Physiological ReviewNoradrenergic modulation of wakefulness/arousal
Introduction
The regulation of sleep and waking serves a critical role in behavior and ultimately survival. Moreover, during waking, arousal levels fluctuate, ranging from sleepiness/sedation associated with a relative insensitivity to sensory stimuli to high-arousal stress or fear-related conditions associated with a hypersensitivity to sensory events (hyperalertness, hypervigilance). Fluctuations in sleep-wake/arousal state are accompanied by alterations in forebrain neuronal activity that are reflected in electroencephalographic (EEG) signals.1, 2 The formal examination of the neurobiology of arousal/waking dates back to the work of von Economo,3 Bremer4 and Moruzzi and Magoun,5 which identified a critical role of the brainstem in the induction and maintenance of arousal. Subsequent work has identified a large array of brainstem and basal forebrain neural systems that participate in the regulation of behavioral state. Included among these is the locus coeruleus (LC)-noradrenergic system.
The LC is a small pontine nucleus that provides the majority of brain norepinephrine (NE).6 NE acts at three major receptor families, α1, α2, and β, each comprised of multiple subtypes. α1- and β-receptors are thought to exist primarily postsynaptically whereas α2-receptors are present both pre- and postsynaptically. Early electrophysiological observations indicated that the LC-NE system may play a role in the regulation of behavioral state.6, 7 For example, LC neurons display higher discharge rates during waking than in sleep while within waking LC discharge rate is positively correlated with behavioral and EEG indices of arousal.8, *9, *10 Importantly, these alterations in LC discharge rate precede changes in behavioral state.8, *9, *10 Combined, these observations suggested a potentially causal role of the LC-noradrenergic system in the regulation of sleep-wake/arousal state. Results from studies conducted over the past two decades provide unambiguous evidence for a prominent wake/arousal-promoting role of the LC and other brain noradrenergic systems (e.g., A1, A2), as reviewed below.
Section snippets
Wake/arousal-promoting actions of the locus coeruleus
Early lesion and pharmacological studies attempted to address whether there exists a causal relationship between LC neuronal activity and behavioral and EEG indices of waking/arousal (for review11, 12). In general, lesions of noradrenergic systems have had an inconsistent impact on indices of arousal (for review12). There is now strong reason to believe this limited action of noradrenergic lesions on behavioral state likely reflects the occurrence of time-dependent lesion-induced compensation
Neurocircuitry and receptor mechanisms of noradrenergic dependent waking: wake-promoting actions of α1- and β-receptors in the medial septal and medial preoptic areas
Collectively the observations reviewed above provide strong evidence that the LC-NE system exerts wake-promoting actions. This raises the question of which LC terminal fields and which postsynaptic receptors participate in these actions. Subcortically, the general regions of the medial septal area (MSA), the medial preoptic area (MPOA), and the substantia innominata (SI) are known to modulate forebrain EEG activity state25, 26, 27 and each of these regions receives LC-noradrenergic input.28, 29
Additional regions involved in NE-dependent waking
In addition to the MSA and MPOA, the lateral hypothalamus (LH) has been implicated in the regulation of sleep-wake state and state-dependent processes.65, 66 In particular, the neuropeptide family, hypocretin (HCRT; orexin), exerts potent wake-promoting actions.67, 68 HCRT-synthesizing neurons are located solely in the perifornical region of the LH, an area that receives a moderately dense noradrenergic innervation most of which arises from outside the LC.69, 70 Recently completed studies
Synergistic actions of β- and α1-receptors in the maintenance of alert waking
Substantial evidence indicates that stimulation of either α1- or β-receptors within any one of a number of brain regions is sufficient to induce the alert waking state. This high degree of redundancy suggests that α1-/β-receptor action in any given region is unlikely to be necessary for the maintenance of alert waking, consistent with observations reviewed above regarding a lack of effect of β-antagonist infusions into the MSA on indices of arousal in unanesthetized animals. To initially
Potential sleep-promoting actions of α1-receptors within the MPOA
In contrast to the robust wake-promoting effects of NE agonists infused into the MPOA and MSA, 6-OHDA lesions of the ventral noradrenergic bundle (VNAB) have been reported to increase time spent awake.85 This has been interpreted as suggesting a potential sleep-promoting action of NE, particularly within the MPOA.86 However, as noted above, 6-OHDA lesion of the VNAB will not eliminate all VNAB noradrenergic input to the MPOA. Moreover there are multiple sources of the noradrenergic innervation
Behavioral state modulatory actions of norepinephrine occur in conjunction with other behavioral actions
Evidence reviewed above indicates potent arousal-promoting actions of the LC-NE and presumably other noradrenergic systems. However, this is not to say that the sole function of the central noradrenergic systems is the regulation of arousal. Indeed, NE-induced arousal occurs in tandem with a large variety of modulatory actions of NE on physiological and behavioral processes, including endocrine regulation, perception, motor function, attention and memory, and decision and action (for review12).
Clinical relevance
The wake and arousal-promoting actions of central noradrenergic neurotransmission may have clinical relevance in a number of conditions associated with the dysregulation of sleep and waking and/or arousal. For example, the data reviewed above demonstrate that under normal conditions, acute activation of LC-noradrenergic signaling is incompatible with the state of sleep. Thus, inappropriate excitatory drive on this system, which can arise from upstream regions including the prefrontal cortex and
Conclusion
The regulation of arousal is a critical aspect of normal behavior. A substantial body of work demonstrates a prominent role of the LC and other noradrenergic systems in the regulation of waking and arousal. NE-dependent waking/arousal involves additive/synergistic actions of α1- and β-receptors located within multiple subcortical regions. Combined, the available evidence indicates that under normal physiological conditions even moderate activity of the LC-NE system is incompatible with the
Acknowledgments
This work was supported by PHS grants MH62359, DA10681, DA00389 and the University of Wisconsin Graduate School.
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