Functional Anatomy of Non-REM Sleep

Abstract

The state of non-REM sleep (NREM), or slow wave sleep, is associated with a synchronized EEG pattern in which sleep spindles and/or K complexes and high-voltage slow wave activity (SWA) can be recorded over the entire cortical surface. In humans, NREM is subdivided into stages 2 and 3-4 (presently named N3) depending on the proportions of each of these polygraphic events. NREM is necessary for normal physical and intellectual performance and behavior. An overview of the brain structures involved in NREM generation shows that the thalamus and the cerebral cortex are absolutely necessary for the most significant bioelectric and behavioral events of NREM to be expressed; other structures like the basal forebrain, anterior hypothalamus, cerebellum, caudal brain stem, spinal cord and peripheral nerves contribute to NREM regulation and modulation. In NREM stage 2, sustained hyperpolarized membrane potential levels resulting from interaction between thalamic reticular and projection neurons gives rise to spindle oscillations in the membrane potential; the initiation and termination of individual spindle sequences depends on corticothalamic activities. Cortical and thalamic mechanisms are also involved in the generation of EEG delta SWA that appears in deep stage 3-4 (N3) NREM; the cortex has classically been considered to be the structure that generates this activity, but delta oscillations can also be generated in thalamocortical neurons. NREM is probably necessary to normalize synapses to a sustainable basal condition that can ensure cellular homeostasis. Sleep homeostasis depends not only on the duration of prior wakefulness but also on its intensity, and sleep need increases when wakefulness is associated with learning. NREM seems to ensure cell homeostasis by reducing the number of synaptic connections to a basic level; based on simple energy demands, cerebral energy economizing during NREM sleep is one of the prevalent hypotheses to explain NREM homeostasis.

Keywords: NREM sleep homeostasis; caudal hypnogenic system; rostral hypnogenic system; sleep need; slow wave sleep; thalamus–cerebral cortex unit.

Figure 1

Nocturnal hypnogram of a young man. Modified from Reinoso-Suárez et al. (2010).

Figure 2

Schematic representation of the encephalic NREM sleep-promoting structures. A parasagittal section of cat brain shows a shaded area representing the brain structures where lesion decreases NREM sleep and/or EEG synchronization or stimulation increases NREM sleep. The main connections between these structures and the structures responsible of the organization of wakefulness (encompassed in red line) or REM sleep (blue lines) – with the exception of the efferent hypothalamic and midbrain connections and the brainstem connections from the basal forebrain – are shown. The thalamus–cerebral cortex complex or unit is darker to emphasize that these structures are necessary for the behavioral and bioelectric signs that characterize NREM sleep. AC, anterior commissure; CC, corpus callosum; DCN, deep cerebellar nuclei; Fo, fornix; G7, genu of the facial nerve; IC, inferior colliculus; IO, inferior olive; LV, lateral ventricle; MRF; midbrain reticular formation; MT, medullary tegmentum; OCh, optic chiasm; PGS, periaqueductal gray substance; RPC, caudal pontine reticular nucleus; RPO, oral pontine reticular nucleus; SC, superior colliculus; SC and PN, spinal cord and peripheral nerves; SN, solitary nucleus; TB, trapezoid body. Modified from Reinoso-Suárez et al. (2011).

Figure 3

Thalamic nuclei, cell types, and thalamocortical relationships. The lower part of the figure represents a schematic coronal section of the primate diencephalon and the upper drawing depicts a schematic section of the primary and association cerebral cortices. Thalamic lateral posterior (LP) and ventral posterior (VP) nuclei are represented as examples of high-order and first-order thalamic nuclei, respectively. C, core-type cells; Intr, thalamic intralaminar nuclei; It, GABAergic interneurons; M, matrix-type cells; MD, medial dorsal thalamic nucleus; NR, thalamic reticular nucleus; I–VI, cortical layers. Modified from Reinoso-Suárez et al. (2011).

