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      Serotonin improves behavioral contrast sensitivity of freely moving rats

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          Abstract

          Serotonin (5-HT) is a neuromodulator secreted from serotonergic neurons located in the pons and upper brain stem in a behavioral context-dependent manner. The serotonergic axon terminals innervate almost the whole brain, causing modulatory actions on various brain functions including vision. Our previous study demonstrated the visual responses of neurons in the primary visual cortex (V1) of anesthetized monkeys were modulated by the activation of 5-HT receptors depending on the response magnitude, in which 5-HT2A receptor-selective agonists enhanced weak visual responses but not strong responses. This observation suggests that the activation of serotonergic receptors modulates neuronal visual information processing to improve the behavioral detectability of a stimulus. However, it remains unknown if 5-HT improves visual detectability at the behavioral level. To investigate this point, visual detectability was measured as contrast sensitivity (CS) in freely moving rats using a two-alternative forced-choice visual detection task (2AFC-VDT) combined with the staircase method. The grating contrast was decreased or increased step by step after a correct choice (hit) or incorrect choice (miss), respectively. CS was evaluated as an inverse value of the visual contrast threshold. The effect of the intraperitoneal administration of fluoxetine (FLX, 5 mg/kg), a selective serotonin reuptake inhibitor, on CS was tested. The CS of rats was significantly higher in FLX than control conditions, and the drug effect showed specificity for the spatial frequency (SF) of a grating stimulus, in which CS improvement was observed at optimal SF but not non-optimal high SF. Thus, we conclude that endogenously-secreted serotonin in the brain improves visual detectability, which may be mediated by vision-related neurons acquiring SF information of the visual stimulus.

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          Serotonin control of sleep-wake behavior.

          Based on electrophysiological, neurochemical, genetic and neuropharmacological approaches, it is currently accepted that serotonin (5-HT) functions predominantly to promote wakefulness (W) and to inhibit REM (rapid eye movement) sleep (REMS). Yet, under certain circumstances the neurotransmitter contributes to the increase in sleep propensity. Most of the serotonergic innervation of the cerebral cortex, amygdala, basal forebrain (BFB), thalamus, preoptic and hypothalamic areas, raphe nuclei, locus coeruleus and pontine reticular formation comes from the dorsal raphe nucleus (DRN). The 5-HT receptors can be classified into at least seven classes, designated 5-HT(1-7). The 5-HT(1A) and 5-HT(1B) receptor subtypes are linked to the inhibition of adenylate cyclase, and their activation evokes a membrane hyperpolarization. The actions of the 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptor subtypes are mediated by the activation of phospholipase C, with a resulting depolarization of the host cell. The 5-HT(3) receptor directly activates a 5-HT-gated cation channel which leads to the depolarization of monoaminergic, aminoacidergic and cholinergic cells. The primary signal transduction pathway of 5-HT(6) and 5-HT(7) receptors is the stimulation of adenylate cyclase which results in the depolarization of the follower neurons. Mutant mice that do not express 5-HT(1A) or 5-HT(1B) receptor exhibit greater amounts of REMS than their wild-type counterparts, which could be related to the absence of a postsynaptic inhibitory effect on REM-on neurons of the laterodorsal and pedunculopontine tegmental nuclei (LDT/PPT). 5-HT(2A) and 5-HT(2C) receptor knock-out mice show a significant increase of W and a reduction of slow wave sleep (SWS) which has been ascribed to the increase of catecholaminergic neurotransmission involving mainly the noradrenergic and dopaminergic systems. Sleep variables have been characterized, in addition, in 5-HT(7) receptor knock-out mice; the mutants spend less time in REMS that their wild-type counterparts. Direct infusion of the 5-HT(1A) receptor agonists 8-OH-DPAT and flesinoxan into the DRN significantly enhances REMS in the rat. In contrast, microinjection of the 5-HT(1B) (CP-94253), 5-HT(2A/2C) (DOI), 5-HT(3) (m-chlorophenylbiguanide) and 5-HT(7) (LP-44) receptor agonists into the DRN induces a significant reduction of REMS. Systemic injection of full agonists at postsynaptic 5-HT(1A) (8-OH-DPAT, flesinoxan), 5-HT(1B) (CGS 12066B, CP-94235), 5-HT(2C) (RO 60-0175), 5-HT(2A/2C) (DOI, DOM), 5-HT(3) (m-chlorophenylbiguanide) and 5-HT(7) (LP-211) receptors increases W and reduces SWS and REMS. Of note, systemic administration of the 5-HT(2A/2C) receptor antagonists ritanserin, ketanserin, ICI-170,809 or sertindole at the beginning of the light period has been shown to induce a significant increase of SWS and a reduction of REMS in the rat. Wakefulness was also diminished in most of these studies. Similar effects have been described following the injection of the selective 5-HT(2A) receptor antagonists volinanserin and pruvanserin and of the 5-HT(2A) receptor inverse agonist nelotanserin in rodents. In addition, the effects of these compounds have been studied on the sleep electroencephalogram of subjects with normal sleep. Their administration was followed by an increase of SWS and, in most instances, a reduction of REMS. The administration of ritanserin to poor sleepers, patients with chronic primary insomnia and psychiatric patients with a generalized anxiety disorder or a mood disorder caused a significant increase in SWS. The 5-HT(2A) receptor inverse agonist APD-125 induced also an increase of SWS in patients with chronic primary insomnia. It is known that during the administration of benzodiazepine (BZD) hypnotics to patients with insomnia there is a further reduction of SWS and REMS, whereas both variables tend to remain decreased during the use of non-BZD derivatives (zolpidem, zopiclone, eszopiclone, zaleplon). Thus, the association of 5-HT(2A) antagonists or 5-HT(2A) inverse agonists with BZD and non-BZD hypnotics could be a valid alternative to normalize SWS in patients with primary or comorbid insomnia. Copyright © 2010 Elsevier Ltd. All rights reserved.
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            A PHA-L analysis of ascending projections of the dorsal raphe nucleus in the rat.

