Direct modulation of GFAP-expressing glia in the arcuate nucleus bi-directionally regulates feeding

eLife

Volumn 5, Issue OCTOBER2016, 2016, Pages

  Chen, Naiyan ^a,b   Sugihara, Hiroki ^c   Kim, Jinah ^b   Fu, Zhanyan ^b,d   Barak, Boaz ^b   Sur, Mriganka ^c   Feng, Guoping ^b,d   Han, Weiping ^a  

^a AGENCY FOR SCIENCE   (Singapore)

^b MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^c MASSACHUSETTS INSTITUTE OF TECHNOLOGY   (United States)

^d BROAD INSTITUTE OF MIT AND HARVARD   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLIAL FIBRILLARY ACIDIC PROTEIN; VIMENTIN; GLIAL FIBRILLARY ASTROCYTIC PROTEIN, MOUSE;

ADULT; ANIMAL MODEL; ANIMAL TISSUE; ARCUATE NUCLEUS; ARTICLE; CONFOCAL MICROSCOPY; CONTROLLED STUDY; ELECTROPHYSIOLOGY; FEEDING BEHAVIOR; FOOD INTAKE; GLIA CELL; IMMUNOHISTOCHEMISTRY; MOUSE; NONHUMAN; PROTEIN EXPRESSION; SIGNAL TRANSDUCTION; VIRUS EXPRESSION; ANIMAL; BIOSYNTHESIS; CALCIUM SIGNALING; CYTOLOGY; GLIA; PHYSIOLOGY;

ANIMALS; ARCUATE NUCLEUS OF HYPOTHALAMUS; CALCIUM SIGNALING; FEEDING BEHAVIOR; GLIAL FIBRILLARY ACIDIC PROTEIN; MICE; NEUROGLIA;

EID: 84992130085     PISSN: None     EISSN: 2050084X     Source Type: Journal    
DOI: 10.7554/eLife.18716     Document Type: Article

References (79)

