Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation?

Abstract

Norepinephrine (NE) is synthesized in the Locus Coeruleus (LC) of the brainstem, from where it is released by axonal varicosities throughout the brain via volume transmission. A wealth of data from clinics and from animal models indicates that this catecholamine coordinates the activity of the central nervous system (CNS) and of the whole organism by modulating cell function in a vast number of brain areas in a coordinated manner. The ubiquity of NE receptors, the daunting number of cerebral areas regulated by the catecholamine, as well as the variety of cellular effects and of their timescales have contributed so far to defeat the attempts to integrate central adrenergic function into a unitary and coherent framework. Since three main families of NE receptors are represented—in order of decreasing affinity for the catecholamine—by: α2 adrenoceptors (α2Rs, high affinity), α1 adrenoceptors (α1Rs, intermediate affinity), and β adrenoceptors (βRs, low affinity), on a pharmacological basis, and on the ground of recent studies on cellular and systemic central noradrenergic effects, we propose that an increase in LC tonic activity promotes the emergence of four global states covering the whole spectrum of brain activation: (1) sleep: virtual absence of NE, (2) quiet wake: activation of α2Rs, (3) active wake/physiological stress: activation of α2- and α1-Rs, (4) distress: activation of α2-, α1-, and β-Rs. We postulate that excess intensity and/or duration of states (3) and (4) may lead to maladaptive plasticity, causing—in turn—a variety of neuropsychiatric illnesses including depression, schizophrenic psychoses, anxiety disorders, and attention deficit. The interplay between tonic and phasic LC activity identified in the LC in relationship with behavioral response is of critical importance in defining the short- and long-term biological mechanisms associated with the basic states postulated for the CNS. While the model has the potential to explain a large number of experimental and clinical findings, a major challenge will be to adapt this hypothesis to integrate the role of other neurotransmitters released during stress in a centralized fashion, like serotonin, acetylcholine, and histamine, as well as those released in a non-centralized fashion, like purines and cytokines.

Cortical map plasticity as a function of vagus nerve stimulation rate

“…However, the temporal pattern evoked is quite different, because the same number of action potentials is spread out over 2000, 500, or 125 ms. It is possible that the inverted-U function of VNS rate on cortical plasticity results from inadequate norepinephrine concentration to activate the high affinity alpha receptors at low rates and overly high norepinephrine concentration that activates low affinity beta receptors at high rates [43]. Pharmacology studies will be needed to test this hypothesis.…”

Expecting the unexpected: the paranoid style of belief updating across species

“…However, unexpected uncertainty, and the κ parameter of the HGF in particular 51 , are thought to be signalled via the locus coeruleus and noradrenaline (i.e., neural gain) 25-28 . This mechanism is thought to coordinate rapid shifts in cortical networks through patterns of widespread norepinephrine release, modulating exploratory versus exploitative behaviours (i.e., switching and staying) 52-55 and responding to stress 56-58 , unexpected uncertainty 25 , 27 and subliminal fear cues 59 to coordinate fight-or-flight responses 58 . In fact, visual fear stimuli presented below the threshold of conscious perception activate the locus coeruleus, amygdala, and fronto-temporal orienting regions, suggesting a neural ‘alarm’ system for rapid threat detection 59 .…”

Relationships of Subjective Insomnia and Sleep Duration with Depression, Anxiety, and Pain Problems in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

“…Insomnia may share common neurobiological mechanisms with depression, anxiety, and pain, particularly regarding serotonin [43], norepinephrine functioning [44], and circadian clock genes [45]. Moreover, insomnia is a stressor that may worsen emotions through impairing cognitive judgment and impulse control [39,46].…”