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.

Keywords: ageing; cognition; motility; noradrenergic neurons; skeletal muscle.

FIGURE 1

Brainstem noradrenergic and adrenergic neurons. Scheme of rat medulla and pons noradrenergic (A groups) and adrenergic (C groups) neurons. The A2 and C2, located in the dorsal medulla, are part of the nucleus of the solitary tract. A1 and C1 and located near the nucleus ambiguous. The location of A neuron groups is similar to that described in the human brainstem. Arrows indicate noradrenergic neuron projections. Darker lines and dots correspond to noradrenergic neurons, while brown lines and dots to adrenergic neurons. AO, anterior olfactory nucleus; C, cingulate bundle; CC, corpus callosum; CT, central tegmental tract; CTX, cerebral cortex; DT, dorsal tegmental bundle; EC, external capsule; F, fornix; HF, hippocampal formation. OB, olfactory bulb; PT, pretectal nuclei; RF, reticular formation; S, septum; T, tectum; Th, thalamus. Adapted from Ref. [1]

FIGURE 2

A set of transcription factors determines sympathetic neuron development and maintenance. (A) Gene regulatory network controlling sympathetic neuron specification, differentiation, proliferation, survival, and maintenance. (B) Target‐derived signals regulate the resulting functional subtype of sympathetic neurons as illustrated for cholinergic differentiation of sudomotor neurons, mediated by the gp130 cytokine‐induced Satb2 transcriptional regulator. BMP, bone morphogenetic protein; ChAT, choline acetyltransferase; DBH, dopamine‐beta‐hydroxylase; TH, tyrosine hydroxylase; VAChT, vesicular acetylcholine transporter. Adapted from Ref. [51]

FIGURE 3

Identification of brainstem noradrenaline neurons defined by genetic lineage tracking using intersectional genetic fate mapping. (A) Sagittal view of the embryonic mouse brain showing rhombomere 1–8 of the hindbrain. (B) Adult mouse sagittal section, showing anatomically defined nuclei of the transcription factors Hoxa2 (r2), Krox20‐ (r3 and r5), and/or Hoxb1 (r4); genes provide the signature of the heterogenous A5 neuronal group. LoC, locus coeruleus; SubCD, subcoeruleus dorsal; subCV, subcoeruleus ventral. Adapted from Ref. [149]

FIGURE 4

Segmental LC and A5 neurons connection. Diagram. After direct injection into the LC, the E1/E3‐deleted, replication‐defective, CAV‐2 vector harboring the PRS promoter CAV2‐PRS‐ChR2‐mCherry transduces LC noradrenergic neurons locally and retrogradely in the contralateral LC and in the A7 and A5 cell groups both ipsilateral and contralaterally. LC axons also show ascending projections to the midbrain (dorsal noradrenergic bundle, DNB) and descending to the spinal cord lumbar L4 level. Histological sections show mCherry fluorescence converted to grey‐scale at DNB, contralateral A7, rostral LC, A5, and spinal cord. 4 V, fourth ventricle; PAG, peri‐aqueductal grey. Adapted from Ref. [150]

FIGURE 5

Hierarchical organization of central and peripheral noradrenergic and cholinergic neurons that potentially regulate skeletal muscle innervation. Relationship between LC and the spinal cord dorsal horn sensory neurons. Ventrally located A5 noradrenergic neurons ① project to cholinergic pre‐ganglionic neurons located at the spinal cord IML ②. The sympathetic pre‐ganglionic neurons at the IML synapse with paravertebral sympathetic post‐ganglionic neurons ③, which in turn innervate the myofiber ④. Sympathetic neuron axons display periodic bulbous enlargements also known as varicosities. The diagram shows both the sympathetic and motor innervation of the skeletal muscle fiber. Adapted from Ref. [45]

FIGURE 6

Triple phosphorylation of Ser202, Thr205, and Ser208 promotes tau mislocalization and aggregation, leading to NFT formation. (1) Physiological tau protein distribution in neuronal axons. (2) Tau phosphorylation at Ser202 and Thr205 leads to tau redistribution to the soma and dendrites. (3) Tau phosphorylation at Ser202, Thr205, and Ser208 induces the formation of tau filaments and neurofibrillary tangles. Adapted from Ref. [132]