**1. Introduction**

Perhaps no behavioral feature is more evident and more widely distributed, nor more sought after than sleep. Yet, it is for its distinctiveness that sleep has often seemed at odds with daily needs, where attention and responsivity are critical to survival. Its presence, therefore, reveals the existence of some undetermined physical need, which no other mechanism can physically respond to.

Given the prominence and regularity of sleep, this physical need, and the physiological mechanisms used to satisfy it, can be expected to exert an influence on many bodily processes. Indeed, the events of sleep are now known to affect a broad number of fundamental bodily systems that may be enhanced or diminished in parallel with sleep phases. Sleep or circadian-related influences, for example, have been documented for autonomic function [1], hormone secretion/core-body temperature rhythm [2], energy production such as glucose metabolism [3], and coordinated motor and immune functions. By extension, disruption of sleep mechanisms can be expected to negatively impact the many processes that are subject to their influence [4].

A growing body of evidence indicates that the events of sleep have their origin in properties of the brain and nervous system circuitry. During NREM sleep, for instance, down states have been shown to be associated with a slowly traveling, oscillation wave that is synchronized throughout the cortex and substantial portions of the subcortex [5]. Transitioning between sleep stages, additionally, involves the modulation of an arousal system that is distributed throughout the brain and that choreographs the shape of sleep architecture. These and many other details imply that the systemic processes affected by sleep are initially affected by a global impact exerted at the level of the brain, which potentially affects such events as developmental regimes of synaptogenesis [6], psychiatric dysfunctions [7], addiction [8], hormonal rhythms [1], and cognitive processes like memory and learning [9].

Those dysfunctional sleep mechanisms that can be linked to secondary systemic dysfunctions offer the intriguing possibility of medically managing and even of therapeutically alleviating such dysfunctions through treatment modalities developed chiefly for sleep disturbances. Drugs that enhance states of sleep, for instance, are also known to alter autonomic physiology, behavior, cognition, and affect [10]. While the complexities of the brain's neurochemistry and circuits mediating

wakefulness and sleep make the control of the precise physiological mechanisms uncertain, there has been considerable progress in developing medications that are narrowly tailored to various features of sleep, such as rapid sleep onset, minimal hangover, and low abuse potential, among other properties [11]. That is, the current evolution in sleep pharmacotherapy has generated an armamentarium of sufficient precision that it may be redirected to other neural systems. An improving database, moreover, can be expected to further the ability to tailor sleep modulation so as to selectively modulate events directly affected by sleep mechanisms.

An important component of rational therapeutic intervention, nonetheless, clearly also requires a continually improving understanding of the sleep mechanisms themselves [12]. This is to say that only from a knowledge of sleep can the understanding of how it affects other systems be discerned. Accordingly, this chapter will review several leading hypotheses regarding the physical properties that govern sleep mechanisms, the prospects for modulating these properties pharmacologically, and the systemic effects such therapy may have.

#### **2. The universal need for sleep**

Each time sleep occurs the ability to appraise the events around us is lost. This interruption of sensorial content represents a definitional and unique feature of sleep, one that distinguishes it from other behavioral states, all of which otherwise retain the ability to promptly respond to stimuli. Although it is unknown why it should be necessary to prevent the brain from receiving input for prolonged intervals, the fact that humans and all other animal species require sleep indicates the existence of a fundamental physical and neural reason for it to occur; that is, sleep serves at least one essential function that cannot be carried out while awake.

One widely acknowledged proposal links this essential function to neuronal properties evoked by centrally directed communication, which involves changes in interneuronal exchange at the level of the synapse. This hypothesis, termed the synaptic homeostasis hypothesis (SHY), privileges the unique ability of the brain to learn from external events of the world that become inscribed through neuroplastic changes in synaptic connections [12]. The SHY hypothesis proposes that these neuroplastic changes entail sensorium-induced increases in synaptic potentiation, which can be visualized electrophysiologically in miniature endplate potentials; that is, there is a *sensorium-induced* increase in synaptic potentiation. Because the extent of potentiation necessarily possesses an upper limit, there is a need to regularly reduce the level of potentiation so that the brain can continue to learn. This readjustment is proposed to occur during sleep.

Hence, sleep is the mechanism that has evolved to account for the cost of the physical events of neuroplasticity, which enable the organism to adapt and survive in a constantly changing environment [13]. When this cost is not accounted for cognitive function is poor. Acute and chronic sleep loss, for example, have pervasive negative effects on performance and many brain functions, including the ability to learn, remember, speak clearly, judge risk, and understand complex information needed for decision making [14]. Post-training "fatigue," for example, the impaired capacity for new learning that follows intense training in a motor or visual task, is restored only by sleep. Physically, therefore, sleep assists in maintaining an overall balance of synaptic strength across brain circuits, which may be conceived as a synaptic renormalization. The hypothesis thus predicts that overall synaptic strength in the brain should not be balanced at all times, but instead should be biased toward a net potentiation during the major wake period and toward a net depression during sleep.

#### *Introductory Chapter: The Promise of Sleep Pharmacotherapy - Healing Systems Level Dysfunction DOI: http://dx.doi.org/10.5772/intechopen.101177*

Similar to the SHY hypothesis, the free energy principle of Friston and colleagues hypothesizes that ongoing informational input from the sensorium leads to a rise in the information-related, state variable, entropy [15]. Like potentiation, entropy is a saturable quantity driven by sensorial input that progressively approaches an upper bound. Unlike the potentiation hypothesis, the free energy principle does not postulate a specific period devoted to recovery from synaptic changes. Instead, the brain is proposed to counter the ensuing information accumulation by optimizing behavioral patterns that minimize the need for future change. For instance, inputs that occur together more frequently than would be expected by chance are registered because they suggest regularities in the environment that are predictable. Once these "coincidences" are detected, a neuron communicates them to its target neuron, typically through synaptic strengthening. The effect of registering these "coincidences" thus enables the brain to structure its behavior so as to minimize surprisal and guide the selection of behavioral responses. By such active inferencing [16], the brain comes to reflect the regularities observed in the external world, an organizational arrangement that serves to maximize free energy efficiency.

The free energy principle governing cognition resembles aspects of the SHY hypothesis in providing an explanation for changes in synaptic events that are due to sensorial input and that build on the brain's ability to enable the organism to better confront a continually changing, environmental landscape. Moreover, by staging causal optimization in terms of an entropic cost function, the model accounts for some physical constraints that place an upper bound on synaptic change.

Nonetheless, the free energy principle only indirectly addresses the issue of saturability due to ongoing sensorial novelty, which is inherent in the interactive circumstances of the external world and presumably greatly amplified by the presence of living organisms [17]. This means that the persistence of novel input from the sensorium will continue to generate synaptic reorganization, despite causal inferencing that may diminish the overall level of reorganization. Faced with ongoing novelty, organizational resources of brain synapses can be expected to operate within physical ranges that regularly encounter upper limits under the assumptions of both proposals. Indeed, the observation that all known animal species need to "regularly disconnect" constitutes a strong argument that sensorial novelty is persistent and that its input repeatedly saturates a physical condition that must subsequently be replenished; that is, the brain is "awash" in new experiences for which physical compensation is required. *Hence, while the free energy principle is agnostic with regard to underlying mechanisms that result in saturability, both it and the SHY hypothesis link sleep to ongoing afferent input that modifies the brain's synaptic organization in such a manner as to regularly require renormalization.*
