Review
The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes

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Abstract

Through a widespread efferent projection system, the locus coeruleus–noradrenergic system supplies norepinephrine throughout the central nervous system. Initial studies provided critical insight into the basic organization and properties of this system. More recent work identifies a complicated array of behavioral and electrophysiological actions that have in common the facilitation of processing of relevant, or salient, information. This involves two basic levels of action. First, the system contributes to the initiation and maintenance of behavioral and forebrain neuronal activity states appropriate for the collection of sensory information (e.g. waking). Second, within the waking state, this system modulates the collection and processing of salient sensory information through a diversity of concentration-dependent actions within cortical and subcortical sensory, attention, and memory circuits. Norepinephrine-dependent modulation of long-term alterations in synaptic strength, gene transcription and other processes suggest a potentially critical role of this neurotransmitter system in experience-dependent alterations in neural function and behavior. The ability of a given stimulus to increase locus coeruleus discharge activity appears independent of affective valence (appetitive vs. aversive). Combined, these observations suggest that the locus coeruleus–noradrenergic system is a critical component of the neural architecture supporting interaction with, and navigation through, a complex world. These observations further suggest that dysregulation of locus coeruleus–noradrenergic neurotransmission may contribute to cognitive and/or arousal dysfunction associated with a variety of psychiatric disorders, including attention-deficit hyperactivity disorder, sleep and arousal disorders, as well as certain affective disorders, including post-traumatic stress disorder. Independent of an etiological role in these disorders, the locus coeruleus–noradrenergic system represents an appropriate target for pharmacological treatment of specific attention, memory and/or arousal dysfunction associated with a variety of behavioral/cognitive disorders.

Introduction

Norepinephrine (NE)-containing axons are distributed widely throughout the central nervous system (CNS), suggesting a prominent role of this neurotransmitter in CNS function and behavior. A majority of brain noradrenergic neurons are concentrated in the brainstem nucleus, locus coeruleus (LC). This nucleus is the primary source of an extensive, yet regionally-specialized, noradrenergic innervation of the forebrain. Importantly, the LC provides the sole source of NE to hippocampus and neocortex, regions critical for higher cognitive and affective processes. Despite intense examination of the LC–noradrenergic system and substantial progress in our understanding of the neurobiology of this system, the ultimate impact of LC neurotransmission on behavioral processes has, for the most part, remained unresolved.

This situation has changed gradually as relatively recent work provides unambiguous evidence that through a variety of actions, the LC–noradrenergic system exerts a widespread influence on neuronal circuits that are essential substrates of alert waking and state-dependent cognitive processes. Together with previous anatomical, electrophysiological and behavioral evidence, these observations indicate that the LC, and possibly other noradrenergic pathways, serves at least two general behavioral functions. First, this system contributes to the induction and maintenance of forebrain neuronal and behavioral activity states appropriate for the acquisition of sensory information (e.g. waking). Second, within the waking state, NE enhances and/or modulates the collection and processing of salient sensory information via actions on sensory, memory, attentional, and motor processes. Actions within this latter category can be both short-term and long-term in nature, and can occur within perceptual, attentional, and memory systems. Noradrenergic modulation of behavioral state and state-dependent processes involves actions distributed across multiple anatomical regions and multiple receptor subtypes. Based on these observations, it is posited that dysregulation of the LC–noradrenergic system may result in deficits in a variety of cognitive and affective processes that are, in turn, associated with numerous cognitive and affective disorders such as attention deficit/hyperactivity disorder (ADHD), narcolepsy, and stress-related disorders. Whether or not deficiencies in noradrenergic neurotransmission contribute to the etiology of these cognitive/affective disorders, actions of noradrenergic systems likely contribute to the efficacy of a variety of drugs used in the treatment of these conditions.

Over the past 40 years, a large body of information has been garnered regarding the basic neurobiology of the LC–noradrenergic system, as reviewed in a number of excellent reviews [10], [37], [168], [170], [517]. The current report summarizes relatively recent anatomical, molecular, physiological and behavioral data demonstrating a role for the LC–noradrenergic system in the regulation of behavioral state and state-dependent cognitive processes and the neural circuitry underlying these actions. Within this framework we attempt to identify existing lacunae in our understanding of the neurobiology of this system and suggest potential implications of available information for better understanding the involvement of this neurotransmitter system in the etiology and treatment of a subset of cognitive/psychiatric disorders.

