Thursday, October 31, 2013

Sleeping Cleans Your Brain

Why we need sleep and what happens during that process is an area of great interest for both the basic and clinical neurosciences. I recall listening to a lecture by Giulio Tononi at the 75th Anniversary of the University of Wisconsin's Department of Psychiatry on a theory of how synapses were processed during sleep in order to renew the brain's learning capacity for the next day.

I encountered a fascinating paper in this week's Science magazine on a possible sleep function that I have never seen described before - flushing toxins out of the brain.  The lead author hails from the Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical School.  That probably says a lot about the focus of the paper and that is the movement of interstitial fluid (ISF) as it circulates through the interstitial spaces around neurons and removes toxic waste products including β-amyloid (Aβ)  Since the brain lacks a lymphatic system convective exchange between CSF and ISF controls this turnover.  One author named the system the glymphatic system since the system is dependent on astrocytic aquaporin-4 (APQ-4) channels for establishing the  convective movement of ISF and this is homologous to peripheral lymphatic movement and removal of toxic byproducts from peripheral tissue by the lymphatic system.  The authors also note that the observation that (Aβ)  protein has been observed to be at a higher concentration in the daytime as opposed to during sleep.  To explain this one hypothesis was that production was greater in the daytime.  They tested the alternate hypothesis that glymphatic clearance is greater at night.

The basic experiment for the paper involved teaching mice to sleep on a two-photon microscope.  That allows imaging of dye moving through living tissue.  The researcher would inject mice with  green dye at sleep onset and red dye upon awakening.  They could determine that during sleep a much higher volume or CSF flowed through the brain.  They also injected labelled (Aβ)  protein and showed that the brain of a sleeping mouse cleared these proteins twice as fast.  The art below shows the experiment and the 60% increase in channels carrying CSF during sleep.  I would encourage anyone interested to read the original in color as Science has outstanding graphics.  To download my original PowerPoint slide use this link.

The authors went on to demonstrate that the increase in interstitial space was a sleep related phenomenon because it could be induced by natural sleep and anesthesia but not circadian rhythm.  In looking for a mechanism they postulated that adrenergic mechanisms associated with arousal like locus ceruleus derived noradrenergic signaling was involved.  They demonstrated that adrenergic antagonists could induce the expected increase in tracer influx and interstitial volume so that it was similar to what was seen in the sleep state. 

Implications for psychiatry?  To some extent, those of us interested in neuroscience and not forgetting what we learned in PChem will always be interested in article at the interface between the biochemical and the biophysical.  Despite having this elegant system coupled with our arousal state and metabolic state none of this information was around during the recent Decade of the Brain.  The authors discuss the sensitivity of neurons to various toxic products and proteins and the implications for neurodegenerative diseases.  I can start with insomnia and build from there.  People with addictions can have sustained insomnia and associated impairment in cognition the next day.  Delirium also affects the sleep-wake cycle and some experts have suggested that two different types of delirium can be distinguished based on EEG spectra.  The obvious questions are is the insomnia associated with these states literally toxic to the patient by restricting ISF clearance?    Another key correlate mentioned by the authors is the decrease in ISF with age.  Does that account for the predisposition to delirium and protracted delirium as people age?  And finally what about the toxicity of medication?  We are used to receptor based explanations of why certain medications have sustained or unexpected toxicity.  How much of that is due to a collapsed ISF and restricted clearance to the CSF?

Brain energetics is also an interesting question specifically the AQP-4 channels.  Most psychiatrists are familiar with the renal aquaporin channels when considering renal water metabolism.  The fact that you have these channels on astrocytes and that removing them reduces (Aβ)  clearance by 65% is fascinating and seems like another potential intervention point for brain disease.  What needs to happen to keep these AQP-4 channels healthy and what happens when they are not? 

There are many more questions that come to mind based on the mechanism these authors have elucidated.  I hope that papers like these are translated into both clinical research and our thinking about newer and more innovative ways to think about whole brain function and think about all of the mechanisms instead of just the usual receptors.

George Dawson, MD, DFAPA

Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. doi: 10.1126/science.1241224. PubMed PMID: 24136970

Footnote:  I decided to update (12/13/2013) this post by adding this interesting piece of news.  According to Altmetric, this paper received the 4th highest rating of online interest in scientific papers.  For the Top 100 papers click on the link.

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