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.

Keywords: ADHD; adrenoceptors; anxiety; depression; fight-or-flight response; norepinephrine; psychosis; stress.

Figure 1

Stress pathways. The Nucleus Paraventricularis of the Hypothalamus (PVN) and the Locus Ceruleus lie at the core of the CNS stress pathways. Both areas are at the center of an intense bi-directional information exchange with multiple targets in the periphery, within the brain, and with each other. The PVN sends and receives information to and from the autonomic nervous system through the brain stem, and from and to the periphery through the neuroendocrine axes. The LC sends and receives information to and from the spinal cord and the whole brain. Furthermore, PVN and LC also share monosynaptic bi-directional communication through the medial forebrain bundle.

Figure 2

Feedback loops to PVN and LC: Vulnerability of the LC in the stress axes. The LC is integral part of the stress response, in addition to the HPA axis. Different from the HPA axis, which receives a double negative-feedback (minus signs) of corticosteroids from the suprarenal gland, both at the level of the pituitary and the paraventricular nucleus of the hypothalamus (PVN), PVN, and other CRH-releasing cells in the CNS are connected to the LC through a positive-feedback loop (plus signs), which has the potential to derange the energy equilibrium of the system.

Figure 3

CNS function of different LC firing modes. Seminal work from Aston-Jones groups has shown the existence of a relationship between behavioral states and LC tonic and phasic firing patterns: During sleep, LC cells display low or no activity (vertical axis in arbitrary units—A.U.); during quiet wake they display modest tonic firing, and phasic responses to behavioral stimuli; in conditions of intermediate tonic release, associated with moderate stress and energy demand, LC presents its highest phasic response during biologically relevant behavioral responses; the highest level of LC tonic firing occurs in situations of arousal and fight-or-flight response, and is associated with the lowest levels of phasic LC activity.

Figure 4

Second messengers involved in the effects of NE: time-scales and metabolic energy allocation. Increasing levels of NE activate noradrenergic receptors by first decreasing cAMP levels by activation of α2Rs, probably reducing homestead maintenance cellular function active during sleep. A further increase in NE concentration activates α1R, activating the phospholipase C (PLC) cascade while cAMP levels are still low. For still higher levels both PLC and cAMP levels are heightened, consistent with highest levels of cellular activation. Energetic considerations suggest that this high-demand state need to be associated with decreased function in at least some brain areas, and has necessarily to be short-lasting, in order to prevent depletion of organismic energy stores and desensitization of membrane receptor mechanisms. Periods of brief and intense LC activation like during its phasic release may induce temporary activation of βRs associated with memory and learning. Prolonged high LC activity may be detrimental for learning and memory as it would necessarily reduce phasic LC activity and reduce the spatial and temporal specificity of βR synaptic effects.

Figure 5

Brain areas regulated by LC activation. LC activity controls in a centralized fashion the level of activity and functional connectivity among of virtually all brain area. Keeping in mind that the effects of LC might have regionally specific effects, for the purpose of this discussion we will only consider differential LC effects onto prefrontal, motor, sensory, and limbic cortices, and lump together the activity subcortical nuclei. Different levels of activity are indicated by increasing color intensity, while the strength of inter-regional connectivity will be represented by the thickness of the arrows. This figure represents the legend for the Figures 6–8. The number (1–4) on the side of each sketch represents the putative resting energy demand of each activated state, from the least-demanding (LA) to the most demanding (PFC).

Figure 6

LC-regulated brain activation states. Refer to Figure 5 as legend for the representation of different brain areas. While many intermediate states are likely to exist, we depict in the sketch only four of them, in order of energy demand. During the sleep state (upper left) the LC is inactive, all cortices (except possibly limbic cortices) are virtually inactive, maintenance processes (like memory consolidation and basal immune activity) are on-going, while cellular energy content is restored. During quiet wake(upper right), LC is moderately active in the tonic mode, maximizing phasic release of NE which allows optimal intracortical communication and flexible behavioral and decision-making strategies and memory and learning associated with high phasic LC activation and βR-mediated activation. During high-energy demand (stress, lower left), an increased drive in the limbic cortex induces higher LC activation and hyperactivity in other cortical areas relevant to the specific stressor (most often the PFC, but on occasion could be other areas like motor or sensory cortices could be over-activated to carry out specific behavioral tasks). Extreme stress induces hyperactivity in parts of the limbic system, fight- or-flight response (lower right), overdrive and functional shut-down of the PFC, and hyper-activation of motor areas and subcortical nuclei (symbolized by the grid lines, MA: motor areas, SA sensory areas, SCN: subcortical nuclei, PFC: prefrontal cortex, LA: limbic areas, LC: locus ceruleus).

Figure 7

Maladaptive plasticity: Examples of LC hypofunction. Left: ADHD. Attention deficit disorder with hyperactivity (ADHD) is treated clinically with pro-monoaminergic drugs, particularly with NE re-uptake blockers. This condition may represent a dysfunction of the active wake (Figure 6) caused by NE/LC hypofunction. The condition is characterized by a prevalence of a motor-sensory areas and a decrease of working memory and inhibitory control. The deficit should not be considered a severe impairment insofar it is not associated with major alteration of limbic function. Right: Depression. The use of NE- (along with 5HT-) reuptake blockers is also in the mainstream treatment for depression. While depressed patients also display similar traits of ADHD subjects, like impaired working memory and low threshold for sensory activation, contrary to ADHD, depression is associated with long-term impairment of limbic function. According to our model, in depression, the normal physiological cycling between the 4 states illustrated in Figure 5 is turned into a single dysfunctional state. Refer to Figure 5 as legend for the representation of different brain areas. Captions as in Figure 6.

Figure 8

Maladaptive plasticity: Examples of LC hyperfunction. Left: Anxiety. Prolonged or intense stress may deplete organismic energy stores, possibly along with α₁R overexpression, and βR β arrestin-induced internalization, leading to sensitization of the limbic areas (limbic cortices and amygdala) and of sensory areas. This condition would simulate a permanent reality-detached state of fight-or-flight. Right: Psychosis. Failure to eliminate a stress can turn an anxious condition into psychosis, by furthering the impairment of PFC function, possibly accompanied with aggression. Stress and stimulants may precipitate this condition by increasing monoaminergic—particularly dopaminergic and noradrenergic tone—in the PFC, where catecholamine transporter is responsible for the re-uptake of both molecules. Depression would differ from psychosis mainly in monoaminergic function (decreased in depression but increased in psychosis), causing an exaggerated motor response, but would share with it working memory impairment and sensory and limbic sensitization (compare with Figure 7, captions as in Figure 6).