Abstract
The locus coeruleus (LC) is a brainstem nucleus distinguished by its supply of noradrenaline throughout the central nervous system. Apart from modulating a range of brain functions, such as arousal, cognition and the stress response, LC neuronal excitability also corresponds to the activity of various peripheral systems, such as pelvic viscera and the cardiovascular system. Neurochemically diverse inputs set the tone for LC neuronal activity, which in turn modulates these adaptive physiological and behavioral responses essential for survival. One such LC afferent system which is poorly understood contains the neurohormone arginine-vasopressin (AVP). Here we provide the first demonstration of the molecular and functional characteristics of the LC-AVP system, by characterizing its receptor-specific modulation of identified LC neurons and plasticity in response to stress. High resolution confocal microscopy revealed that immunoreactivity for the AVP receptor 1b (V1b) was located on plasma membranes of noradrenergic and non-noradrenergic LC neurons. In contrast, immunoreactivity for the V1a receptor was exclusively located on LC noradrenergic neurons. No specific signal, either at the mRNA or protein level, was detected for the V2 receptor in the LC. Clusters immunoreactive for V1a-b were located in proximity to profiles immunoreactive for GABAergic and glutamatergic synaptic marker proteins. AVP immunopositive varicosities were also located adjacent to labeling for such synaptic markers. Whole-cell patch clamp electrophysiology revealed that the pharmacological activation of V1b receptors significantly increased the spontaneous activity of 45% (9/20) of recorded noradrenergic neurons, with the remaining 55% (11/20) of cells exhibiting a significant decrease in their basal firing patterns. Blockade of V1a and V1b receptors on their own significantly altered LC neuronal excitability in a similar heterogeneous manner, demonstrating that endogenous AVP sets the basal LC neuronal firing rates. Finally, exposing animals to acute stress increased V1b, but not V1a receptor expression, whilst decreasing AVP immunoreactivity. This study reveals the AVP-V1a-b system as a considerable component of the LC molecular architecture and regulator of LC activity. Since AVP primarily functions as a regulator of homeostasis, the data suggest a novel pathway by modulating the functioning of a brain region that is integral to mediating adaptive responses.
Highlights
The LC is a cluster of neurons located within the pons distinguished from surrounding cell groups by their production of the neurotransmitter noradrenaline (NA) (Dahlstroem and Fuxe, 1964)
In tissue from wild type (WT) mice, V1a receptor immunoreactivity presented as individual clusters enriched on the somata and dendrites of LC noradrenergic neurons, identified by immunoreactivity for the NA synthesizing enzyme tyrosine hydroxylase (TH) (Figure 1A1)
In WT tissue, immunoreactivity for the V1b receptor presented as clustered signal on somatodendritic compartments of LC noradrenergic neurons
Summary
The LC is a cluster of neurons located within the pons distinguished from surrounding cell groups by their production of the neurotransmitter noradrenaline (NA) (Dahlstroem and Fuxe, 1964). The result is a LC-NA system that modulates some of the most salient aspects of brain function such as arousal (Carter et al, 2010), attention (Usher et al, 1999), and memory (Sara, 2015) These neural processes are combined to mediate a core responsibility of the LC-NA system, that being the modulation of adaptive responses to emotional and physiological stressors, which is a process essential for survival in an ever dynamic world (Valentino and Van Bockstaele, 2008). This is accomplished by a highly dynamic excitability profile of LC neurons, which results in the release of NA in precise spatiotemporal and brainstate specific patterns. The factors that govern LC neuronal excitability have the potential to impact on a vast array of physiological processes both within the CNS and in a number of major peripheral organs in health and disease
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