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      Neuropeptide and Small Transmitter Coexistence: Fundamental Studies and Relevance to Mental Illness

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          Abstract

          Neuropeptides are auxiliary messenger molecules that always co-exist in nerve cells with one or more small molecule (classic) neurotransmitters. Neuropeptides act both as transmitters and trophic factors, and play a role particularly when the nervous system is challenged, as by injury, pain or stress. Here neuropeptides and coexistence in mammals are reviewed, but with special focus on the 29/30 amino acid galanin and its three receptors GalR1, -R2 and -R3. In particular, galanin’s role as a co-transmitter in both rodent and human noradrenergic locus coeruleus (LC) neurons is addressed. Extensive experimental animal data strongly suggest a role for the galanin system in depression–like behavior. The translational potential of these results was tested by studying the galanin system in postmortem human brains, first in normal brains, and then in a comparison of five regions of brains obtained from depressed people who committed suicide, and from matched controls. The distribution of galanin and the four galanin system transcripts in the normal human brain was determined, and selective and parallel changes in levels of transcripts and DNA methylation for galanin and its three receptors were assessed in depressed patients who committed suicide: upregulation of transcripts, e.g., for galanin and GalR3 in LC, paralleled by a decrease in DNA methylation, suggesting involvement of epigenetic mechanisms. It is hypothesized that, when exposed to severe stress, the noradrenergic LC neurons fire in bursts and release galanin from their soma/dendrites. Galanin then acts on somato-dendritic, inhibitory galanin autoreceptors, opening potassium channels and inhibiting firing. The purpose of these autoreceptors is to act as a ‘brake’ to prevent overexcitation, a brake that is also part of resilience to stress that protects against depression. Depression then arises when the inhibition is too strong and long lasting – a maladaption, allostatic load, leading to depletion of NA levels in the forebrain. It is suggested that disinhibition by a galanin antagonist may have antidepressant activity by restoring forebrain NA levels. A role of galanin in depression is also supported by a recent candidate gene study, showing that variants in genes for galanin and its three receptors confer increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events. In summary, galanin, a neuropeptide coexisting in LC neurons, may participate in the mechanism underlying resilience against a serious and common disorder, MDD. Existing and further results may lead to an increased understanding of how this illness develops, which in turn could provide a basis for its treatment.

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          Most cited references 544

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          Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study.

          Prevention and control of disease and injury require information about the leading medical causes of illness and exposures or risk factors. The assessment of the public-health importance of these has been hampered by the lack of common methods to investigate the overall, worldwide burden. The Global Burden of Disease Study (GBD) provides a standardised approach to epidemiological assessment and uses a standard unit, the disability-adjusted life year (DALY), to aid comparisons. DALYs for each age-sex group in each GBD region for 107 disorders were calculated, based on the estimates of mortality by cause, incidence, average age of onset, duration, and disability severity. Estimates of the burden and prevalence of exposure in different regions of disorders attributable to malnutrition, poor water supply, sanitation and personal and domestic hygiene, unsafe sex, tobacco use, alcohol, occupation, hypertension, physical inactivity, use of illicit drugs, and air pollution were developed. Developed regions account for 11.6% of the worldwide burden from all causes of death and disability, and account for 90.2% of health expenditure worldwide. Communicable, maternal, perinatal, and nutritional disorders explain 43.9%; non-communicable causes 40.9%; injuries 15.1%; malignant neoplasms 5.1%; neuropsychiatric conditions 10.5%; and cardiovascular conditions 9.7% of DALYs worldwide. The ten leading specific causes of global DALYs are, in descending order, lower respiratory infections, diarrhoeal diseases, perinatal disorders, unipolar major depression, ischaemic heart disease, cerebrovascular disease, tuberculosis, measles, road-traffic accidents, and congenital anomalies. 15.9% of DALYs worldwide are attributable to childhood malnutrition and 6.8% to poor water, and sanitation and personal and domestic hygiene. The three leading contributors to the burden of disease are communicable and perinatal disorders affecting children. The substantial burdens of neuropsychiatric disorders and injuries are under-recognised. The epidemiological transition in terms of DALYs has progressed substantially in China, Latin America and the Caribbean, other Asia and islands, and the middle eastern crescent. If the burdens of disability and death are taken into account, our list differs substantially from other lists of the leading causes of death. DALYs provide a common metric to aid meaningful comparison of the burden of risk factors, diseases, and injuries.
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              We describe a hypothalamus-specific mRNA that encodes preprohypocretin, the putative precursor of a pair of peptides that share substantial amino acid identities with the gut hormone secretin. The hypocretin (Hcrt) protein products are restricted to neuronal cell bodies of the dorsal and lateral hypothalamic areas. The fibers of these neurons are widespread throughout the posterior hypothalamus and project to multiple targets in other areas, including brainstem and thalamus. Hcrt immunoreactivity is associated with large granular vesicles at synapses. One of the Hcrt peptides was excitatory when applied to cultured, synaptically coupled hypothalamic neurons, but not hippocampal neurons. These observations suggest that the hypocretins function within the CNS as neurotransmitters.
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                Author and article information