1. Agulhon C, Boyt KM, Xie AX, Friocourt F, Roth BL, McCarthy KD. 2013. Modulation of the autonomic nervous system and behaviour by acute glial cell Gq protein-coupled receptor activation in vivo. The Journal of Physiology 591:5599-5609. doi: 10.1113/jphysiol.2013.261289
2. Agulhon C, Petravicz J, McMullen AB, Sweger EJ, Minton SK, Taves SR, Casper KB, Fiacco TA, McCarthy KD. 2008. What is the role of astrocyte calcium in neurophysiology? Neuron 59:932-946. doi: 10.1016/j.neuron.2008.09.004
3. Agulhon C, Sun MY, Murphy T, Myers T, Lauderdale K, Fiacco TA. 2012. Calcium signaling and gliotransmission in normal vs. reactive astrocytes. Frontiers in Pharmacology 3:139. doi: 10.3389/fphar.2012.00139
4. Alexander GM, Rogan SC, Abbas AI, Armbruster BN, Pei Y, Allen JA, Nonneman RJ, Hartmann J, Moy SS, Nicolelis MA, McNamara JO, Roth BL. 2009. Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron 63:27-39. doi: 10.1016/j.neuron.2009.06.014
5. Allen NJ, Barres BA. 2009. Neuroscience: Glia - more than just brain glue. Nature 457:675-677. doi: 10.1038/457675a
6. Aponte Y, Atasoy D, Sternson SM. 2011. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nature Neuroscience 14:351-355. doi: 10.1038/nn.2739
7. Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, Pirola RC, Wilson JS. 1998. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 43:128-133. doi: 10.1136/gut.43.1.128
8. Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL. 2007. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. PNAS 104:5163-5168. doi: 10.1073/pnas.0700293104
9. Atasoy D, Betley JN, Su HH, Sternson SM. 2012. Deconstruction of a neural circuit for hunger. Nature 488:172-177. doi: 10.1038/nature11270
10. Bazargani N, Attwell D. 2016. Astrocyte calcium signaling: the third wave. Nature Neuroscience 19:182-189. doi:10.1038/nn.4201
11. Bjørbaek C, Kahn BB. 2004. Leptin signaling in the central nervous system and the periphery. Recent Progress in Hormone Research 59:305-332. doi: 10.1210/rp.59.1.305
12. Bolborea M, Dale N. 2013. Hypothalamic tanycytes: potential roles in the control of feeding and energy balance. Trends in Neurosciences 36:91-100. doi: 10.1016/j.tins.2012.12.008
13. Buckman LB, Thompson MM, Lippert RN, Blackwell TS, Yull FE, Ellacott KL. 2015. Evidence for a novel functional role of astrocytes in the acute homeostatic response to high-fat diet intake in mice. Molecular Metabolism 4: 58-63. doi: 10.1016/j.molmet.2014.10.001
14. Buniatian G, Traub P, Albinus M, Beckers G, Buchmann A, Gebhardt R, Osswald H. 1998. The immunoreactivity of glial fibrillary acidic protein in mesangial cells and podocytes of the glomeruli of rat kidney in vivo and in culture. Biology of the Cell 90:53-61. doi: 10.1016/S0248-4900(98)80232-3
15. Chen N, Sugihara H, Sharma J, Perea G, Petravicz J, Le C, Sur M. 2012. Nucleus basalis-enabled stimulus-specific plasticity in the visual cortex is mediated by astrocytes. PNAS 109:E2832-E2841. doi: 10.1073/pnas.1206557109
16. Chen Y, Lin YC, Kuo TW, Knight ZA. 2015. Sensory detection of food rapidly modulates arcuate feeding circuits. Cell 160:829-841. doi: 10.1016/j.cell.2015.01.033
17. Cheunsuang O, Morris R. 2005. Astrocytes in the arcuate nucleus and median eminence that take up a fluorescent dye from the circulation express leptin receptors and neuropeptide Y Y1 receptors. Glia 52:228-233. doi: 10.1002/glia.20239
18. Cowley MA, Smart JL, Rubinstein M, Cerdán MG, Diano S, Horvath TL, Cone RD, Low MJ. 2001. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411:480-484. doi: 10.1038/35078085
