Sleep protects excitatory cortical circuits against oxidative damage
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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