Noradrenergic modulation of cognitive function: clinical implications of anatomical, electrophysiological and behavioural studies in animal models

Noradrenergic modulation of cognitive function: clinical implications of anatomical, electrophysiological and behavioural studies in animal models 1The early demonstration of the neurotransmitter role of norepinephrine (NE) within the brain stimulated intense study of its functions over the subsequent three decades.A large majority of brain noradrenergic neurons are concentrated in the brainstem nucleus, locus coeruleus (LC).This nucleus gives rise to an extensive and regionally specialized noradrenergic innervation of the CNS, including providing the sole source of NE to hippocampus and neocortex.Despite the intense examination of the LC/noradrenergic system, and the knowledge gained concerning various properties of this system, its functions remain enigmatic.This editorial will provide a brief review of electrophysiological and behavioural studies which indicate that NE enhances cortical information processing through a variety of actions distributed across multiple anatomical regions and involving multiple receptors.It is proposed that the LC/noradrenergic system acts to create dynamic, widespread patterns of electrophysiological activity in neocortex and other forebrain areas that provide essential substrates for the operation of attentional and other cognitive processes.A greater understanding of the actions of the LC/noradrenergic system may provide the opportunity to treat cognitive dysfunction better in certain patient populations. CHARACTERISTICS OF THE LC/NORADRENERGIC SYSTEMThe LC is a well-delineated cluster of noradrenergic neurons, located adjacent to the fourth ventricle in the pontine brainstem.It is composed of a small number of neurons (approximately 1600 per nucleus in rat, several thousand in monkey, and 10000-15000 in human).However, these cells possess immensely ramified axons such that the nucleus projects throughout the neuraxis, from spinal cord to neocortex (reviewed in Foote et al. 1983).In rodents, there appears to be little topographic specificity in these projections in the sense that individual LC neurons project to widely dispersed regions.However, within terminal fields noradrenergic axons are characterized by regionally specific patterns of innervation.For example, LC axons preferentially innervate particular cortical regions and laminae, especially in primates (reviewed in Foote & Morrison, 1987).The dense innervation of layer I is particularly interesting, given that this is considered an important site for cortical integration (Vogt, 1991).Heterogeneity is also observed at the receptor level.Thus, traditionally three noradrenergic receptor subtypes have been recognized: a v a 2 , and /?.OL X -and ^-receptors are thought to exist primarily at post-synaptic sites whereas a 2 -receptors are believed to be present both pre-and post-synaptically; presynaptic <z 2receptors exert an inhibitory influence on LC neuronal discharge and NE release (Svensson et al. 1975), whereas the actions of post-synaptic a 2 -receptors are largely unknown.The distribution across and within cortical regions varies between the specific receptor subtypes, as does secondmessenger coupling.For example, /?-receptors appear to be more broadly distributed across cortical laminae and are positively coupled to the Gs/cAMP second-messenger system, whereas a x -and a 2receptors are concentrated in the superficial layers and are coupled to the phosphoinositol and