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

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          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: α 2 adrenoceptors (α 2Rs, high affinity), α 1 adrenoceptors (α 1Rs, 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 α 2Rs, (3) active wake/physiological stress: activation of α 2- and α 1-Rs, (4) distress: activation of α 2-, α 1-, 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.

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          Most cited references 205

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          Reactivation of hippocampal ensemble memories during sleep.

          Simultaneous recordings were made from large ensembles of hippocampal "place cells" in three rats during spatial behavioral tasks and in slow-wave sleep preceding and following these behaviors. Cells that fired together when the animal occupied particular locations in the environment exhibited an increased tendency to fire together during subsequent sleep, in comparison to sleep episodes preceding the behavioral tasks. Cells that were inactive during behavior, or that were active but had non-overlapping spatial firing, did not show this increase. This effect, which declined gradually during each post-behavior sleep session, may result from synaptic modification during waking experience. Information acquired during active behavior is thus re-expressed in hippocampal circuits during sleep, as postulated by some theories of memory consolidation.
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            The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes.

            Through a widespread efferent projection system, the locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. Initial studies provided critical insight into the basic organization and properties of this system. More recent work identifies a complicated array of behavioral and electrophysiological actions that have in common the facilitation of processing of relevant, or salient, information. This involves two basic levels of action. First, the system contributes to the initiation and maintenance of behavioral and forebrain neuronal activity states appropriate for the collection of sensory information (e.g. waking). Second, within the waking state, this system modulates the collection and processing of salient sensory information through a diversity of concentration-dependent actions within cortical and subcortical sensory, attention, and memory circuits. Norepinephrine-dependent modulation of long-term alterations in synaptic strength, gene transcription and other processes suggest a potentially critical role of this neurotransmitter system in experience-dependent alterations in neural function and behavior. The ability of a given stimulus to increase locus coeruleus discharge activity appears independent of affective valence (appetitive vs. aversive). Combined, these observations suggest that the locus coeruleus-noradrenergic system is a critical component of the neural architecture supporting interaction with, and navigation through, a complex world. These observations further suggest that dysregulation of locus coeruleus-noradrenergic neurotransmission may contribute to cognitive and/or arousal dysfunction associated with a variety of psychiatric disorders, including attention-deficit hyperactivity disorder, sleep and arousal disorders, as well as certain affective disorders, including post-traumatic stress disorder. Independent of an etiological role in these disorders, the locus coeruleus-noradrenergic system represents an appropriate target for pharmacological treatment of specific attention, memory and/or arousal dysfunction associated with a variety of behavioral/cognitive disorders.
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              The neuropsychopharmacology of fronto-executive function: monoaminergic modulation.

              We review the modulatory effects of the catecholamine neurotransmitters noradrenaline and dopamine on prefrontal cortical function. The effects of pharmacologic manipulations of these systems, sometimes in comparison with the indoleamine serotonin (5-HT), on performance on a variety of tasks that tap working memory, attentional-set formation and shifting, reversal learning, and response inhibition are compared in rodents, nonhuman primates, and humans using, in a behavioral context, several techniques ranging from microiontophoresis and single-cell electrophysiological recording to pharmacologic functional magnetic resonance imaging. Dissociable effects of drugs and neurotoxins affecting these monoamine systems suggest new ways of conceptualizing state-dependent fronto-executive functions, with implications for understanding the molecular genetic basis of mental illness and its treatment.
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                Author and article information

                Contributors
                Journal
                Front Synaptic Neurosci
                Front Synaptic Neurosci
                Front. Synaptic Neurosci.
                Frontiers in Synaptic Neuroscience
                Frontiers Media S.A.
                1663-3563
                26 August 2016
                2016
                : 8
                Affiliations
                1Neurobiology of Stress Laboratory, Facultad de Ciencias, Universidad Autónoma de San Luis Potosí San Luis Potosí, Mexico
                2School for Behavior and Brain Sciences, University of Texas at Dallas Richardson, TX, USA
                3Department of Psychiatry, University of Texas Southwestern Dallas, TX, USA
                4Laboratory of Cortical Plasticity and Learning, Universidad de Guadalajara Guadalajara, Mexico
                5Electrophysiology Laboratory, Centro de Investigaciones Regionales “Dr. Hideyo Noguchi”, Universidad Autónoma de Yucatán Mérida, Mexico
                Author notes

                Edited by: Dirk Feldmeyer, RWTH Aachen University, Germany

                Reviewed by: Gonzalo Flores, Benemérita Universidad Autónoma de Puebla, Mexico; Maria Concetta Miniaci, University of Naples Federico II, Italy

                †These authors have contributed equally to this work.

                Article
                10.3389/fnsyn.2016.00025
                4999448
                Copyright © 2016 Atzori, Cuevas-Olguin, Esquivel-Rendon, Garcia-Oscos, Salgado-Delgado, Saderi, Miranda-Morales, Treviño, Pineda and Salgado.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 8, Tables: 3, Equations: 0, References: 228, Pages: 26, Words: 19099
                Funding
                Funded by: Consejo Nacional de Ciencia y Tecnología 10.13039/501100007350
                Award ID: CB-2013-01 221653
                Categories
                Neuroscience
                Hypothesis and Theory

                Neurosciences

                norepinephrine, adrenoceptors, stress, fight-or-flight response, adhd, depression, psychosis, anxiety

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