Sleep protects excitatory cortical circuits against oxidative damage

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Abstract

Activity in excitatory cortical pathways increases the oxidative metabolism of the brain and the risk of oxidative damage. Oxyradicals formed during periods of activity are mopped up by neural pools of nuclear factor κ-B resulting in their activation and translocation to cell nuclei. During waking hours, glucocorticoids inhibit transactivation by nuclear factor κ-B, increase central norepinephrine release, and elevate expression of prostaglandin D2. The build-up of nuclear factor κ-B and prostaglandin D2 produces sleep pressures leading to sleep onset, normally gated by circadian melatonin release. During slow wave sleep nuclear factor κ-B induces transcription of synaptogenic and antioxidant products and synaptic remodeling follows. Synaptically remodeled neural circuits have modified conductivity patterns and timescales and need to be resynchronized with existing unmodified neural circuits. The resynchronization process, mediated by theta rhythm, occurs during rapid eye movement sleep and is orchestrated from pontine centers. Resynchronization of remodeled neural circuits produces dreams. The waking state results upon successful resynchronization. Rapid eye movement sleep deprivation results in a lack of resynchronization and leads to cognitive inefficiencies. The model presented here proposes that the primary purpose of sleep is to protect cortical circuits against oxidative damage by reducing cortical activity and by remodeling and resynchronizing cortical circuits during this period of reduced activity to sustain new patterns of activation more effectively.

Introduction

Sleep occurs in mammalian, avian, and reptilian species [1] and plays a critical role in neural development [2], [3], [4] and mental functions [5], [6], [7]. Sleep is generally considered to be under the control of two processes: a circadian rhythm and a homeostatic process [8], [9], [10]. Circadian rhythms often reflect gene expression, the products of gene expression such as enzymatic activity, or are due to metabolic cycling in cell activity [11], [12], [13]. In mammals, circadian rhythms, even though they can persist in isolated tissues, are coordinated by the suprachiasmatic nucleus (SCN) [13].

Studies in vertebrates show that the circadian rhythms of sleep and wakefulness have evolved in the direction of greater consolidation of these cycles: increased nighttime sleep at the expense of daytime sleep and a differentiation of nighttime types of sleep [1]. This evolutionary progression suggests an increased coordination of rest and activity cycles in different tissues.

The homeostatic inferences regarding sleep arise from the build-up of pressures following various types of sleep deprivation – decreasing the latency to sleep onset, increasing the amount of slow wave sleep (SWS), and increasing the amount of rapid eye movement (REM) sleep [14], [15], [16]. The homeostatic process predicts slow wave activity [17]. Higher rates of cerebral protein synthesis are associated with SWS compared to REM sleep [18].

Section snippets

Sleep pressures

High cognitive demand that occurs during waking hours increases excitatory cortical glutaminergic neurotransmission, oxygen consumption, and oxygen supply [19], [20], [21]. Increased (oxygen) metabolism will increase the risk of damage due to glutamate overexcitation, increased levels of intracellular Ca2+, increased levels of auto-oxidation susceptible neurotransmitters, and increased levels of reactive oxygen species [22], [23]. Since glutamate-induced overexcitation [24] and high levels of

Sleep onset

Sleep occurs when the build-up of activated NF-κB is sufficient to overcome the inhibition by glucocorticoids and when PGD2-mediated adenosine release inhibits the tuberomammillary histaminergic wake center [40], [41], [42]. This process is likely gated by circadian activity in the SCN and the action of melatonin [43], [44], except possibly during extreme fatigue and disease states when sleep may be induced by cytokines [7], [30].

Synaptic remodeling

Sleep protects the cortex from glutamate-induced oxidative stress by reducing cortical activity to permit synaptogenesis. During periods of reduced activity, neural circuit capacity in waking state-challenged circuits is boosted via neuroplastic repair and augmentation. Circuit improvement requires removal of damaged sites and associated debris and subsequent remodeling. Elimination of damaged synapses may occur by astrocytic phagocytosis of inactive synaptic terminals [45], [46] and cytokine

Network resynchronization

Changes in synaptic function produce changes in network excitability and function and become manifest as changes in behavior [56], [57], [58], [59]. For example, estradiol increases the density of glutaminergic receptors in cultured rat hippocampal pyramidal neurons, the cellular calcium response to glutamate, and the network synaptic activity amongst the cultured neurons [58]. Estrous hormones also facilitate motor behaviors such as limb stepping [60]. The foregoing suggests that network

Dreaming

Dreaming is a consequence of the transient activation of modified neural circuits during the resynchronization process (or during the synchronization process in normal development). This process is progressive, starting with smaller modified networks and integrating them in successive REM episodes with other such networks and finally with non-modified networks. Progressive changes in dream content from more disjointed and bizarre to more lucid and episodic over successive periods of REM sleep

Conclusions

The model outlined here and elaborated in detail elsewhere [73] hypothesizes the functions of sleep to be the protection of cortical circuits against oxidative damage. This is effected by the reduction of neural activity, the induction of synaptic remodeling in stressed neural circuits, and the resynchronization of modified circuits with other structures. Dreaming reflects the (re)synchronization process. Remodeled and resynchronized neural circuits process the same tasks more efficiently than

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