Figure 4

Schematic representation of the fiber and neuronal organization of the cerebral cortex. The projection neurons, pyramidal neurons in layers II–III, V, and VI, are represented in different colors according to their origin and targets. The two types of interneurons are represented in different colors: (1) the excitatory interneuron, a spiny stellate cell, is in pink; and (2) the inhibitory interneurons are in light green. There are four specific examples of inhibitory interneuron: two dendrite-and tuft-targeting cells [Cajal-Retzius (C-R) and Martinotti (M) neurons], one dendrite targeting cell [double bouquet (DB) neuron], and one axon targeting cell [chandelier (C) neuron]. Afferent fibers from cortical and subcortical origins are represented in different colors and specific distributions. The wide distributions of dopaminergic (DA), serotonergic (5-HT), noradrenergic (NA), histaminergic (His), orexinergic (Orx), and GABAergic (GABA) fibers originating in brainstem, diencephalic, and basal prosencephalic structures are represented by their terminals, as is the topographically organized terminals of the basal forebrain cholinergic (Ach) fibers. Thalamocortical fibers targeting cortical layers I (M-type) and IV (C-type) are also shown. I to VI, cortical layers one to six. Open triangles, excitatory terminals; solid triangles, inhibitory terminals. From Reinoso-Suárez et al. (2011).

Figure 5

Schematic representation of the anatomical bases for the sleep spindles of NREM sleep and the intermediate- to high-voltage theta EEG activity of drowsiness. From Reinoso-Suárez et al. (2011).

Figure 6

Top: microphotographs illustrating the location of the saline and opioid microinjections in two cats injected in the medial nucleus (arrow) of the solitary tract (SOL). Bottom: Bars show the mean duration in minutes spent in the different sleep–wakefulness states during the first hour of recordings in controls (saline, 40 nl) and after morphiceptin (mu opioid agonist) or DPDPE (delta opioid agonist) microinjections (2.4 nmol, 40 nl). Respiratory rate (triangles) in breaths per minute and heart rate (circles) in beats per minute are also shown for each sleep–wakefulness state during the first hour of recordings. Note the decreased respiratory and heart rates in sleep states in comparison with values during wakefulness in the control saline experiments; both opioid treatments produced a further decrease in both autonomic variables. W, wakefulness; D, drowsiness; NREM, non-REM sleep; REM, REM sleep. (After Reinoso-Barbero, 1993).

Figure 7

Activating and synchronizing EEG centers in the pontine tegmentum. (A,C–E) show diagrams of the combined extent of lesions in the pontine tegmentum of cats producing either EEG activation (diagonal dashed lines encircled by heavy dashed lines) or EEG synchronization (horizontal lines encircled by heavy solid lines). (A) Parasagittal section 2 mm from the midline; circled numbers indicate frontal plane levels on the Reinoso-Suárez (1961) atlas corresponding to sections (C–E), respectively. (B) Graph showing the percent of increase in activation (dashed line) and decrease in activation (solid line) relative to the pre-lesion control-based zero for each animal. Note that lesions that produced EEG synchronization are located at the level of the oral pontine reticular nucleus and those that produced EEG activation are located caudal, dorsal, and lateral to this nucleus. BC, brachium conjunctivum; BP, brachium pontis; CP, colliculus inferior; FP, fasciculus longitudinalis medialis; LM, lemniscus medialis; MV, tractus mesencephalicus nervi trigemini; NLL, nucleus lemnisci lateralis; NP, nuclei pontis; NR, nucleus ruber; NRV, nucleus reticularis ventralis; NTR, nucleus corporis trapezoidei; OS, oliva superior; P, tractus pyramidalis; RPC, nucleus reticularis pontis caudalis; RPO, nucleus reticularis pontis oralis; SCV, tractus spinocerebellaris anterior; TD, nucleus tegmenti dorsalis; TR, corpus trapezoideum; TF, tractus tectospinalis. From Camacho-Evangelista and Reinoso-Suárez (1964).

Figure 8

Modifications in the total duration of wakefulness, drowsiness, NREM (slow sleep), and REM (paradoxical) sleep, as well as their episode mean duration and number per recording after different cerebellar lesions. The cats with lesions in the brachium conjunctivum showed a significant decrease of NREM (Slow Wave) and REM (Paradoxical) sleep. In contrast, the cats with lesions in the cerebellar cortex and white matter of the anterior vermis showed a significant decrease of drowsiness and a significant increase in REM sleep. Modified from De Andrés and Reinoso-Suárez (1979).