The locus ceruleus norepinephrine system

Abstract

The locus ceruleus (LC) contains norepinephrine (NE)-synthesizing neurons that send diffuse projections throughout the CNS. The LC-NE system has a major role in arousal, attention, and stress response. In the brain, NE may also contribute to long-term synaptic plasticity, pain modulation, motor control, energy homeostasis, and control of local blood blow. The LC is severely affected in neurodegenerative disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Dysregulation of LC-NE system has been implicated in sleep and arousal disorders, attention deficit hyperactivity disorder, and posttraumatic stress disorder and constitutes a target for pharmacologic treatment of these conditions. The neurobiology of the LC–noradrenergic system has been the subject of several excellent reviews.1–9 The LC is a cluster of NE-containing neurons located in the upper dorsolateral pontine tegmentum (figure 1). These neurons have extensively branched axons that project throughout the neuraxis and provide the sole source of NE to the neocortex, hippocampus, cerebellum, and most of the thalamus.1,2 Despite its widespread distribution, noradrenergic innervation shows regional specificity. For example, brain areas involved in spatial attention (such as the prefrontal and parietal cortices) receive particularly dense LC-NE inputs. In general, individual LC neurons send axon collaterals to multiple targets that process the same sensory information. Norepinephrine is released both at typical synapses and at nonsynaptic release sites; extrasynaptic NE mediates paracrine effects on neurons, glial cells, and microvessels.1–4,8 Figure 1 Anatomic organization of the locus ceruleus–norepinephrine system The norepinephrine (NE) neurons of the locus ceruleus (LC) are located in the upper dorsolateral pontine tegmentum and can be identified by their immunoreactivity for tyrosine hydroxylase, the rate-limiting enzyme for catecholamine synthesis. These neurons have extensively branched axons that project throughout the neuraxis and provide the sole source of NE to the neocortex, hippocampus, cerebellum, and most of the thalamus. Modified, …