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      Sleep drives metabolite clearance from the adult brain.

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      Journal: Science (New York, N.Y.)
      Keywords: Adrenergic Antagonists, administration & dosage, Amyloid beta-Peptides, metabolism, Animals, Brain, physiology, Cerebral Cortex, Cerebrospinal Fluid, Diffusion, Electroencephalography, Extracellular Space, Intracellular Space, Male, Mice, Mice, Inbred C57BL, Neurodegenerative Diseases, Quaternary Ammonium Compounds, chemistry, Receptors, Adrenergic, Sleep, Wakefulness

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          Abstract

          The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.

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          Brain-wide pathway for waste clearance captured by contrast-enhanced MRI.

          Jeffrey J. Iliff, Hedok Lee, Mei Yu … (2013)
          The glymphatic system is a recently defined brain-wide paravascular pathway for cerebrospinal fluid (CSF) and interstitial fluid (ISF) exchange that facilitates efficient clearance of solutes and waste from the brain. CSF enters the brain along para-arterial channels to exchange with ISF, which is in turn cleared from the brain along para-venous pathways. Because soluble amyloid β clearance depends on glymphatic pathway function, we proposed that failure of this clearance system contributes to amyloid plaque deposition and Alzheimer's disease progression. Here we provide proof of concept that glymphatic pathway function can be measured using a clinically relevant imaging technique. Dynamic contrast-enhanced MRI was used to visualize CSF-ISF exchange across the rat brain following intrathecal paramagnetic contrast agent administration. Key features of glymphatic pathway function were confirmed, including visualization of para-arterial CSF influx and molecular size-dependent CSF-ISF exchange. Whole-brain imaging allowed the identification of two key influx nodes at the pituitary and pineal gland recesses, while dynamic MRI permitted the definition of simple kinetic parameters to characterize glymphatic CSF-ISF exchange and solute clearance from the brain. We propose that this MRI approach may provide the basis for a wholly new strategy to evaluate Alzheimer's disease susceptibility and progression in the live human brain.
          Article 0 comments Cited 382 times – based on 0 reviews     Review now
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            Thalamocortical oscillations in the sleeping and aroused brain.

            M Steriade, T Sejnowski, D McCormick … (1993)
            Sleep is characterized by synchronized events in billions of synaptically coupled neurons in thalamocortical systems. The activation of a series of neuromodulatory transmitter systems during awakening blocks low-frequency oscillations, induces fast rhythms, and allows the brain to recover full responsiveness. Analysis of cortical and thalamic networks at many levels, from molecules to single neurons to large neuronal assemblies, with a variety of techniques, ranging from intracellular recordings in vivo and in vitro to computer simulations, is beginning to yield insights into the mechanisms of the generation, modulation, and function of brain oscillations.
            Article 0 comments Cited 282 times – based on 0 reviews     Review now
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              Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks.

              Kishore V Kuchibhotla, Samuel T Goldman, Carli R Lattarulo … (2008)
              Alzheimer's disease is characterized by the deposition of senile plaques and progressive dementia. The molecular mechanisms that couple plaque deposition to neural system failure, however, are unknown. Using transgenic mouse models of AD together with multiphoton imaging, we measured neuronal calcium in individual neurites and spines in vivo using the genetically encoded calcium indicator Yellow Cameleon 3.6. Quantitative imaging revealed elevated [Ca(2+)]i (calcium overload) in approximately 20% of neurites in APP mice with cortical plaques, compared to less than 5% in wild-type mice, PS1 mutant mice, or young APP mice (animals without cortical plaques). Calcium overload depended on the existence and proximity to plaques. The downstream consequences included the loss of spinodendritic calcium compartmentalization (critical for synaptic integration) and a distortion of neuritic morphologies mediated, in part, by the phosphatase calcineurin. Together, these data demonstrate that senile plaques impair neuritic calcium homeostasis in vivo and result in the structural and functional disruption of neuronal networks.
              Article 0 comments Cited 199 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                PubMed ID:: 24136970
                PMC ID:: 3880190
                DOI:: 10.1126/science.1241224

                ScienceOpen disciplines: Chemistry
                Keywords: Adrenergic Antagonists,administration & dosage,Amyloid beta-Peptides,metabolism,Animals,Brain,physiology,Cerebral Cortex,Cerebrospinal Fluid,Diffusion,Electroencephalography,Extracellular Space,Intracellular Space,Male,Mice,Mice, Inbred C57BL,Neurodegenerative Diseases,Quaternary Ammonium Compounds,chemistry,Receptors, Adrenergic,Sleep,Wakefulness
                Data availability:
                ScienceOpen disciplines: Chemistry
                Keywords: Adrenergic Antagonists, administration & dosage, Amyloid beta-Peptides, metabolism, Animals, Brain, physiology, Cerebral Cortex, Cerebrospinal Fluid, Diffusion, Electroencephalography, Extracellular Space, Intracellular Space, Male, Mice, Mice, Inbred C57BL, Neurodegenerative Diseases, Quaternary Ammonium Compounds, chemistry, Receptors, Adrenergic, Sleep, Wakefulness

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