Abstract

Sleep spindles are burstlike signals in the electroencephalogram (EEG) of the sleeping mammalian brain and electrical surface correlates of neuronal oscillations in thalamus. As one of the most inheritable sleep EEG signatures, sleep spindles probably reflect the strength and malleability of thalamocortical circuits that underlie individual cognitive profiles. We review the characteristics, organization, regulation, and origins of sleep spindles and their implication in non-rapid-eye-movement sleep (NREMS) and its functions, focusing on human and rodent. Spatially, sleep spindle-related neuronal activity appears on scales ranging from small thalamic circuits to functional cortical areas, and generates a cortical state favoring intracortical plasticity while limiting cortical output. Temporally, sleep spindles are discrete events, part of a continuous power band, and elements grouped on an infraslow time scale over which NREMS alternates between continuity and fragility. We synthesize diverse and seemingly unlinked functions of sleep spindles for sleep architecture, sensory processing, synaptic plasticity, memory formation, and cognitive abilities into a unifying sleep spindle concept, according to which sleep spindles 1) generate neural conditions of large-scale functional connectivity and plasticity that outlast their appearance as discrete EEG events, 2) appear preferentially in thalamic circuits engaged in learning and attention-based experience during wakefulness, and 3) enable a selective reactivation and routing of wake-instated neuronal traces between brain areas such as hippocampus and cortex. Their fine spatiotemporal organization reflects NREMS as a physiological state coordinated over brain and body and may indicate, if not anticipate and ultimately differentiate, pathologies in sleep and neurodevelopmental, -degenerative, and -psychiatric conditions.

Highlights

  • HISTORICAL LANDMARKSDEFINITIONS AND MEASUREMENTSROLE IN SLEEP’S MACRO- AND...NEUROPHYSIOLOGICAL MECHANISMS 821CORTICAL STATES AND THEIR ORIGINS 830SLEEP SPINDLES ACROSS THE LIFESPAN 836MEMORY CONSOLIDATIONCOGNITIVE ABILITIES AND INTELLIGENCE 844SLEEP DISORDERS AND...PHARMACOLOGICAL AND TARGETED... 849 UNIFYING VIEWS

  • hyperpolarization-activated cation-nonselective (HCN) channel subunit expression is variable across thalamic nuclei in rodents [315], with the slow and highly cAMP-sensitive HCN4 subtype enriched in somatosensory thalamus, which contributes to strong sleep spindles in rodent somatosensory cortex

  • Hippocampal sharp-wave ripples contain brief, high-frequency network discharges called ripples (80 –100 Hz in humans, up to 250 Hz in rodents) that arise within the feedforward circuitry of the CA1 pyramidal layer during non-rapid-eye-movement sleep (NREMS) [89, 229] and that are involved in replay of wakerelated hippocampal activity [504]

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Summary

INTRODUCTION

Sleep spindles refer to a well recognizable, burstlike sequence of 10 –15 Hz sinusoidal cycles in the electroencephalogram (EEG) of sleeping mammals. Since these landmark discoveries, sleep spindles have led to insights into novel organizing principles of mammalian sleep and into how sleep relates to cognitive abilities and disease. Sleep spindles have led to insights into novel organizing principles of mammalian sleep and into how sleep relates to cognitive abilities and disease Their phasic appearance over a hierarchy of time scales divides non-rapid-eye-movement sleep (NREMS) into time windows with variable cortical states and sensory arousability. Sleep spindles are becoming a tool to monitor the inner workings of TC loops as they are unconstrained by wakefulness-related activity These advances increase their diagnostic and therapeutic usefulness Ca2ϩ and signaling pathways, gating of synaptic plasticity, and their role in the complex sequence of events leading to sleep-dependent memory consolidation are other aspects awaiting to be clarified Progress on the role of sleep spindles in healthy sleep, and their implication in pathology, requires more insight into these mechanistic questions

Electroencephalographic Identification
Thalamic Origin of Sleep Spindles
Histological Identification of the TRN
DEFINITIONS AND MEASUREMENTS
Sigma power in humans
Sigma power in rodents
Discrete Spindles
Visual detection
Automated detection
Machine-learning based quantification
Outlook
ROLE IN SLEEP’S MACRO- AND MICROARCHITECTURE
Sigma power
Sleep spindles
Regulation of NREMS macroarchitecture
Homeostatic Regulation
Circadian Regulation
Sex Differences
Infraslow Dynamics and NREMS Microarchitecture
Autonomic correlates of fragility and continuity periods
Neuronal correlates of fragility and continuity periods
NEUROPHYSIOLOGICAL MECHANISMS
The TRN
Initiation
Cellular and molecular mechanisms of TRN burst discharge
Synaptic initiation of TRN burst discharge
TRN-mediated synaptic inhibition of TC cells
Rebound excitation in TC cells
Synchronization
Mechanisms promoting synchrony
Antisynchronizing mechanisms
Termination and Refractory Period
Thalamic mechanisms
Cortical mechanisms
Brain stem mechanisms
Heterogeneity in Thalamic Sleep SpindleGenerating Circuits
Cellular heterogeneities
Heterogeneities in synaptic connectivity
CORTICAL STATES AND THEIR ORIGINS
Anatomy of the TC microcircuitry
Activation of cortical interneurons by sleep spindles
Modulation of dendritic activity by sleep spindles
Current-Source Density Profile
Global and Local Sleep Spindles
Fast and Slow Sleep Spindles
Coupling to the cortical SO
Coupling to hippocampal ripples
Coupling to beta and gamma bands
Sensory Gating
Sleep spindles as protective elements
Sleep spindles as reactive elements
SLEEP SPINDLES ACROSS THE LIFESPAN
Prenatal Spindle-like Activity
Postnatal Maturation and Adolescence
Developmental time course in early postnatal periods
Developmental time course until adolescence
Correlation between brain and sleep spindle maturation
VIII. MEMORY CONSOLIDATION
Synaptic Plasticity Associated with Sleep Spindles
Sleep spindles promote plasticity
Experience-dependent plasticity modifies sleepspindle-generating circuits
Active Systems Consolidation
Nondeclarative Forms of Memory
Declarative Forms of Memory
COGNITIVE ABILITIES AND INTELLIGENCE
Relation to White Matter Integrity
Relation to Intelligence Quotients
SLEEP DISORDERS AND NEUROLOGICAL DISEASE
Primary insomnia
Sleep-related movement disorders
Epilepsy
Age-Related Neurodegenerative Disorders
Neurodevelopmental and Neuropsychiatric Disorders
PHARMACOLOGICAL AND TARGETED INTERFERENCE WITH SLEEP SPINDLES
Pharmacological Interference
Targeted Interference
Boosting sleep spindles through resonance
Targeted memory reactivation involving sleep spindles
UNIFYING VIEWS
From Phenomenological Markers to Timers of NREMS Core Functions
From Sinusoidal Waves to Determinants of the Cortical State
From Memory Correlates to Time Frames for Active Systems Consolidation
Findings
XIII. THE EPILOGUE
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