wa Wong, Yuan Huang, Raddy L. Ramos, Randy F. Stout & Weikang Cai

  3. Program in Pharmacology and Experimental Therapeutics and Pharmacology and Drug Development, Graduate School of Biomedical Sciences and Department of Immunology, Tufts University School of Medicine, Boston, MA, USA

    Qingchen Zhang, Chang Xue, Yahia R. Abuhasan, Lingyun Li, Jeremy S. Yang, Julie Egholm & Emmanuel N. Pothos

  4. Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA

    Brian C. Liu & C. Ronald Kahn

  5. Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Cristina Gutierrez-Vazquez & Francisco J. Quintana

  6. Key Laboratory of Genetic Engineering, Department of Endocrinology and Metabolism, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, PR China

    Tiemin Liu

  7. Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA

    Tiemin Liu & Bradford B. Lowell

  8. Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA

    Abdelfattah El Ouaamari

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Contributions

HQ designed the study, performed experiments, and analyzed data. HHL, BV, QZ, CX, BCL, YRA, LL, JSY, JE, CGV, AL, AL, ST, CWW, TL, YH, RLR, RFS, AEO, FJQ, and BBL helped design and performed experiments. CRK and ENP helped design the experiments and provided edits for the manuscript. WC designed the study, supervised all work, and wrote the manuscript.

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Correspondence to Weikang Cai.

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Huang, Q., Lee, H.H., Volpe, B. et al. Deletion of murine astrocytic vesicular nucleotide transporter increases anxiety and depressive-like behavior and attenuates motivation for reward. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02692-5

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  • DOI: https://doi.org/10.1038/s41380-024-02692-5

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