Neuropeptides as transmitters and regulators of the locus coeruleus noradrenergic system

The locus coeruleus (LC), the brain's main source of noradrenaline, has received increased attention due to the recently unveiled heterogeneity of its cell types. Departing from the long-standing idea of molecular, anatomical, and functional uniformity of the structure, we now understand the LC as a multiplexed nucleus, capable of temporally precise and targeted neuromodulation of distinct brain regions and functions. The LC neuropeptidergic landscape provides a window into this remarkable neuronal diversity. Stemming from recent technological advances that have allowed for LC transcriptional profiling, a wealth of data on the (co)expression of LC neuropeptides and their cognate receptors has come to light. Peptidergic systems are ideally situated to exert neuromodulatory control over the LC noradrenergic system. This peptidergic control can occur both locally, within the LC and the neighboring peri-LC microcircuitry, and at distal LC terminal fields. The functional significance of LC neuropeptidergic signaling in physiological processes and pathological conditions is an emerging field. Here we compile existing literature on the expression, anatomical distribution, physiological effects, and, when available, behavioral role of the major neuropeptidergic populations of, and innervating, the LC and peri-LC. Furthermore, we highlight current methodologies that delineate LC peptidergic input/output, aiming at uncovering their functional role. Finally, we discuss how neuropeptidergic signaling enables LC modularity and thus sustains a multifaceted role of physiological noradrenaline release dynamics with a rich feature set of behavioral representations. SIGNIFICANCE STATEMENT: The locus coeruleus (LC) noradrenergic system influences a variety of neurophysiological processes to coordinate complex behaviors. These far-reaching neuromodulatory effects are not solely mediated by noradrenaline, but rather, by a variety of coreleased neuropeptides that can alter postsynaptic responses in LC terminal regions. In addition, the LC itself is regulated by a multitude of incoming peptidergic signals that drive wide-ranging changes in LC neuronal physiology and the subsequent patterns of noradrenaline release. It is important to understand how neuropeptide (co)transmitters and regulators of the LC can drive circuit-level plasticity and adaptive behavioral responses to changing environmental stimuli. This review compiles our current understanding of these processes, providing additionally crucial insights into the mechanisms underlying LC dysfunction and its many related neuropsychiatric conditions.