19. Dale N. 2011. Purinergic signaling in hypothalamic tanycytes: potential roles in chemosensing. Seminars in Cell & Developmental Biology 22:237-244. doi: 10.1016/j.semcdb.2011.02.024
20. Dorfman MD, Thaler JP. 2015. Hypothalamic inflammation and gliosis in obesity. Current Opinion in Endocrinology & Diabetes and Obesity 22:325-330. doi: 10.1097/MED.0000000000000182
21. Eroglu C, Barres BA. 2010. Regulation of synaptic connectivity by glia. Nature 468:223-231. doi: 10.1038/nature09612
22. Fields RD, Burnstock G. 2006. Purinergic signalling in neuron-glia interactions. Nature Reviews Neuroscience 7: 423-436. doi: 10.1038/nrn1928
23. Fu LY, van den Pol AN. 2010. Kisspeptin directly excites anorexigenic proopiomelanocortin neurons but inhibits orexigenic neuropeptide Y cells by an indirect synaptic mechanism. Journal of Neuroscience 30:10205-10219. doi: 10.1523/JNEUROSCI.2098-10.2010
24. García-Cáceres C, Fuente-Martín E, Díaz F, Granado M, Argente-Arizón P, Frago LM, Freire-Regatillo A, Barrios V, Argente J, Chowen JA. 2014. The opposing effects of ghrelin on hypothalamic and systemic inflammatory processes are modulated by its acylation status and food intake in male rats. Endocrinology 155:2868-2880. doi: 10.1210/en.2014-1074
25. García-Cáceres C, Quarta C, Varela L, Gao Y, Gruber T, Legutko B, Jastroch M, Johansson P, Ninkovic J, Yi CX, Le Thuc O, Szigeti-Buck K, Cai W, Meyer CW, Pfluger PT, Fernandez AM, Luquet S, Woods SC, Torres-Alemán I, Kahn CR, et al. 2016. Astrocytic insulin signaling couples brain glucose uptake with nutrient availability. Cell 166:867-880. doi: 10.1016/j.cell.2016.07.028
26. Gautron L, Elmquist JK. 2011. Sixteen years and counting: an update on leptin in energy balance. Journal of Clinical Investigation 121:2087-2093. doi: 10.1172/JCI45888
27. Georgescu D, Sears RM, Hommel JD, Barrot M, Bolan˜ os CA, Marsh DJ, Bednarek MA, Bibb JA, Maratos-Flier E, Nestler EJ, DiLeone RJ. 2005. The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance. Journal of Neuroscience 25: 2933-2940. doi: 10.1523/JNEUROSCI.1714-04.2005
28. Gourine AV, Kasymov V, Marina N, Tang F, Figueiredo MF, Lane S, Teschemacher AG, Spyer KM, Deisseroth K, Kasparov S. 2010. Astrocytes control breathing through pH-dependent release of ATP. Science 329:571-575. doi: 10.1126/science.1190721
29. Halassa MM, Fellin T, Haydon PG. 2007. The tripartite synapse: roles for gliotransmission in health and disease. Trends in Molecular Medicine 13:54-63. doi: 10.1016/j.molmed.2006.12.005
30. Halassa MM, Florian C, Fellin T, Munoz JR, Lee SY, Abel T, Haydon PG, Frank MG. 2009. Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss. Neuron 61:213-219. doi: 10.1016/j.neuron.2008.11.024
31. Halassa MM, Haydon PG. 2010. Integrated brain circuits: astrocytic networks modulate neuronal activity and behavior. Annual Review of Physiology 72:335-355. doi: 10.1146/annurev-physiol-021909-135843
32. Haydon PG, Carmignoto G. 2006. Astrocyte control of synaptic transmission and neurovascular coupling. Physiological Reviews 86:1009-1031. doi: 10.1152/physrev.00049.2005
33. Hommel JD, Trinko R, Sears RM, Georgescu D, Liu ZW, Gao XB, Thurmon JJ, Marinelli M, DiLeone RJ. 2006. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51:801-810. doi: 10.1016/j.neuron.2006.08.023