            R Vertes (1991)
            Ascending projections from the dorsal raphe nucleus (DR) were examined in the rat by using the anterograde anatomical tracer, Phaseolus vulgaris leucoagglutinin (PHA-L). The majority of labeled fibers from the DR ascended through the forebrain within the medial forebrain bundle. DR fibers were found to terminate heavily in several subcortical as well as cortical sites. The following subcortical nuclei receive dense projections from the DR: ventral regions of the midbrain central gray including the 'supraoculomotor central gray' region, the ventral tegmental area, the substantia nigra-pars compacta, midline and intralaminar nuclei of the thalamus including the posterior paraventricular, the parafascicular, reuniens, rhomboid, intermediodorsal/mediodorsal, and central medial thalamic nuclei, the central, lateral and basolateral nuclei of the amygdala, posteromedial regions of the striatum, the bed nucleus of the stria terminalis, the lateral septal nucleus, the lateral preoptic area, the substantia innominata, the magnocellular preoptic nucleus, the endopiriform nucleus, and the ventral pallidum. The following subcortical nuclei receive moderately dense projections from the DR: the median raphe nucleus, the midbrain reticular formation, the cuneiform/pedunculopontine tegmental area, the retrorubral nucleus, the supramammillary nucleus, the lateral hypothalamus, the paracentral and central lateral intralaminar nuclei of the thalamus, the globus pallidus, the medial preoptic area, the vertical and horizontal limbs of the diagonal band nuclei, the claustrum, the nucleus accumbens, and the olfactory tubercle. The piriform, insular and frontal cortices receive dense projections from the DR; the occipital, entorhinal, perirhinal, frontal orbital, anterior cingulate, and infralimbic cortices, as well as the hippocampal formation, receive moderately dense projections from the DR. Some notable differences were observed in projections from the caudal DR and the rostral DR. For example, the hippocampal formation receives moderately dense projections from the caudal DR and essentially none from the rostral DR. On the other hand, virtually all neocortical regions receive significantly denser projections from the rostral than from the caudal DR. The present results demonstrate that dorsal raphe fibers project significantly throughout widespread regions of the midbrain and forebrain.
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              Projections of the median raphe nucleus in the rat.

