Brainstem noradrenergic neurons: Identifying a hub at the intersection of cognition, motility, and skeletal muscle regulation

Abstract

Brainstem noradrenergic neuron clusters form a node integrating efferents projecting to distinct areas such as those regulating cognition and skeletal muscle structure and function, and receive dissimilar afferents through established circuits to coordinate organismal responses to internal and environmental challenges. Genetic lineage tracing shows the remarkable heterogeneity of brainstem noradrenergic neurons, which may explain their varied functions. They project to the locus coeruleus, the primary source of noradrenaline in the brain, which supports learning and cognition. They also project to pre‐ganglionic neurons, which lie within the spinal cord and form synapses onto post‐ganglionic neurons. The synapse between descending brainstem noradrenergic neurons and pre‐ganglionic spinal neurons, and these in turn with post‐ganglionic noradrenergic neurons located at the paravertebral sympathetic ganglia, support an anatomical hierarchy that regulates skeletal muscle innervation, neuromuscular transmission, and muscle trophism. Whether any noradrenergic neuron subpopulation is more susceptible to damaged protein deposit and death with ageing and neurodegeneration is a relevant question that answer will help us to detect neurodegeneration at an early stage, establish prognosis, and anticipate disease progression. Loss of muscle mass and strength with ageing, termed sarcopenia, may predict impaired cognition with ageing and neurodegeneration and establish an early time to start interventions aimed at reducing central noradrenergic neurons hyperactivity. Complex multidisciplinary approaches, including genetic tracing, specific circuit labelling, optogenetics and chemogenetics, electrophysiology, and single‐cell transcriptomics and proteomics, are required to test this hypothesis pre‐clinical.

Did you know? Dopamine, pop culture and beyond

“…9 Delbono et al describe a monoaminergic group of neurons that function as a brainstem "hub", where cognitive and motile functions intersect. 10 Interestingly, however, current research into monoamine function does not necessarily focus on its role in behavior and addiction.…”

“…Baronio et al recently described a novel animal model of deficient monoamine transport, 8 which will potentially help elucidate the role of monoamine signaling in both brain development and disease 9 . Delbono et al describe a monoaminergic group of neurons that function as a brainstem “hub”, where cognitive and motile functions intersect 10 . Interestingly, however, current research into monoamine function does not necessarily focus on its role in behavior and addiction.…”

Sex differences in single neuron function and proteomics profiles examined by patch‐clamp and mass spectrometry in the locus coeruleus of the adult mouse

“…These clusters receive varied afferents through established circuits to coordinate organismal responses to internal and environmental challenges. 11 Genetic lineage tracing has unveiled the remarkable heterogeneity of brainstem noradrenergic neurons, which may account for the wide range of functions among the various neurons groups. 12 However, the LC constitutes a compact and homogenous nucleus mainly derived from rhombomere-1 expressing the engrailed homeobox 1 (En1) gene.…”

“…These neurons, in turn, interact with post-ganglionic noradrenergic neurons located at the paravertebral sympathetic ganglia, forming an anatomical hierarchy regulating skeletal muscle innervation, neuromuscular transmission, and muscle trophism. 11,[15][16][17] To examine pre-clinically the hypothesis that LC neurons from both sexes inherently differ in their excitability and proteomic profiles, a multidisciplinary approach encompassing genetic tracing, specific circuit labeling, electrophysiology, and single-cell proteomics is essential. By prioritizing these concepts, we can better understand the role of brainstem noradrenergic neurons in regulating diverse functions and the potential impact of sex differences on their vulnerability in the context of advanced age and neurodegeneration.…”

Vessels in motion

“…Still, novel mechanisms are discovered in different vascular beds. Recent publications in Acta Physiologica report on novel insights into central control of vasomotor function 4,5 and local control of intracerebral vascular tone. 6,7 In the kidney, the regulation of glomerular perfusion, 8 short-term recruitment of the renal functional reserve 9,10 and aftereffects of ischemiareperfusion injury 11 and the respective immediate role of the microcirculation have recently been studied.…”