709CHAPTER 58 Structure, Function, and Development of the Nervous System encephalopathies, septic encephalopathy, and traumatic brain in jury In addition to effects on inflammatory cells, gut microbio[.]
CHAPTER 58 Structure, Function, and Development of the Nervous System encephalopathies, septic encephalopathy, and traumatic brain injury In addition to effects on inflammatory cells, gut microbiota can directly influence brain levels of neurotransmitters, including GABA and glutamate.129 A recent study demonstrated that transplantation of the gut microbiome from children with autistic spectrum disorder into pathogen-free normal mice elicited behavioral and social deficits traditionally associated with mouse genetic models of autism.130 Intriguingly, correction of specific metabolite disturbances in transplanted mice also corrected the behavioral deficits These and other studies suggest that the gut-microbiomebrain communication axis contributes to brain development and function, representing a fertile area for future discoveries Conclusion The nervous system is undergoing active development and is often the primarily affected organ when children are hospitalized with a life-threatening illness Appreciation of normal anatomy and development, as well as knowledge of neurotransmitter systems and homeostatic mechanisms, is required for prompt diagnosis and effective clinical care Most important, ongoing research into the interaction between developmental processes and injury is likely to yield a wealth of new information, implying the need for continuous reevaluation of current knowledge and clinical practice in light of new discoveries Key References Begley DJ ABC Transporters and the blood-brain barrier Curr Pharm Des 2004;10:1295-1312 Belelli D, Harrison NL, Maguire J, Macdonald RL, Walker MC, Cope DW Extrasynaptic GABAA receptors: form, pharmacology, and function J Neurosci 2009;29(41):12757-12763 709 Bowie D Ionotropic glutamate receptors & CNS disorders CNS Neurol Disord Drug Targets 2008;7(2):129-143 Chugani HT, Phelps ME, Mazziotta JC Positron emission tomography study of human brain functional development Ann Neurol 1987; 22(4):487-497 Conn PJ, Pin JP Pharmacology and functions of metabotropic glutamate receptors Annu Rev Pharmacol Toxicol 1997;37(1):205-237 Dani JA, Bertrand D Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system Annu Rev Pharmacol Toxicol 2007;47:699-729 Engelhardt B, Sorokin L The blood–brain and the blood–cerebrospinal fluid barriers: function and dysfunction Semin Immunopathol 2009; 31:497-511 Eyo UB, Dailey ME Microglia: key elements in neural development, plasticity, and pathology J Neuroimmune Pharmacol 2013;8(3):494-509 Herlenius E, Lagercrantz H Development of neurotransmitter systems during critical periods Exp Neurol 2004;190(suppl 1):S8-S21 Kennedy C, Sokoloff L An adaptation of the nitrous oxide method to the study of the cerebral circulation in children; normal values for cerebral blood flow and cerebral metabolic rate in childhood J Clin Invest 1957;36(7):1130-1137 Lang B, Vincent A Autoimmune disorders of the neuromuscular junction Curr Opin Pharmacol 2009;9(3):336-340 Lassen NA Cerebral blood flow and oxygen consumption in man Physiol Rev 1959;39(2):183-238 Paus T, Collins DL, Evans AC, Leonard G, Pike B, Zijdenbos A Maturation of white matter in the human brain: a review of magnetic resonance studies Brain Res Bull 2001;54(3):255-266 Prins ML Cerebral metabolic adaptation and ketone metabolism after brain injury J Cereb Blood Flow Metab 2008;28(1):1-16 Qutub AA, Hunt CA Glucose transport to the brain: a systems model Brain Res Brain Res Rev 2005;49(3):595-617 The full reference list for this chapter is available at ExpertConsult.com e1 References Thameem Dheen S, Kaur C, Ling E-A Microglial activation and its implications in the brain diseases Curr Med Chem 2007;14: 1189-1197 Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B Microglia: dynamic mediators of synapse development and