                Contributors
                Journal
                Front Neural Circuits
                Front Neural Circuits
                Front. Neural Circuits
                Frontiers in Neural Circuits
                Frontiers Media S.A.
                1662-5110
                21 December 2018
                2018
                : 12
                Affiliations
                1Department of Neuroscience, Karolinska Institutet , Stockholm, Sweden
                2Department of Neurobiology, Beijing Key Laboratory of Neural Regeneration and Repair, Beijing Laboratory of Brain Disorders (Ministry of Science and Technology), Beijing Institute for Brain Disorders, Capital Medical University , Beijing, China
                3Department of Clinical Neuroscience, Karolinska Institutet , Stockholm, Sweden
                4The Center for Molecular Medicine , Stockholm, Sweden
                5Swedish Toxicology Sciences Research Center, Swetox , Södertälje, Sweden
                6Pronexus Analytical AB , Solna, Sweden
                7Department of Physiology and Pharmacology, Karolinska Institutet , Stockholm, Sweden
                8Department of Clinical Chemistry, Linköping University , Linköping, Sweden
                9Department of Clinical and Experimental Medicine, Linköping University , Linköping, Sweden
                10Department of Anatomy, Histology and Embryology, Semmelweis University , Budapest, Hungary
                11Neuroscience and Psychiatry Unit, University of Manchester , Manchester, United Kingdom
                12Department of Pharmacodynamics, Semmelweis University , Budapest, Hungary
                13MTA-SE Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Semmelweis University , Budapest, Hungary
                14NAP 2-SE New Antidepressant Target Research Group, Hungarian Brain Research Program, Semmelweis University , Budapest, Hungary
                15SE-NAP2 Genetic Brain Imaging Migraine Research Group, Hungarian Brain Research Program, Semmelweis University , Budapest, Hungary
                16Douglas Hospital Research Centre , Verdun, QC, Canada
                17Department of Psychiatry, McGill University , Montreal, QC, Canada
                Author notes

                Edited by: Miguel Angel Morales, Universidad Nacional Autónoma de México, Mexico

                Reviewed by: Istvan Jozsef Merchenthaler, University of Maryland, Baltimore, United States; Andrew L. Gundlach, The Florey Institute of Neuroscience and Mental Health, Australia; Jacki Crawley, University of California, Davis, United States

                *Correspondence: Tomas Hökfelt, Tomas.Hokfelt@ 123456ki.se

                Present address: Eugenia Kuteeva, Atlas Antibodies AB, Bromma, Sweden; Erwan Le Maitre, Unit of Rheumatology, Center for Molecular Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

                Article
                10.3389/fncir.2018.00106
                6309708
                Copyright © 2018 Hökfelt, Barde, Xu, Kuteeva, Rüegg, Le Maitre, Risling, Kehr, Ihnatko, Theodorsson, Palkovits, Deakin, Bagdy, Juhasz, Prud’homme, Mechawar, Diaz-Heijtz and Ögren.

                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) and the copyright owner(s) 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: 11, Tables: 2, Equations: 0, References: 616, Pages: 40, Words: 0
                Categories
                Neuroscience
                Review

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