              No previous report in any species has examined comprehensively the projections of the median raphe (MR) nucleus with modern tracing techniques. The present report represents an in depth analysis of the projections of MR by use of the anterograde anatomical tracer Phaseolus vulgaris-leucoagglutinin. MR fibers descend along the midline within the brainstem and mainly ascend within the medial forebrain bundle in the forebrain. MR fibers distribute densely to the following brainstem/forebrain sites: caudal raphe nuclei, laterodorsal tegmental nucleus, dorsal raphe nucleus, interpeduncular nucleus, medial mammillary body, supramammillary nucleus, posterior nucleus and perifornical region of the hypothalamus, midline and intralaminar nuclei of thalamus, dopamine-containing cell region of medial zona incerta, lateral habenula, horizontal and vertical limbs of the diagonal band nuclei, medial septum, and hippocampal formation. Virtually all of these structures lie on or close to the midline, indicating that the MR represents a midline/para-midline system of projections. Overall, MR projections to the cortex are light. MR projects moderately to the perirhinal, entorhinal and frontal cortices, but sparingly to remaining regions of cortex. A comparison of MR with dorsal raphe (DR) projections (Vertes RP. 1991. J Comp Neurol 313:643-668) shows that these two major serotonin-containing cell groups of the midbrain distribute to essentially nonoverlapping regions of the forebrain; that is, the MR and DR project to complementary sites in the forebrain. A direct role for the MR in the desynchronization of the electroencephalographic activity of the hippocampus and its possible consequences for memory-associated functions of the hippocampus is discussed.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: MethodologyRole: Software
                Role: MethodologyRole: Software
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                19 March 2020
                2020
                : 15
                : 3
                : e0230367
                Affiliations
                [1 ] Laboratory of Brain Information Science in Sports, Graduate School of Frontier Biosciences, Osaka University, Toyonaka, Osaka, Japan
                [2 ] Laboratory of Brain Information Science in Sports, Center for Education in Liberal Arts and Sciences, Osaka University, Toyonaka, Osaka, Japan
                [3 ] Laboratory of Brain Information Science in Sports, Graduate School of Medicine, Osaka University, Toyonaka, Osaka, Japan
                Radboud University Medical Centre, NETHERLANDS
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-5635-6669
                Article
                PONE-D-19-31125
                10.1371/journal.pone.0230367
                7082012
                32191757
                b7dea6d5-705d-4e7d-aeff-6e164f8b6c70
                © 2020 Sato et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 November 2019
                : 27 February 2020
                Page count
                Figures: 4, Tables: 0, Pages: 11
                Funding
                Funded by: KAKENHI
                Award ID: JP22500573
                Award Recipient :
                Funded by: KAKENHI
                Award ID: JP25282216
                Award Recipient :
                Funded by: KAKENHI
                Award ID: JP25560302
                Award Recipient :
                Funded by: KAKENHI
                Award ID: JP16H01869
                Award Recipient :
                Funded by: KAKENHI
                Award ID: JP17J08499
                Award Recipient :
                This work was supported by KAKENHI JP22500573, JP25282216, JP25560302, and JP16H01869 to S.S, and Grant-in-Aid for JSPS Fellows JP17J08499 to A.Y.S.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Neurochemistry
                Neurotransmitters
                Biogenic Amines
                Serotonin
                Biology and Life Sciences
                Neuroscience
                Neurochemistry
                Neurotransmitters
                Biogenic Amines
                Serotonin
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                Sensory Perception
                Vision
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                Psychology
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                All raw data files are available from the figshare (DOI: 10.6084/m9.figshare.11845611).

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