plasticity Trends Immunol 2015;36(10):605-613 Tang M, Alexander H, Clark RS, Kochanek PM, Kagan VE, Bayir H Minocycline reduces neuronal death and attenuates microglial response after pediatric asphyxial cardiac arrest J Cereb Blood Flow Metab 2010;30:119-129 Yong VW, Rivest S Taking advantage of the systemic immune system to cure brain diseases Neuron 2009;64(1):55-60 Lampl Y, Boaz M, Gilad R, et al Minocycline treatment in acute stroke: an open-label, evaluator-blinded study Neurology 2007; 69(14):1404-1410 Sohl G, Maxeiner S, Willecke K Expression and functions of neuronal gap junctions Nat Rev Neurosci 2005;6(3):191-200 Bargiotas P, Monyer H, Schwaninger M Hemichannels in cerebral ischemia Curr Mol Med 2009;9(2):186-194 Bergoffen J, Scherer SS, Wang S, et al Connexin mutations in X-linked Charcot-Marie-Tooth disease Science 1993;262(5142): 2039-2042 Tseng-Ong L, Mitchell WG Infant botulism: 20 years’ experience at a single institution J Child Neurol 2007;22(12):1333-1337 10 Lang B, Vincent A Autoimmune disorders of the neuromuscular junction Curr Opin Pharmacol 2009;9(3):336-340 11 Zeisel SH The fetal origins of memory: the role of dietary choline in optimal brain development J Pediatr 2006;149(suppl 5): S131-S136 12 Steinfeld R, Grapp M, Kraetzner R, et al Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism Am J Hum Genet 2009;85(3):354-363 13 Buchman AL, Dubin MD, Moukarzel AA, et al Choline deficiency: a cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation Hepatology 1995;22(5):1399-1403 14 Buchman AL, Sohel M, Brown M, et al Verbal and visual memory improve after choline supplementation in long-term total parenteral nutrition: a pilot study JPEN J Parenter Enteral Nutr 2001;25(1): 30-35 15 Duncan JR, Paterson DS, Hoffman JM, et al Brainstem serotonergic deficiency in sudden infant death syndrome JAMA 2010;303(5): 430-437 16 Lin LH Glutamatergic neurons say NO in the nucleus tractus solitarii J Chem Neuroanat 2009;38(3):154-165 17 Qu K, Lee SW, Bian JS, Low CM, Wong PT Hydrogen sulfide: neurochemistry and neurobiology Neurochem Int 2008;52(1-2): 155-165 18 Blackstone E, Morrison M, Roth MB H2S induces a suspended animation-like state in mice Science 2005;308(5721):518 19 Minamishima S, Bougaki M, Sips PY, et al Hydrogen sulfide improves survival after cardiac arrest and cardiopulmonary resuscitation via a nitric oxide synthase 3-dependent mechanism in mice Circulation 2009;120(10):888-896 20 Dani JA, Bertrand D Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system Annu Rev Pharmacol Toxicol 2007;47:699-729 21 Steinlein OK, Mulley JC, Propping P, et al A missense mutation in the neuronal nicotinic acetylcholine receptor alpha subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy Nat Genet 1995;11(2):201-203 22 Oldani A, Zucconi M, Asselta R, et al Autosomal dominant nocturnal frontal lobe epilepsy A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome Brain 1998;121( Pt 2):205-223 23 Eglen RM Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function Auton Autacoid Pharmacol 2006;26(3): 219-233 24 Langmead CJ, Watson J, Reavill C Muscarinic acetylcholine receptors as CNS drug targets Pharmacol Ther 2008;117(2):232-243 25 Barthold CL, Schier JG Organic phosphorus compounds—nerve agents Crit Care Clin 2005;21(4):673-689, v-vi 26 Bowie D Ionotropic glutamate receptors & CNS disorders CNS Neurol Disord Drug Targets 2008;7(2):129-143 27 Conn PJ, Pin J-P Pharmacology and functions of metabotropic glutamate receptors Annu Rev Pharmacol Toxicol 1997;37(1): 205-237 28 Tang FR, Bradford HF, Ling EA Metabotropic glutamate receptors in the control of neuronal activity and as targets for development of anti-epileptogenic drugs Curr Med Chem 2009;16(17):2189-2204 29 D’Hulst C, Atack JR, Kooy RF The complexity of the GABAA receptor shapes unique pharmacological profiles Drug Discov Today 2009;14(17-18):866-875 30 Belelli D, Harrison NL, Maguire J, Macdonald RL, Walker MC, Cope DW Extrasynaptic GABAA receptors: form, pharmacology, and function J Neurosci 2009;29(41):12757-12763 31 Baulac S, Huberfeld G, Gourfinkel-An I, et al First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene Nat Genet 2001;28(1):46-48 32 Wallace RH, Marini C, Petrou S, et al Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures Nat Genet 2001;28(1):49-52 33 Loup F, Wieser HG, Yonekawa Y, Aguzzi A, Fritschy JM Selective alterations in GABAA receptor subtypes in human temporal lobe epilepsy J Neurosci 2000;20(14):5401-5419 34 Cohen I, Navarro V, Clemenceau S, Baulac M, Miles R On the origin of interictal activity in human temporal lobe epilepsy in vitro Science 2002;298(5597):1418-1421 35 Mohler H GABAA receptors in central nervous system disease: anxiety, epilepsy, and insomnia J Recept Signal Transduct Res 2006;26(5-6):731-740 36 Bowery NG GABAB receptor: a site of therapeutic benefit Curr Opin Pharmacol 2006;6(1):37-43 37 Misgeld U, Bijak M, Jarolimek W A physiological role for GABAB receptors and the effects of baclofen in the mammalian central nervous system Prog Neurobiol 1995;46(4):423-462 38 Francois B, Vacher P, Roustan J, et al Intrathecal baclofen after traumatic brain injury: early treatment using a new technique to prevent spasticity J Trauma 2001;50(1):158-161 39 Penn RD, Savoy SM, Corcos D, et al Intrathecal baclofen for severe spinal spasticity N Engl J Med 1989;320(23):1517-1521 40 Albright AL Neurosurgical treatment of spasticity and other pediatric movement disorders J Child Neurol 2003;18(suppl 1): S67-S78 41 Nolte J The Human Brain An Introduction to Its Functional Anatomy 3rd ed St Louis, MO: Mosby-Year Book; 1993 42 Hershman E, Halberthal M, Goldsher D, Golz A, Bar-Joseph G Life threatening medullary injury following adenoidectomy and local anesthetic infiltration of the operative bed Paediatr Anaesth 2009;19(2):164-167 43 Petersen SE, Fox PT, Posner MI, Mintun M, Raichle ME Positron emission tomographic studies of the cortical anatomy of single-word processing Nature 1988;331(6157):585-589 44 Strick PL, Dum RP, Fiez JA Cerebellum and nonmotor function Annu Rev Neurosci 2009;32:413-434 45 Jones EG Thalamic circuitry and thalamocortical synchrony Philos Trans R Soc Lond B Biol Sci 2002;357(1428):1659-1673 46 Lawrence RK, Inder TE Anatomic changes and imaging in assessing brain injury in the term infant Clin Perinatol 2008;35(4):679-693, vi 47 Baltagi SA, Shoykhet M, Felmet K, Kochanek PM, Bell MJ Neurological sequelae of 2009 influenza A (H1N1) in children: a case series observed during a pandemic Pediatr Crit Care Med 2010; 11(2):179-184 e2 48 Mizuguchi M Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan Brain Dev 1997;19(2):81-92 49 Ashtekar CS, Jaspan T, Thomas D, Weston V, Gayatri NA, Whitehouse WP Acute bilateral thalamic necrosis in a child with Mycoplasma pneumoniae Dev Med Child Neurol 2003;45(9):634-637 50 Shibata M, Kibe T, Fujimoto S, et al Diffuse central nervous system lupus involving white matter, basal ganglia, thalami and brainstem Brain Dev 1999;21(5):337-340 51 Gupta S, Fernandez D, Siddiqui A, Lin JP, Garside L, Lim M Thalamic infarct presenting as apparent life-threatening event in infants Acta Paediatr 2009;98(12):2002-2005 52 Tabaee A, Anand VK, Barron Y, et al Endoscopic pituitary surgery: a systematic review and meta-analysis J Neurosurg 2009;111(3):545-554 53 Ho VB, Fitz CR, Chuang SH, Geyer CA Bilateral basal ganglia lesions: pediatric differential considerations Radiographics 1993;13(2): 269-292 54 Ohman L, Simren M Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions Nat Rev Gastroenterol Hepatol 2010;7:163-173 55 Dumont RJ, Okonkwo DO, Verma S, et al Acute spinal cord injury, part I: pathophysiologic mechanisms Clin Neuropharmacol 2001; 24(5):254-264 56 Dumont RJ, Verma S, Okonkwo DO, et al Acute spinal cord injury, part II: contemporary pharmacotherapy Clin Neuropharmacol 2001; 24(5):265-279 57 AHA Part 7.3: Management of symptomatic bradycardia and tachycardia Circulation 2005;112(24_suppl):IV-67-77 58 Ehrlich