Section snippets

Anatomical organization of the LC–noradrenergic system

The basic anatomical features of the LC–noradrenergic system have been defined in great detail by a variety of investigators [37]. The LC nucleus is a well-delineated cluster of NE-containing neurons, located adjacent to the fourth ventricle in the pontine brainstem. It is composed of a small number of neurons: approximately 1500 per nucleus in rat, several thousand in monkey, and 10,000–15,000 in human. However, these neurons possess immensely ramified axons such that the nucleus projects

NE-elicits long-term alterations in synaptic efficacy within neuronal ensembles

LC-dependent alterations in responsiveness to afferent information are also observed at the level of large-population neuronal ensembles. For example, potent modulatory actions of NE have been observed in an extensively studied cellular model of memory, long-term potentiation (LTP). LTP refers to a use-dependent, long-lasting increase in synaptic strength or efficacy. Thus, when excitatory synapses are rapidly and repetitively stimulated for brief periods (tetanic stimulation), the postsynaptic

LC–noradrenergic modulation of neuronal energy availability

Neuronal activity is tightly linked to energy utilization. Astrocytes are a repository of stored glucose in the form of glycogen, which appears to be highly metabolically active and linked to neuronal activity [225], [385], [542]. For example, glycogen levels are increased during slow-wave sleep, suggesting increased glucose utilization during waking [245]. Evidence suggests that NE exerts a robust modulatory effect on astrocytic glycogen levels. Thus, application of NE to cortical slice or

LC–noradrenergic-dependent alterations in transcription rates of immediate–early and other plasticity-related genes

Long-term alterations in CNS function involve, at least in part, alterations in rates of gene transcription and protein production. A set of ‘immediate–early genes’ (IEGs) has been identified that are activated rapidly by a variety of neuromodulators. The IEG’s in this group include c-fos, c-jun, Arc, nur77, tis-1, tis-7, tis-21, NGFI-A and -B, and zif-268. These genes, in part, regulate transcription rates of a variety of genes. Through these actions, IEGs may provide an intervening step

Actions of the LC–noradrenergic system on state-dependent cognitive processes

The above-described actions of the LC–NE efferent system suggest widespread influences of this monoaminergic pathway on processing of sensory information at both the single neuron and neuronal network levels. Consistent with these observations, additional work indicates that the LC–NE system plays a prominent role in cognitive processes related to the collection, processing, utilization and retention of sensory information. In particular, as reviewed below, experimental evidence suggests a

Noradrenergic modulation of motor function

Currently, much of the information regarding the actions of NE within the brain concerns actions on sensory systems. Less is known about the actions of NE on central motor systems. However, available information suggests, as in sensory neuronal circuits, LC efferent pathway stimulation or NE application enhances motoneuron responsiveness to excitatory synaptic inputs [177], [178], [412], [532], [566]. Further, in vitro, locally applied NE increases the excitability of motor cortex pyramidal

Noradrenergic participation in the behavioral and electrophysiological effects of amphetamine-like stimulants

Amphetamine (AMPH)-like stimulants, including cocaine, have in common the ability to facilitate dopaminergic and noradrenergic neurotransmission. Some, but not all, of these agents also enhance serotonergic neurotransmission [261], [265]. Over the years much insight has been gained regarding the neural mechanisms through which these drugs exert their reinforcing, locomotor-activating, and stereotypy-inducing actions. In each of these behavioral effects, enhanced dopaminergic neurotransmission

Summary: LC and behavioral processes

An impressive array of information has been collected concerning the electrophysiological and anatomical properties as well as the neural and behavioral actions of the LC–NE system. Alterations in activity of a small number of LC neurons are broadcast globally across functionally diverse regions of the brain, affecting neuronal populations of immense number (excluding basal ganglia). However, within this system there exists a degree of specificity conferred by the pattern of fiber termination,

Clinical implications

The LC–NE system impacts widespread neural circuits involved in the collection and processing of sensory information. As such, dysregulation of LC–NE neurotransmission might impact any number of cognitive and affective processes. In keeping with this, multiple cognitive and affective disorders have been posited to involve a dysregulation of noradrenergic neurotransmission. Much of the evidence suggesting a potential role of the LC–NE system in these disorders derives from the therapeutic

Summary

In conclusion, results from a variety of investigations of LC and/or NE function reveal a surprising degree of cohesion: whether at the level of the single cell, populations of neurons, or behavior, NE increases the organism’s ability to process relevant or salient stimuli while suppressing responses to irrelevant stimuli. This involves two basic categories of action. First, the system contributes to the initiation of behavioral and forebrain neuronal activity states appropriate for the

Acknowledgements

Preparation of this review and research by the authors was supported by the PHS grants NS32461, DA05117, MH14602 (BDW), and DA10681, DA00389, and MH62359 and the University of Wisconsin Graduate School (CWB). The authors acknowledge the insightful comments of an anonymous reviewer.

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