Manipulating sleep spindles – expanding views on sleep, memory, and disease

Abstract

Abstract:Sleep spindles are distinctive electroencephalographic (EEG) oscillations emerging during non-rapid-eye-movement sleep (NREMS) that have been implicated in multiple brain functions, including sleep quality, sensory gating, learning and memory. Despite considerable knowledge about the mechanisms underlying these neuronal rhythms, their function remains poorly understood and current views are largely based on correlational evidence. Here, we review recent studies in humans and rodents that have begun to broaden our understanding of the role of spindles in the normal and disordered brain. We show that newly identified molecular substrates of spindle oscillations, in combination with evolving technological progress, offer novel targets and tools to selectively manipulate spindles and dissect their role in sleep-dependent processes. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationAstori et al. Highlights Newly recognized ion channel subtypes generating spindle rhythms are described. The contribution of spindles to arousal threshold and sleep quality is discussed. The proposed role of spindles in memory consolidation is examined. A function of thalamic spindles in neural development is suggested. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 4 Previous excellent reviews have thoroughly described cellular and network bases of spindle generation [3,6,7]. Here, we first review recent work on genetic models that has expanded the mechanistic understanding of this EEG rhythm through the modification of novel molecular substrates. We then discuss the current views about the functional aspects of spindles in brain physiology and pathology, as obtained from studies in naturally sleeping animals and humans. We highlight studies indicating that spindles are accessible for selective interventions, and that, with emerging technologies, will open avenues to decipher spindle function. Novel molecular aspects of spindle generationSleep spindles emerge from a limited set of cellular participants: the resonating core of these waxing-and-waning oscillations resides in the nRt-TC loop, which sustains repetitive burst discharges of its cellular components under the control of cortical inputs (Figure 1 Another important factor in the generation and maintenance of reticular intrinsic oscillations is the aforementioned SK2 or Kcnn2 channel. The vigorous Ca 2+ influx in nRt dendrites originating from Ca V 3.3 channels gates SK2 channels, thereby creating a burstafterhyperpolarization (bAHP) [12,19]. As T channels recover partially from inactivation duri...

Thalamic Inhibition: Diverse Sources, Diverse Scales

“…While the Ca 2+ spike is readily observable in intracellular recordings, a burst is inferred in extracellular recordings using criteria that capture their intracellular statistics (100msec silence followed by <4msec interspike intervals) [43] (Fig 2B). Thalamic Ca 2+ spikes are generated by low-threshold T-type Ca 2+ channels (CaV 3 family) [44], which are recruited at hyperpolarized membrane potentials that are thought to be more prevalent during periods of behavioral quiescence and sleep [45]. For the TRN, this would mean enhanced bursting during these states resulting in more widespread and longer-lasting inhibition of thalamic targets.…”

“…Spindles are 7–14Hz phasic transients that are observed in the cortical electroencephalograph (EEG) during sleep, and have been linked to sensory processing and memory consolidation [45]. Spindles are known to require interactions between TRN and connected thalamus, but the detailed synaptic interactions have only been revealed recently.…”

Sleep spindles provide indirect support to the consolidation of emotional encoding contexts

“…Sleep spindles, which originate in the thalamus and propagate to widespread cortical regions (De Gennaro & Ferrara, 2003), are robustly associated with offline memory processes (Astori, Wimmer, & Lüthi, 2013;Diekelmann, 2014;Rasch & Born, 2013). Human studies have reported increased spindle activity after learning (Gais, Molle, Helms, & Born, 2002;Schmidt et al 2006), as well as predictive relationships between spindle activity and subsequent memory performance; an effect observed across naturally occurring sleep (Clemens, Fabo, & Halasz, 2005;Schabus et al, 2004) and following pharmacological manipulations of spindle density .…”

Characterizing sleep spindles in 11,630 individuals from the National Sleep Research Resource

“…Spindle activity is modifiable24252627 and could represent an attractive therapeutic target if causally implicated in disease risk. In light of recent progress in schizophrenia genetics2829, genetically characterizing variation in spindle activity could help to elucidate pathways between genetic risk and neuropsychiatric disease23.…”