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      Turning a Negative into a Positive: Ascending GABAergic Control of Cortical Activation and Arousal

      review-article
      1 , * , 1
      Frontiers in Neurology
      Frontiers Media S.A.
      wakefulness, gamma rhythm, theta rhythm, EEG, arousal, hypnotics

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          Abstract

          Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. Recent technological advances have illuminated the role of GABAergic neurons in control of cortical arousal and sleep. Sleep-promoting GABAergic neurons in the preoptic hypothalamus are well-known. Less well-appreciated are GABAergic projection neurons in the brainstem, midbrain, hypothalamus, and basal forebrain, which paradoxically promote arousal and fast electroencephalographic (EEG) rhythms. Thus, GABA is not purely a sleep-promoting neurotransmitter. GABAergic projection neurons in the brainstem nucleus incertus and ventral tegmental nucleus of Gudden promote theta (4–8 Hz) rhythms. Ventral tegmental area GABAergic neurons, neighboring midbrain dopamine neurons, project to the frontal cortex and nucleus accumbens. They discharge faster during cortical arousal and regulate reward. Thalamic reticular nucleus GABAergic neurons initiate sleep spindles in non-REM sleep. In addition, however, during wakefulness, they tonically regulate the activity of thalamocortical neurons. Other GABAergic inputs to the thalamus arising in the globus pallidus pars interna, substantia nigra pars reticulata, zona incerta, and basal forebrain regulate motor activity, arousal, attention, and sensory transmission. Several subpopulations of cortically projecting GABAergic neurons in the basal forebrain project to the thalamus and neocortex and preferentially promote cortical gamma-band (30–80 Hz) activity and wakefulness. Unlike sleep-active GABAergic neurons, these ascending GABAergic neurons are fast-firing neurons which disinhibit and synchronize the activity of their forebrain targets, promoting the fast EEG rhythms typical of conscious states. They are prominent targets of GABAergic hypnotic agents. Understanding the properties of ascending GABAergic neurons may lead to novel treatments for diseases involving disorders of cortical activation and wakefulness.

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          Most cited references182

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          Interneurons of the hippocampus.

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            Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse.

            Gamma-aminobutyric acid (GABA)ergic neurons in the central nervous system regulate the activity of other neurons and play a crucial role in information processing. To assist an advance in the research of GABAergic neurons, here we produced two lines of glutamic acid decarboxylase-green fluorescence protein (GAD67-GFP) knock-in mouse. The distribution pattern of GFP-positive somata was the same as that of the GAD67 in situ hybridization signal in the central nervous system. We encountered neither any apparent ectopic GFP expression in GAD67-negative cells nor any apparent lack of GFP expression in GAD67-positive neurons in the two GAD67-GFP knock-in mouse lines. The timing of GFP expression also paralleled that of GAD67 expression. Hence, we constructed a map of GFP distribution in the knock-in mouse brain. Moreover, we used the knock-in mice to investigate the colocalization of GFP with NeuN, calretinin (CR), parvalbumin (PV), and somatostatin (SS) in the frontal motor cortex. The proportion of GFP-positive cells among NeuN-positive cells (neocortical neurons) was approximately 19.5%. All the CR-, PV-, and SS-positive cells appeared positive for GFP. The CR-, PV, and SS-positive cells emitted GFP fluorescence at various intensities characteristics to them. The proportions of CR-, PV-, and SS-positive cells among GFP-positive cells were 13.9%, 40.1%, and 23.4%, respectively. Thus, the three subtypes of GABAergic neurons accounted for 77.4% of the GFP-positive cells. They accounted for 6.5% in layer I. In accord with unidentified GFP-positive cells, many medium-sized spherical somata emitting intense GFP fluorescence were observed in layer I. Copyright 2003 Wiley-Liss, Inc.
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              Opioids excite dopamine neurons by hyperpolarization of local interneurons.

              Increased activity of dopamine-containing neurons in the ventral tegmental area is necessary for the reinforcing effects of opioids and other abused drugs. Intracellular recordings from these cells in slices of rat brain in vitro showed that opioids do not affect the principal (dopamine-containing) neurons but hyperpolarize secondary (GABA-containing) interneurons. Experiments with agonists and antagonists selective for opioid receptor subtypes indicated that the hyperpolarization of secondary cells involved the mu-receptor. Most principal cells showed spontaneous bicuculline-sensitive synaptic potentials when the extracellular potassium concentration was increased from 2.5 to 6.5 or 10.5 mM; these were prevented by TTX and assumed to result from action potentials arising in slightly depolarized local interneurons. The frequency of these synaptic potentials, but not their amplitudes, was reduced by opioids selective for mu-receptors. It is concluded that hyperpolarization of the interneurons by opioids reduces the spontaneous GABA-mediated synaptic input to the dopamine cells. In vivo, this would lead to excitation of the dopamine cells by disinhibition, which would be expected to contribute to the positive reinforcement seen with mu-receptor agonists such as morphine and heroin.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/46978
                URI : http://frontiersin.org/people/u/237239
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                11 June 2015
                2015
                : 6
                : 135
                Affiliations
                [1] 1Laboratory of Neuroscience, Department of Psychiatry, VA Boston Healthcare System, Harvard Medical School , Brockton, MA, USA
                Author notes

                Edited by: Hruda N. Mallick, All India Institute of Medical Sciences, India

                Reviewed by: Axel Steiger, Max Planck Institute of Psychiatry, Germany; Velayudhan Mohan Kumar, Sree Chitra Tirunal Institute for Medical Sciences and Technology, India

                *Correspondence: Ritchie E. Brown, Laboratory of Neuroscience, Department of Psychiatry, VA Boston Healthcare System, Harvard Medical School, VA Medical Center Brockton, Research 151C, 940, Belmont Street, Brockton, MA 02301, USA, ritchie_brown@ 123456hms.harvard.edu

                Specialty section: This article was submitted to Sleep and Chronobiology, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2015.00135
                4463930
                26124745
                2c5bb9ff-309e-432f-9d58-9913fa2073e8
                Copyright © 2015 Brown and McKenna.

                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.

                History
                : 02 February 2015
                : 28 May 2015
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 211, Pages: 16, Words: 14570
                Funding
                Funded by: NIMH
                Award ID: R01 MH039683
                Funded by: NHLBI
                Award ID: HL095491
                Funded by: NIMH
                Award ID: R21 MH094803
                Categories
                Neuroscience
                Review

                Neurology
                wakefulness,gamma rhythm,theta rhythm,eeg,arousal,hypnotics
                Neurology
                wakefulness, gamma rhythm, theta rhythm, eeg, arousal, hypnotics

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