P Das Sauerstoff-Bedorfnis des Organismus Eine Farbenanalytische Studie Berlin: Hirschwold; 1885 59 Goldman E Die aussere und innere Sekretion des gesunden und kranken Organismus im Lichte der “virtalen Farbung.” Beitr Klin Chirurg 1909;64:192-265 60 de Boer AG, Gaillard PJ Drug targeting to the brain Annu Rev Pharmacol Toxicol 2007;47(1):323-355 61 Engelhardt B, Sorokin L The blood–brain and the blood–cerebrospinal fluid barriers: function and dysfunction Semin Immunopathol 2009;31:497-511 62 Yemisci M, Gursoy-Ozdemir Y, Vural A, Can A, Topalkara K, Dalkara T Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery Nat Med 2009;15(9):1031-1037 63 Lindahl P, Johansson BR, Leveen P, Betsholtz C Pericyte loss and microaneurysm formation in PDGF-B-deficient mice Science 1997;277(5323):242-245 64 Kim JA, Tran ND, Li Z, Yang F, Zhou W, Fisher MJ Brain endothelial hemostasis regulation by pericytes J Cereb Blood Flow Metab 2006;26(2):209-217 65 Rubin LL, Staddon JM The cell biology of the blood-brain barrier Annu Rev Neurosci 1999;22(1):11-28 66 Gould DB, Phalan FC, Breedveld GJ, et al Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly Science 2005;308(5725):1167-1171 67 Vahedi K, Kubis N, Boukobza M, et al COL4A1 mutation in a patient with sporadic, recurrent intracerebral hemorrhage Stroke 2007;38(5):1461-1464 68 Brockmann K The expanding phenotype of GLUT1-deficiency syndrome Brain Dev 2009;31(7):545-552 69 Qutub AA, Hunt CA Glucose transport to the brain: a systems model Brain Res Brain Res Rev 2005;49(3):595-617 70 Klepper J, Wang D, Fischbarg J, et al Defective glucose transport across brain tissue barriers: a newly recognized neurological syndrome Neurochem Res 1999;24(4):587-594 71 Begley DJ ABC Transporters and the blood-brain barrier Curr Pharm Des 2004;10:1295-1312 72 Abrahamson EE, Ikonomovic MD, Dixon CE, DeKosky ST Simvastatin therapy prevents brain trauma-induced increases in beta-amyloid peptide levels Ann Neurol 2009;66(3):407-414 73 Trinkl A, Vosko MR, Wunderlich N, Dichgans M, Hamann GF Pravastatin reduces microvascular basal lamina damage following focal cerebral ischemia and reperfusion Eur J Neurosci 2006; 24(2):520-526 74 Vaughan CJ, Delanty N Neuroprotective properties of statins in cerebral ischemia and stroke Stroke 1999;30(9):1969-1973 75 Kochanek PM, Berger RP, Bayir H, Wagner AK, Jenkins LW, Clark RS Biomarkers of primary and evolving damage in traumatic and ischemic brain injury: diagnosis, prognosis, probing mechanisms, and therapeutic decision making Curr Opin Crit Care 2008;14(2): 135-141 76 Lassen NA Cerebral blood flow and oxygen consumption in man Physiol Rev 1959;39(2):183-238 77 Philip S, Udomphorn Y, Kirkham FJ, Vavilala MS Cerebrovascular pathophysiology in pediatric traumatic brain injury J Trauma 2009;67(suppl 2):S128-S134 78 van de Bor M, Walther FJ Cerebral blood flow velocity regulation in preterm infants Biol Neonate 1991;59(6):329-335 79 Pearce WJ Mechanisms of hypoxic cerebral vasodilatation Pharmacol Ther 1995;65(1):75-91 80 Tomiyama Y, Brian Jr JE, Todd MM Cerebral blood flow during hemodilution and hypoxia in rats: role of ATP-sensitive potassium channels Stroke 1999;30(9):1942-1947; discussion 1947-1948 81 Johnston AJ, Steiner LA, Gupta AK, Menon DK Cerebral oxygen vasoreactivity and cerebral tissue oxygen reactivity Br J Anaesth 2003;90(6):774-786 82 Gupta AK, Menon DK, Czosnyka M, Smielewski P, Jones JG Thresholds for hypoxic cerebral vasodilation in volunteers Anesth Analg 1997;85(4):817-820 83 Park CW, Sturzenegger M, Douville CM, Aaslid R, Newell DW Autoregulatory response and CO2 reactivity of the basilar artery Stroke 2003;34(1):34-39 84 Fox PT, Raichle ME Focal physiological uncoupling of cerebral blood flow and oxidative metabolism during somatosensory stimulation in human subjects Proc Natl Acad Sci U S A 1986;83(4):1140-1144 85 Logothetis NK, Wandell BA Interpreting the BOLD signal Annu Rev Physiol 2004;66:735-769 86 Kennedy C, Sokoloff L An adaptation of the nitrous oxide