Kukley M, Capetillo-Zarate E, Dietrich D. Vesicular glutamate release from axons in white matter. Nat Neurosci. 2007;10(3):311–20. Touchette E, Petit D, Seguin JR, Boivin M, Tremblay RE, Montplaisir JY. Associations between sleep duration patterns and behavioral/cognitive functioning at school entry. Sleep. 2007;30(9):1213–9. 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):255–66.

Kurth S, Ringli M, Geiger A, LeBourgeois M, Jenni OG, Huber R. Mapping of cortical activity in the first two decades of life: a high-density sleep electroencephalogram study. J Neurosci: Off J Soc Neurosci. 2010;30(40):13211–9. Jha SK, Jones BE, Coleman T, Steinmetz N, Law CT, Griffin G, et al. Sleep-dependent plasticity requires cortical activity. J Neurosci: Off J Soc Neurosci. 2005;25(40):9266–74. Deoni SC, Dean 3rd DC, O’Muircheartaigh J, Dirks H, Jerskey BA. Investigating white matter development in infancy and early childhood using myelin water faction and relaxation time mapping. Neuroimage. 2012;63(3):1038–53.Fields RD. Imaging learning: the search for a memory trace. Neuroscientist : Rev J Bringing Neurobiol Neurol Psychiatry. 2011;17(2):185–96. In vivo experiments in mice allow for the quantification of cortical plasticity in relation to sleep or wakefulness. In adolescent mice, synaptic remodeling is state dependent: While a gain in cortical spines prevailed during waking, spine loss was larger during sleep, resulting in a negative spine balance at this developmental stage [ 92, 93]. Importantly, this spine elimination was only found during development, while no sleep-wake-dependent net changes of spine density were observed in adult mice. These findings confirm that in adolescent mice, a few hours of sleep and wake affect the density of cortical synapses while after adolescence primarily changes in synaptic strength rather than number can be observed. As shown in adult rats, an overall synaptic balance is preserved [ 94]. Recent research shows that specific burst firing, the characteristic firing pattern of sleep slow oscillations [ 95], can impact the functional change of glutamatergic synapses [ 96•]. Induced burst firing in pyramidal neurons (cortical slices) eliminates AMPA receptors and induces input-specific long-term depression because neuronal plasticity represents a continuum from malleability of existing synapses to structural plasticity, including synapse formation and elimination [ 97], the impact of SWA on synaptic plasticity may ultimately result in changes in cortical connectivity. Sleep Increases the Interstitial Space Thereby Reducing Neurotoxic Waste Hypothesis: Rakic P, Bourgeois JP, Goldman-Rakic PS. Synaptic development of the cerebral cortex: implications for learning, memory, and mental illness. Prog Brain Res. 1994;102:227–43. Mori S, Zhang J. Principles of diffusion tensor imaging and its applications to basic neuroscience research. Neuron. 2006;51(5):527–39. Attwell D, Laughlin SB. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab. 2001;21(10):1133–45.

Johns JM, Means LW, Means MJ, McMillen BA. Prenatal exposure to cocaine. I: effects on gestation, development, and activity in Sprague–Dawley rats. Neurotoxicol Teratol. 1992;14(5):337–42.Tarokh L, Carskadon MA, Achermann P. Developmental changes in brain connectivity assessed using the sleep EEG. Neuroscience. 2010;171(2):622–34. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373–7. Kurth S, Huber R. Sleep slow oscillations and cortical maturation. In: Frank MG, editor. Sleep and brain activity. Elsevier; 2012. Symptoms of overdose include lethargy, drowsiness, nausea, vomiting, and epigastric pain, and gastrointestinal bleeding. Hypertension, acute renal failure, respiratory depression and coma occur rarely. In case of overdose, provide supportive care and consider inducing emesis and administering activated charcoal if overdose occurred less than 4 hours prior. Wieraszko A. Changes in the hippocampal slices energy metabolism following stimulation and long-term potentiation of Schaffer collaterals-pyramidal cell synapses tested with the 2-deoxyglucose technique. Brain Res. 1982;237(2):449–57.

Brain activity during sleep undergoes dramatic changes across the life span. The preterm infant EEG is characterized by the alternation between high-amplitude burst “on” periods followed by low-amplitude burst “off” periods ( tracé discontinu), which evolves to high-voltage slow-wave activity alternating with low-voltage activity bursts ( tracé alternant) shortly after birth [ 1]. Soon thereafter, rapid-eye-movement (REM)-like sleep (active sleep) appears. In the course of the first years of life, the amount of active sleep diminishes while non-rapid-eye-movement (non-REM)-like sleep (quiet sleep) becomes the predominant state [ 2, 3]. PGE 2 is the primary PG involved in modulation of nociception. It mediates peripheral sensitization through a variety of effects. PGE 2 activates the G q-coupled EP 1 receptor leading to increased activity of the inositol trisphosphate/phospholipase C pathway. Activation of this pathway releases intracellular stores of calcium which directly reduces action potential threshold and activates protein kinase C (PKC) which contributes to several indirect mechanisms. PGE 2 also activates the EP 4 receptor, coupled to G s, which activates the adenylyl cyclase/protein kinase A (AC/PKA) signaling pathway. PKA and PKC both contribute to the potentiation of transient receptor potential cation channel subfamily V member 1 (TRPV1) potentiation, which increases sensitivity to heat stimuli. They also activate tetrodotoxin-resistant sodium channels and inhibit inward potassium currents. PKA further contributes to the activation of the P2X3 purine receptor and sensitization of T-type calcium channels. The activation and sensitization of depolarizing ion channels and inhibition of inward potassium currents serve to reduce the intensity of stimulus necessary to generate action potentials in nociceptive sensory afferents. PGE 2 act via EP 3 to increase sensitivity to bradykinin and via EP 2 to further increase heat sensitivity. Central sensitization occurs in the dorsal horn of the spinal cord and is mediated by the EP 2 receptor which couples to G s. Pre-synaptically, this receptor increases the release of pro-nociceptive neurotransmitters glutamate, CGRP, and substance P. Post-synaptically it increases the activity of AMPA and NMDA receptors and produces inhibition of inhibitory glycinergic neurons. Together these lead to a reduced threshold of activating, allowing low intensity stimuli to generate pain signals. PGI 2 is known to play a role via its G s-coupled IP receptor although the magnitude of its contribution varies. It has been proposed to be of greater importance in painful inflammatory conditions such as arthritis. By limiting sensitization, both peripheral and central, via these pathways NSAIDs can effectively reduce inflammatory pain. Romijn HJ, Hofman MA, Gramsbergen A. At what age is the developing cerebral cortex of the rat comparable to that of the full-term newborn human baby? Early Hum Dev. 1991;26(1):61–7. Recent work has shown that caffeine consumption in adolescent rats exerts short-term stimulating effects and can alter the developmental trajectory of SWA [ 10]. Moreover, caffeine alters behavioral and structural markers of maturation [ 10]. These caffeine-induced lasting morphological changes might be due to alterations in sleep regulatory processes, such that altering sleep-wake regulation by stimulants like caffeine may affect synaptic plasticity. Sleep Is Needed for Plasticity Hypothesis: Italic indicates a move that gets STAB only when used by an evolution or an alternate form of Smoliv

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