34. Horvath TL, Sarman B, García-Cáceres C, Enriori PJ, Sotonyi P, Shanabrough M, Borok E, Argente J, Chowen JA, Perez-Tilve D, Pfluger PT, Bronneke HS, Levin BE, Diano S, Cowley MA, Tschop MH. 2010. Synaptic input organization of the melanocortin system predicts diet-induced hypothalamic reactive gliosis and obesity. PNAS 107:14875-14880. doi: 10.1073/pnas.1004282107
35. Hsuchou H, Kastin AJ, Tu H, Joan Abbott N, Couraud PO, Pan W. 2010. Role of astrocytic leptin receptor subtypes on leptin permeation across hCMEC/D3 human brain endothelial cells. Journal of Neurochemistry 115:1288-1298. doi: 10.1111/j.1471-4159.2010.07028.x
36. Hsuchou H, Pan W, Barnes MJ, Kastin AJ. 2009. Leptin receptor mRNA in rat brain astrocytes. Peptides 30: 2275-2280. doi: 10.1016/j.peptides.2009.08.023
37. Jayaram B, Pan W, Wang Y, Hsuchou H, Mace A, Cornelissen-Guillaume GG, Mishra PK, Koza RA, Kastin AJ. 2013. Astrocytic leptin-receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity. Journal of Applied Physiology 114:734-741. doi: 10.1152/japplphysiol.01499.2012
38. Jennings JH, Rizzi G, Stamatakis AM, Ung RL, Stuber GD. 2013. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science 341:1517-1521. doi: 10.1126/science.1241812
39. Jourdain P, Bergersen LH, Bhaukaurally K, Bezzi P, Santello M, Domercq M, Matute C, Tonello F, Gundersen V, Volterra A. 2007. Glutamate exocytosis from astrocytes controls synaptic strength. Nature Neuroscience 10: 331-339. doi: 10.1038/nn1849
40. Kanemaru K, Kubota J, Sekiya H, Hirose K, Okubo Y, Iino M. 2013. Calcium-dependent N-cadherin up-regulation mediates reactive astrogliosis and neuroprotection after brain injury. PNAS 110:11612-11617. doi: 10.1073/pnas.1300378110
41. Kim JG, Suyama S, Koch M, Jin S, Argente-Arizon P, Argente J, Liu Z-W, Zimmer MR, Jeong JK, Szigeti-Buck K, Gao Y, Garcia-Caceres C, Yi C-X, Salmaso N, Vaccarino FM, Chowen J, Diano S, Dietrich MO, Tschop MH, Horvath TL. 2014. Leptin signaling in astrocytes regulates hypothalamic neuronal circuits and feeding. Nature Neuroscience 17:908-910. doi: 10.1038/nn.3725
42. Klockener T, Hess S, Belgardt BF, Paeger L, Verhagen LA, Husch A, Sohn JW, Hampel B, Dhillon H, Zigman JM, Lowell BB, Williams KW, Elmquist JK, Horvath TL, Kloppenburg P, Bruning JC. 2011. High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nature Neuroscience 14:911-918. doi: 10.1038/nn.2847
43. Koch M, Varela L, Kim JG, Kim JD, Hernández-Nuñ F, Simonds SE, Castorena CM, Vianna CR, Elmquist JK, Morozov YM, Rakic P, Bechmann I, Cowley MA, Szigeti-Buck K, Dietrich MO, Gao XB, Diano S, Horvath TL. 2015. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature 519:45-50. doi: 10.1038/nature14260
44. Kong D, Tong Q, Ye C, Koda S, Fuller PM, Krashes MJ, Vong L, Ray RS, Olson DP, Lowell BB. 2012. GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell 151:645-657. doi: 10.1016/j.cell.2012.09.020
45. Krashes MJ, Koda S, Ye C, Rogan SC, Adams AC, Cusher DS, Maratos-Flier E, Roth BL, Lowell BB. 2011. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. Journal of Clinical Investigation 121: 1424-1428. doi: 10.1172/JCI46229
46. Krashes MJ, Shah BP, Koda S, Lowell BB. 2013. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metabolism 18:588-595. doi: 10.1016/j.cmet.2013.09.009
47. Lalo U, Pankratov Y, Kirchhoff F, North RA, Verkhratsky A. 2006. NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes. Journal of Neuroscience 26:2673-2683. doi: 10.1523/JNEUROSCI.4689-05.2006
48. Lee SJ, Verma S, Simonds SE, Kirigiti MA, Kievit P, Lindsley SR, Loche A, Smith MS, Cowley MA, Grove KL. 2013. Leptin stimulates neuropeptide Y and cocaine amphetamine-regulated transcript coexpressing neuronal activity in the dorsomedial hypothalamus in diet-induced obese mice. Journal of Neuroscience 33:15306-15317. doi:10.1523/JNEUROSCI.0837-13.2013
