The Nature of Noradrenergic Volume Transmission From Locus Coeruleus to Brainstem Mesencephalic Trigeminal Sensory Neurons

Abstract

Noradrenergic neurons in the locus coeruleus (LC) release noradrenaline (NA) that acts via volume transmission to activate extrasynaptic G-protein coupled receptors (GPCRs) in target cells throughout the brain. As the closest projection, the dorsal LC laterally adjoins the mesencephalic trigeminal nucleus (MTN), in which proprioceptive primary sensory neurons innervating muscle spindles of jaw-closing muscles are exceptionally located. MTN neurons express α2-adrenergic receptors (α2-ARs) and display hyperpolarization-activated cyclic nucleotide-gated (HCN) currents (Ihs), which is downregulated by α2-AR activation. To quantify the activity-dependent outcome of volume transmission of NA from LC to MTN, we investigated how direct LC activation inhibits Ih in MTN neurons by performing dual whole-cell recordings from LC and MTN neurons. Repetition of 20 Hz spike-train evoked with 1-s current-pulse in LC neurons every 30 s resulted in a gradual decrease in Ih evoked every 30 s, revealing a Hill-type relationship between the number of spike-trains in LC neurons and the degree of Ih inhibition in MTN neurons. On the other hand, when microstimulation was applied in LC every 30 s, an LC neuron repeatedly displayed a transient higher-frequency firing followed by a tonic firing at 5–10 Hz for 30 s. This subsequently caused a similar Hill-type inhibition of Ih in the simultaneously recorded MTN neuron, but with a smaller Hill coefficient, suggesting a lower signal transduction efficacy. In contrast, 20 Hz activity induced by a 1-s pulse applied every 5–10 s caused only a transient facilitation of Ih inhibition followed by a forced termination of Ih inhibition. Thus, the three modes of LC activities modulated the volume transmission to activate α2-adrenergic GPCR to differentially inhibit Ih in MTN neurons.

Afferent projections to theCalca/CGRP-expressing parabrachial neurons in mice

“…For instance, PB Calca /CGRP neurons respond to norepinephrine and serotonin from the ventrolateral medulla, and raphe nuclei (Boccia et al, 2020; Kaur et al, 2020), yet we observed no rabies labeling in these or other monoaminergic nuclei. This limitation is likely inherent to the rabies method, as the transfer of rabies virus from a starter cell to afferent terminals may require direct, classical symmetric and asymmetric synapses, yet monoaminergic fibers often release neurotransmitters en passant with volume transmission (Toyoda et al, 2022). This general limitation of the rabies method is rarely mentioned but likely significant and probably applies to some peptidergic inputs as well.…”

Locus coeruleus activation contributes to masseter muscle overactivity induced by chronic restraint stress in mice

“…These findings further demonstrate that the activation of noradrenergic neurons in locus coeruleus may play an important role in the anxiety-like behavior as well as the elevated masseter muscle tension caused by restraint stress. Anatomically, the locus coeruleus is in close proximity to the Vme and has been demonstrated to send neural projections directly to the Vme [ 14 , 15 ]; and it has been reported that the cell membrane of Vme neurons contains α 2A -adrenergic receptors and can be activated by noradrenergic neural projections from the locus coeruleus, which subsequently leads to alterations in the electrophysiological properties of neurons in Vme [ 15 ]. Therefore, through the action of the locus coeruleus-Vme neural pathway, the locus coeruleus transmits neuronal activation information to the Vme, which in turn affects the motor status of the masticatory muscles and is likely to be one of the central mechanisms by which noradrenergic neurons in locus coeruleus are involved in the regulation of stress-induced overactivity of the masseter muscle.…”

“…Anatomically, the locus coeruleus is in close proximity to the mesencephalic trigeminal nucleus (Vme), which is an important nucleus that regulates the movement of the masticatory muscles [ 13 ]. Moreover, locus coeruleus also sends out neural projections to the Vme to modulate the excitability of Vme neurons [ 14 , 15 ]. Our previous study has confirmed that chronic stress can lead to elevated excitability of Vme neurons, contributing to overactivity of masseter muscle [ 16 ].…”

Association of Tooth Loss with Alzheimer’s Disease Tau Pathologies Assessed by Positron Emission Tomography

“…Both structures are located in the dorsal brainstem, where A␤ and tau lesions could occur in humans [59]. Vmes, the only primary sensory neuron located within the central nervous system [60,61], receives synaptic and diffusible transmissions of norepinephrine from the LC [62,63], which may act as a suppressor of inflammatory changes [64]. Microglial activation might be provoked in Vmes by tooth extraction in the presence of A␤ [21,65] and may expand to the neighboring LC, leading to hyperphosphorylation and aggrega- tion of tau [66,67] in these regions.…”