Kuhn et al. Sleep Recalibrates Homeostatic & Associative Synaptic Plasticity in the Human Cortex

Nature Communications

Marion Kuhn Elias Wolf Jonathan G. Maier Florian Mainberger Bernd Feige Hanna Schmid Jan Bürklin Sarah Maywald Volker Mall Nikolai H. Jung Janine Reis Kai Spiegelhalder Stefan Klöppel Annette Sterr Anne Eckert Dieter Riemann Claus Normann & Christoph Nissen

Nature Communications 7, Article number: 12455 (2016)
doi:10.1038/ncomms12455
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Synaptic plasticity

Received: 04 November 2015
Accepted: 05 July 2016
Published online: 23 August 2016

Abstract

Sleep is ubiquitous in animals and humans, but its function remains to be further determined. The synaptic homeostasis hypothesis of sleep–wake regulation proposes a homeostatic increase in net synaptic strength and cortical excitability along with decreased inducibility of associative synaptic long-term potentiation (LTP) due to saturation after sleep deprivation. Here we use electrophysiological, behavioural and molecular indices to non-invasively study net synaptic strength and LTP-like plasticity in humans after sleep and sleep deprivation. We demonstrate indices of increased net synaptic strength (TMS intensity to elicit a predefined amplitude of motor-evoked potential and EEG theta activity) and decreased LTP-like plasticity (paired associative stimulation induced change in motor-evoked potential and memory formation) after sleep deprivation. Changes in plasma BDNF are identified as a potential mechanism. Our study indicates that sleep recalibrates homeostatic and associative synaptic plasticity, believed to be the neural basis for adaptive behaviour, in humans.

Introduction

The activity-dependent refinement of transmission across single synapses (associative plasticity) and the up- and downscaling of overall synaptic strength (homeostatic plasticity) represent basic mechanisms for neural network function and adaptive behaviour1. Sleep has been shown to strongly modulate synaptic plasticity2, but its effects on the interplay of homeostatic and associative plasticity remain to be further characterized.

The synaptic homeostasis hypothesis of sleep–wake regulation posits that downscaling (that is, the decrease in strength) of synapses that have been potentiated towards saturation during wakefulness denotes a vital function of sleep3,4. Sleep-dependent synaptic desaturation is thought to result in an improved signal-to-noise ratio and a renewed capacity for the encoding of new information through associative plasticity. This hypothesis is supported by molecular and electrophysiological evidence from animal studies5. Particularly, major markers of synaptic strength show a wake-dependent rise and a sleep-dependent decline, such as the slope of the local field potential elicited by electrical stimulation in the rat cortex6, the level of GluR1-containing AMPA receptors in the rat hippocampus and cortex6, cortical spine density in adolescent mice7, and the number or size of synapses in different neuronal circuits in flies8,9. In humans, molecular mechanisms of synaptic homeostasis are not directly accessible, but non-invasive (indirect) markers indicate net synaptic potentiation during wakefulness and desaturation during sleep. For instance, the slope of the electroencephalographic (EEG) response to transcranial magnetic stimulation (TMS) that shares properties with local field potentials in animal studies increases with time awake and resets after sleep10. Further, EEG theta activity, a marker for homeostatic sleep pressure (net synaptic potentiation) in rats11 and humans12, increases with time awake. Also other neurophysiological markers point to an increase in cortical excitability (that is, the propensity for firing) and overall synaptic strength, such as an increase in short-interval intracortical facilitation and a decrease in short-interval intracortical inhibition in M1 after sleep deprivation10,13,14,15.

These sleep–wake dependent homeostatic modifications of net synaptic strength appear to refine the set-point for the induction of input-specific associative plasticity at single synapses. Particularly, Hebbian long-term potentiation (LTP) of glutamatergic synaptic transmission is a key mechanism of associative plasticity and a molecular correlate for learning and memory16. LTP is a positive feedback process with a tendency to saturation17, which appears to be prevented by sleep-dependent homeostatic desaturation. Consistently, the induction of LTP via high-frequency electrical stimulation in the motor cortex of rats is partially occluded after prolonged wakefulness and restored after sleep6. In humans, hippocampal activity assessed by functional magnetic resonance imaging is reduced during the encoding of episodic memory after sleep deprivation along with a deficit in the formation of new memories as a behavioural correlate of activity-dependent synaptic plasticity18. Yet memory is a complex process including multi-synaptic pathways, and the sleep–wake-dependent interplay of homeostatic and associative synaptic plasticity in humans remains to be further determined. Associative LTP-like plasticity can be non-invasively induced in the human cortex by the brain stimulation protocol paired associative stimulation (PAS)19. The PAS-induced LTP-like plasticity shows similar characteristics to LTP in animal slice experiments, namely associativity, input-specificity and dependency on N-methyl-D-aspartate receptor functioning20.

This study used TMS and EEG to investigate cortical excitability/net synaptic strength (TMS intensity to elicit a predefined amplitude of motor-evoked potential (MEP) and EEG theta activity) and LTP-like plasticity (PAS induced change in MEP and memory formation) in the human cortex. For the first time to our knowledge, our study combines the assessment of indices of homeostatic and associative synaptic plasticity in humans. We demonstrate an increase in cortical excitability/net synaptic strength and a partial occlusion of LTP-like plasticity after sleep deprivation compared with sleep, indicating that sleep recalibrates synaptic plasticity in the human cortex.

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