Axonal projection‐specific differences in somatodendritic α2 autoreceptor function in locus coeruleus neurons

Abstract

The locus coeruleus (LC) contains the majority of central noradrenergic neurons sending wide projections throughout the entire CNS. The LC is considered to be essential for multiple key brain functions including arousal, attention and adaptive stress responses as well as higher cognitive functions and memory. Electrophysiological studies of LC neurons have identified several characteristic functional features such as low‐frequency pacemaker activity with broad action potentials, transient high‐frequency burst discharges in response to salient stimuli and an apparently homogeneous inhibition of firing by activation of somatodendritic α2 autoreceptors (α2AR). While stress‐mediated plasticity of the α2AR response has been described, it is currently unclear whether different LC neurons projecting to distinct axonal targets display differences in α2AR function. Using fluorescent beads‐mediated retrograde tracing in adult C57Bl6/N mice, we compared the anatomical distributions and functional in vitro properties of identified LC neurons projecting either to medial prefrontal cortex, hippocampus or cerebellum. The functional in vitro analysis of LC neurons confirmed their mostly uniform functional properties regarding action potential generation and pacemaker firing. However, we identified significant differences in tonic and evoked α2AR‐mediated responses. While hippocampal‐projecting LC neurons were partially inhibited by endogenous levels of norepinephrine and almost completely silenced by application of saturating concentrations of the α2 agonist clonidine, prefrontal‐projecting LC neurons were not affected by endogenous levels of norepinephrine and only partially inhibited by saturating concentrations of clonidine. Thus, we identified a limited α2AR control of electrical activity for prefrontal‐projecting LC neurons indicative of functional heterogeneity in the LC‐noradrenergic system.

Chewing and Cognitive Improvement: The Side Matters

“…In particular, the ER was larger in right dominant subjects. Since noradrenergic ascending projections are mainly ipsilateral ( Berridge and Waterhouse, 2003 ; Wagner-Altendorf et al, 2019 ), this finding could be related to a larger noradrenergic tone impinging on the right hemisphere ( Kruglikov et al, 1992 ), dominant for those spatial skills ( Joseph, 1988 ) required in the matrices test. An excessive level of basal noradrenergic activity is in fact detrimental for performance, according to the “adaptive gain theory” proposed by Aston-Jones and Cohen (2005) .…”

The mechanistic link between selective vulnerability of the locus coeruleus and neurodegeneration in Alzheimer’s disease

“…Though both cell types are dispersed throughout the LC, the small fusiform cells dominate the densely packed rostral portion, indicating a cytoarchitectonic bias [145]. In addition, recent studies have indicated phenotypic variability among subsets of LC neurons [17,124,165]. Hippocampal and prefrontal-innervating LC neurons differ in their physiological response to the α 2 -adrenoreceptor agonist clonidine, suggesting a functional heterogeneity within the LC neuron population [165].…”

“…In addition, recent studies have indicated phenotypic variability among subsets of LC neurons [17,124,165]. Hippocampal and prefrontal-innervating LC neurons differ in their physiological response to the α 2 -adrenoreceptor agonist clonidine, suggesting a functional heterogeneity within the LC neuron population [165].…”

The nucleus locus coeruleus modulatory effect on memory formation: A literature review

“…In addition to the bilateral relationship between LC and HIPP, according to Mello-Carpes et al findings, the LC-HIPP-NTSparagigantocellularis (PGi) pathway can significantly affect recognition memory performance [31]. Furthermore, the frontal cortex-LC pathway is another modulator of this memory through α2adrenoceptor signaling [32]. Based on the abovementioned reports, it can be concluded that the neurological activity of locus coeruleus and its noradrenergic projections to different brain areas, like the HIPP, play a pivotal role in the development of this higher function memory (Figure 3) [29].…”