method to the study of the cerebral circulation in children; normal values for cerebral blood flow and cerebral metabolic rate in childhood J Clin Invest 1957;36(7):1130-1137 87 Chugani HT, Phelps ME, Mazziotta JC Positron emission tomography study of human brain functional development Ann Neurol 1987;22(4):487-497 88 Bradbury MW, Cserr HF, Westrop RJ Drainage of cerebral interstitial fluid into deep cervical lymph of the rabbit Am J Physiol 1981;240(4):F329-F336 89 Cserr HF, Cooper DN, Suri PK, Patlak CS Efflux of radiolabeled polyethylene glycols and albumin from rat brain Am J Physiol 1981;240(4):F319-F328 90 Louveau A, Smirnov I, Keyes TJ, et al Structural and functional features of central nervous system lymphatic vessels Nature 2015;523(7560):337-341 91 Aspelund A, Antila S, Proulx ST, et al A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules J Exp Med 2015;212(7):991-999 92 Iliff JJ, Wang M, Liao Y, et al A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta SciTransl Med 2012;4(147):147ra111 93 Mathiisen TM, Lehre KP, Danbolt NC, Ottersen OP The perivascular astroglial sheath provides a complete covering of the brain microvessels: an electron microscopic 3D reconstruction Glia 2010;58(9):1094-1103 94 Plog BA, Dashnaw ML, Hitomi E, et al Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system J Neurosci 2015;35(2):518-526 95 Levitt P Structural and functional maturation of the developing primate brain J Pediatr 2003;143(suppl 4):S35-S45 e3 96 Kostovic I, Judas M, Rados M, Hrabac P Laminar organization of the human fetal cerebrum revealed by histochemical markers and magnetic resonance imaging Cereb Cortex 2002;12(5):536-544 97 Olson EC, Walsh CA Smooth, rough and upside-down neocortical development Curr Opin Genet Dev 2002;12(3):320-327 98 Comery TA, Harris JB, Willems PJ, et al Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits Proc Natl Acad Sci U S A 1997;94(10):5401-5404 99 Needelman H, Evans M, Roberts H, Sweney M, Bodensteiner JB Effects of postnatal dexamethasone exposure on the developmental outcome of premature infants J Child Neurol 2008;23(4): 421-424 100 Maffei A, Nataraj K, Nelson SB, Turrigiano GG Potentiation of cortical inhibition by visual deprivation Nature 2006;443(7107): 81-84 101 Brooks-Kayal AR, Pritchett DB Developmental changes in human gamma-aminobutyric acid A receptor subunit composition Ann Neurol 1993;34(5):687-693 102 Ben-Ari Y, Gaiarsa J-L, Tyzio R, Khazipov R GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations Physiol Rev 2007;87(4):1215-1284 103 Herlenius E, Lagercrantz H Development of neurotransmitter systems during critical periods Exp Neurol 2004;190(suppl 1): S8-S21 104 Paus T, Collins DL, Evans AC, Leonard G, Pike B, Zijdenbos A Maturation of white matter in the human brain: a review of magnetic resonance studies Brain Res Bull 2001;54(3):255-266 105 Takashima S, Itoh M, Oka A A history of our understanding of cerebral vascular development and pathogenesis of perinatal brain damage over the past 30 years Semin Pediatr Neurol 2009;16(4): 226-236 106 Greenberg DA, Jin K From angiogenesis to neuropathology Nature 2005;438(7070):954-959 107 LaManna JC, Chavez JC, Pichiule P Structural and functional adaptation to hypoxia in the rat brain J Exp Biol 2004;207(Pt 18):3163-3169 108 Watson RE, Desesso JM, Hurtt ME, Cappon GD Postnatal growth and morphological development of the brain: a species comparison Birth Defects Res B Dev Reprod Toxicol 2006;77(5): 471-484 109 Jayasinghe D, Gill AB, Levene MI CBF reactivity in hypotensive and normotensive preterm infants Pediatr Res 2003;54(6): 848-853 110 Kehrer M, Krageloh-Mann I, Goelz R, Schoning M The development of cerebral perfusion in healthy preterm and term neonates Neuropediatrics 2003;34(6):281-286 111 Kehrer M, Blumenstock G, Ehehalt S, Goelz R, Poets C, Schoning M Development of cerebral blood flow volume in preterm neonates during the first two weeks of life Pediatr Res 2005;58(5):927-930 112 Biagi L, Abbruzzese