What Are Current Concepts on the Functional Organization of the Locus Coeruleus and Its Role in Cognition and Neurodegeneration?

The locus coeruleus noradrenergic (LC-NE) system provides a widespread innervation to the CNS. Through both targeted and diffuse projections, this system has a major role in the control of arousal, attention, working memory, sensory processing, episodic and emotional memory, responses to stress, and goal-directed motivated behavior.^1-10 Recent studies, primarily in rodents, have provided new insights into the organization and function of the LC-NE system, emphasizing its anatomical and functional heterogeneity and distinct modes of operation (Figure).¹¹ Subpopulations of LC-NE neurons can modulate specific cognitive processes through distinct connections with forebrain areas.^12-14 In addition, LC-NE neurons may fire in synchrony and, through axon collaterals to multiple brain areas, provide for a state-dependent global modulation of behavioral states, such as the sleep-wake cycle.¹⁵ Furthermore, the LC-NE system influences glial cells and microvasculature, thereby exerting metabolic and neuroprotective effects.^16,17 These new findings are of clinical relevance because the LC shows pathologic changes at early stages of neurodegenerative diseases, including the Alzheimer disease (AD)^18,19 and Parkinson disease (PD).^19,20 Neuroimaging techniques such as neuromelanin-sensitive MRI sequences to visualize LC cell bodies and PET tracers to assess NE transporter density in NE terminals are increasingly applied to assess the functional connectivity of the LC-NE system during normal cognition^21-23 and its involvement in several neurodegenerative disorders.^24-26 The focus of this brief review is to emphasize some of the new insights provided by these extensive basic, neuropathologic, and imaging studies.