49. Li D, Agulhon C, Schmidt E, Oheim M, Ropert N. 2013. New tools for investigating astrocyte-to-neuron communication. Frontiers in Cellular Neuroscience 7:193. doi: 10.3389/fncel.2013.00193
50. Mandelblat-Cerf Y, Ramesh RN, Burgess CR, Patella P, Yang Z, Lowell BB, Andermann ML. 2015. Arcuate hypothalamic AgRP and putative POMC neurons show opposite changes in spiking across multiple timescales. eLife 4:e07122. doi: 10.7554/eLife.07122
51. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. 2006. Central nervous system control of food intake and body weight. Nature 443:289-295. doi: 10.1038/nature05026
52. Murphy KG, Bloom SR. 2006. Gut hormones and the regulation of energy homeostasis. Nature 444:854-859. doi: 10.1038/nature05484
53. Nedergaard M, Ransom B, Goldman SA. 2003. New roles for astrocytes: redefining the functional architecture of the brain. Trends in Neurosciences 26:523-530. doi: 10.1016/j.tins.2003.08.008
54. Nolte C, Matyash M, Pivneva T, Schipke CG, Ohlemeyer C, Hanisch UK, Kirchhoff F, Kettenmann H. 2001. GFAP promoter-controlled EGFP-expressing transgenic mice: a tool to visualize astrocytes and astrogliosis in living brain tissue. Glia 33:72-86. doi: 10.1002/1098-1136(20010101)33:1<72::AID-GLIA1007>3.0.CO;2-A
55. Palkovits M, Deli MA, Gallatz K, Tóth ZE, Buzás E, Falus A. 2007. Highly activated c-fos expression in specific brain regions (ependyma, circumventricular organs, choroid plexus) of histidine decarboxylase deficient mice in response to formalin-induced acute pain. Neuropharmacology 53:101-112. doi: 10.1016/j.neuropharm.2007.04.001
56. Pan W, Hsuchou H, He Y, Sakharkar A, Cain C, Yu C, Kastin AJ. 2008. Astrocyte leptin receptor (ObR) and leptin transport in adult-onset obese mice. Endocrinology 149:2798-2806. doi: 10.1210/en.2007-1673
57. Pang ZP, Han W. 2012. Regulation of synaptic functions in central nervous system by endocrine hormones and the maintenance of energy homoeostasis. Bioscience Reports 32:423-432. doi: 10.1042/BSR20120026
58. Pannasch U, Freche D, Dallérac G, Ghézali G, Escartin C, Ezan P, Cohen-Salmon M, Benchenane K, Abudara V, Dufour A, Lubke JH, Déglon N, Knott G, Holcman D, Rouach N. 2014. Connexin 30 sets synaptic strength by controlling astroglial synapse invasion. Nature Neuroscience 17:549-558. doi: 10.1038/nn.3662
59. Parpura V, Zorec R. 2010. Gliotransmission: Exocytotic release from astrocytes. Brain Research Reviews 63:83-92. doi: 10.1016/j.brainresrev.2009.11.008
60. Pei H, Sutton AK, Burnett KH, Fuller PM, Olson DP. 2014. AVP neurons in the paraventricular nucleus of the hypothalamus regulate feeding. Molecular Metabolism 3:209-215. doi: 10.1016/j.molmet.2013.12.006
61. Perea G, Yang A, Boyden ES, Sur M. 2014. Optogenetic astrocyte activation modulates response selectivity of visual cortex neurons in vivo. Nature Communications 5:3262. doi: 10.1038/ncomms4262
62. Ramírez D, Saba J, Carniglia L, Durand D, Lasaga M, Caruso C. 2015. Melanocortin 4 receptor activates ERK-cFos pathway to increase brain-derived neurotrophic factor expression in rat astrocytes and hypothalamus. Molecular and Cellular Endocrinology 411:28-37. doi: 10.1016/j.mce.2015.04.008
63. Reeves AM, Shigetomi E, Khakh BS. 2011. Bulk loading of calcium indicator dyes to study astrocyte physiology: key limitations and improvements using morphological maps. Journal of Neuroscience 31:9353-9358. doi: 10.1523/JNEUROSCI.0127-11.2011