A, Bianchi MC, Alsop DC, Del Guerra A, Tosetti M Age dependence of cerebral perfusion assessed by magnetic resonance continuous arterial spin labeling J Magn Reson Imaging 2007;25(4):696-702 113 Panerai RB, Kelsall AW, Rennie JM, Evans DH Cerebral autoregulation dynamics in premature newborns Stroke 1995;26(1):74-80 114 Soul JS, Hammer PE, Tsuji M, et al Fluctuating pressure-passivity is common in the cerebral circulation of sick premature infants Pediatr Res 2007;61(4):467-473 115 Kaiser JR, Gauss CH, Williams DK The effects of hypercapnia on cerebral autoregulation in ventilated very low birth weight infants Pediatr Res 2005;58(5):931-935 116 Hasegawa M, Houdou S, Takashima S, Tatsuno M, Okuyama K, Suzuki S Monitoring of immature rabbit brain during hypoxia with near-infrared spectroscopy Pediatr Neurol 1992;8(1):47-50 117 Szymonowicz W, Walker AM, Cussen L, Cannata J, Yu VY Developmental changes in regional cerebral blood flow in fetal and newborn lambs Am J Physiol 1988;254(1 Pt 2):H52-H58 118 Kinnala A, Suhonen-Polvi H, Aarimaa T, et al Cerebral metabolic rate for glucose during the first six months of life: an FDG positron emission tomography study Arch Dis Child Fetal Neonatal Ed 1996;74(3):F153-F157 119 Prins ML Cerebral metabolic adaptation and ketone metabolism after brain injury J Cereb Blood Flow Metab 2008;28(1):1-16 120 Vannucci RC, Vannucci SJ Glucose metabolism in the developing brain Semin Perinatol 2000;24(2):107-115 121 Ikonomidou C, Bosch F, Miksa M, et al Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain Science 1999;283(5398):70-74 122 Ikonomidou C, Bittigau P, Ishimaru MJ, et al Ethanol-induced apoptotic neurodegeneration and fetal alcohol syndrome Science 2000;287(5455):1056-1060 123 Backeljauw B, Holland SK, Altaye M, Loepke AW Cognition and brain structure following early childhood surgery with anesthesia Pediatrics 2015;136(1):e1-e12 124 Bong CL, Allen JC, Kim JT The effects of exposure to general anesthesia in infancy on academic performance at age 12 Anesth Analg 2013;117(6):1419-1428 125 Erny D, Hrabe de Angelis AL, Jaitin D, et al Host microbiota constantly control maturation and function of microglia in the CNS Nat Neurosci 2015;18(7):965-977 126 Ueno M, Fujita Y, Tanaka T, et al Layer V cortical neurons require microglial support for survival during postnatal development Nat Neurosci 2013;16(5):543-551 127 Eyo UB, Dailey ME Microglia: key elements in neural development, plasticity, and pathology J Neuroimmune Pharmacol 2013;8(3):494-509 128 Chen Z, Jalabi W, Hu W, et al Microglial displacement of inhibitory synapses provides neuroprotection in the adult brain Nat Commun 2014;5:4486 129 Janik R, Thomason LAM, Stanisz AM, Forsythe P, Bienenstock J, Stanisz GJ Magnetic resonance spectroscopy reveals oral Lactobacillus promotion of increases in brain GABA, N-acetyl aspartate and glutamate Neuroimage 2016;125:988-995 130 Sharon G, Cruz NJ, Kang DW, et al Human gut microbiota from autism spectrum disorder promote behavioral symptoms in mice Cell 2019;177(6):1600-1618.e17 e4 Abstract: In a brain-centric approach to pediatric critical care, it can be argued that all interventions are ultimately targeted at preserving and protecting the child’s nervous system function Thus, knowledge of the structure and function of the nervous system, together with understanding of the developmental processes that are active in children who become patients in the intensive care unit, is essential to the practice of the pediatric intensivist As the impact of disease and injury in the context of the developing nervous system is only now beginning to be understood, many new advances in diagnosis and treatment undoubtedly are yet to come Key words: Developing brain, neurodevelopment, neurogenesis, neurotransmitters, synaptogenesis ... clearance of interstitial solutes, including amyloid beta SciTransl Med 2012;4(147):147ra111 93 Mathiisen TM, Lehre KP, Danbolt NC, Ottersen OP The perivascular astroglial sheath provides a complete