64. Rodríguez EM, Blázquez JL, Pastor FE, Peláez B, Peña P, Peruzzo B, Amat P. 2005. Hypothalamictanycytes:a key component of brain-endocrine interaction. International Review of Cytology 247:89-164. doi: 10.1016/S0074-7696(05)47003-5
65. Roth BL. 2016. DREADDs for neuroscientists. Neuron 89:683-694. doi: 10.1016/j.neuron.2016.01.040
66. Schummers J, Yu H, Sur M. 2008. Tuned responses of astrocytes and their influence on hemodynamic signals in the visual cortex. Science 320:1638-1643. doi: 10.1126/science.1156120
67. Scofield MD, Boger HA, Smith RJ, Li H, Haydon PG, Kalivas PW. 2015. Gq-DREADD selectively initiates glial glutamate release and inhibits cue-induced cocaine seeking. Biological Psychiatry 78:441-451. doi: 10.1016/j.biopsych.2015.02.016
68. Sigma-Aldrich. 2016. Clozapine N-Oxide Safety Data Sheet. http://www.sigmaaldrich.com/MSDS/MSDS/DisplayMSDSPage.do?country=US&language=en&productNumber=C0832&brand=SIGMA&PageToGoToURL=http%3A%2F%2Fwww.sigmaaldrich.com%2Fcatalog%2Fproduct%2Fsigma%2Fc0832%3Flang%3Den
69. van den Pol AN, Yao Y, Fu LY, Foo K, Huang H, Coppari R, Lowell BB, Broberger C. 2009. Neuromedin B and gastrin-releasing peptide excite arcuate nucleus neuropeptide Y neurons in a novel transgenic mouse expressing strong Renilla green fluorescent protein in NPY neurons. Journal of Neuroscience 29:4622-4639. doi: 10.1523/JNEUROSCI.3249-08.2009
70. van den Top M, Lee K, Whyment AD, Blanks AM, Spanswick D. 2004. Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus. Nature Neuroscience 7:493-494. doi: 10.1038/nn1226
71. Volterra A, Meldolesi J. 2005. Astrocytes, from brain glue to communication elements: the revolution continues. Nature Reviews Neuroscience 6:626-640. doi: 10.1038/nrn1722
72. Vong L, Ye C, Yang Z, Choi B, Chua S, Lowell BB. 2011. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71:142-154. doi: 10.1016/j.neuron.2011.05.028
73. Wang F, Smith NA, Xu Q, Fujita T, Baba A, Matsuda T, Takano T, Bekar L, Nedergaard M. 2012. Astrocytes modulate neural network activity by Ca2+-dependent uptake of extracellular K+. Science Signaling 5:ra26. doi:10.1126/scisignal.2002334
74. Wu Q, Lemus MB, Stark R, Bayliss JA, Reichenbach A, Lockie SH, Andrews ZB. 2014. The temporal pattern of cfos activation in hypothalamic, cortical, and brainstem nuclei in response to fasting and refeeding in male mice. Endocrinology 155:840-853. doi: 10.1210/en.2013-1831
75. Xie AX, Petravicz J, McCarthy KD. 2015. Molecular approaches for manipulating astrocytic signaling in vivo. Frontiers in Cellular Neuroscience 9:144. doi: 10.3389/fncel.2015.00144
76. Xie Y, Wang T, Sun GY, Ding S. 2010. Specific disruption of astrocytic Ca2+ signaling pathway in vivo by adeno-associated viral transduction. Neuroscience 170:992-1003. doi: 10.1016/j.neuroscience.2010.08.034
77. Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, Tominaga M, Yagami K, Sugiyama F, Goto K, Yanagisawa M, Sakurai T. 2003. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38:701-713. doi: 10.1016/S0896-6273(03)00331-3
78. Yang L, Qi Y, Yang Y. 2015. Astrocytes control food intake by inhibiting AGRP neuron activity via adenosine A1 receptors. Cell Reports 11:798-807. doi: 10.1016/j.celrep.2015.04.002
79. Zhan C, Zhou J, Feng Q, Zhang JE, Lin S, Bao J, Wu P, Luo M. 2013. Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. Journal of Neuroscience 33: 3624-3632. doi: 10.1523/JNEUROSCI.2742-12.2013