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      Direct Retino-Raphe Projection Alters Serotonergic Tone and Affective Behavior

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          Abstract

          Light is a powerful modulator of higher-order cognitive processes such as mood but it remains unclear which neural circuits mediate the impact of light on affective behavior. We found that light deprivation produces a depressive-like behavioral state that is reversed by activation of direct retinal signals to the serotonergic dorsal raphe nucleus (DRN) in a manner equivalent to treatment with the selective serotonin reuptake inhibitor fluoxetine. Surprisingly, the DRN-projecting retinal ganglion cells (RGCs) are indistinguishable from the classic alpha/Y-like RGC type that contributes to image-forming visual pathways. Silencing RGC firing or specific immunotoxin ablation of DRN-projecting RGCs increased depressive-like behavior and reduced serotonin levels in the DRN. Serotonin has a key role in the pathophysiology of depression, and these results demonstrate that retino-raphe signals modulate DRN serotonergic tone and affective behavior.

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          Most cited references 45

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          The contrast sensitivity of retinal ganglion cells of the cat.

          1. Spatial summation within cat retinal receptive fields was studied by recording from optic-tract fibres the responses of ganglion cells to grating patterns whose luminance perpendicular to the bars varied sinusoidally about the mean level. 2. Summation over the receptive fields of some cells (X-cells) was found to be approximately linear, while for other cells (Y-cells) summation was very non-linear. 3. The mean discharge frequency of Y-cells (unlike that of X-cells) was greatly increased when grating patterns drifted across their receptive fields. 4. In twenty-one X-cells the relation between the contrast and spatial frequency of drifting sinusoidal gratings which evoked the same small response was measured. In every case it was found that the reciprocal of this relation, the contrast sensitivity function, could be satisfactorily described by the difference of two Gaussian functions. 5. This finding supports the hypothesis that the sensitivities of the antagonistic centre and surround summating regions of ganglion cell receptive fields fall off as Gaussian functions of the distance from the field centre. 6. The way in which the sensitivity of an X-cell for a contrast-edge pattern varied with the distance of the edge from the receptive field centre was determined and found to be consistent with the cell's measured contrast sensitivity function. 7. Reducing the retinal illumination produced changes in the contrast sensitivity function of an X-cell which suggested that the diameters of the summating regions of the receptive field increased while the surround region became relatively ineffective.
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            Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test.

            Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressant class today and exert their antidepressant-like effects by increasing synaptic concentrations of serotonin (5-HT). The rat forced swim test (FST) is the most widely used animal test predictive of antidepressant action. Procedural modifications recently introduced by our laboratory have enabled SSRI-induced behavioral responses to be measured in the modified FST. The use of this model to understand the pharmacological and physiological mechanisms underlying the role of 5-HT in the behavioral effects of antidepressant drugs is reviewed. Although all antidepressants reduced behavioral immobility, those antidepressants that increase serotonergic neurotransmission predominantly increase swimming behavior whereas those that increase catacholaminergic neurotransmission increase climbing behavior. The 5-HT(1A), 5-HT(1B/1D) and 5-HT(2C) receptors are the 5-HT receptors most important to the therapeutic effects of SSRIs, based on extensive evaluation of agonists and antagonists of individual 5-HT receptor subtypes. Studies involving chronic administration have shown that the effects of antidepressants are augmented following chronic treatment. Other studies have demonstrated strain differences in the response to serotonergic compounds. Finally, a physiological model of performance in the rat FST has been proposed involving the regulation of 5-HT transmission by corticotropin releasing factor (CRF).
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              The efficacy of light therapy in the treatment of mood disorders: a review and meta-analysis of the evidence.

              The purpose of this study was to assess the evidence base for the efficacy of light therapy in treating mood disorders. The authors systematically searched PubMed (January 1975 to July 2003) to identify randomized, controlled trials of light therapy for mood disorders that fulfilled predefined criteria. These articles were abstracted, and data were synthesized by disease and intervention category. Only 13% of the studies met the inclusion criteria. Meta-analyses revealed that a significant reduction in depression symptom severity was associated with bright light treatment (eight studies, having an effect size of 0.84 and 95% confidence interval [CI] of 0.60 to 1.08) and dawn simulation in seasonal affective disorder (five studies; effect size=0.73, 95% CI=0.37 to 1.08) and with bright light treatment in nonseasonal depression (three studies; effect size=0.53, 95% CI=0.18 to 0.89). Bright light as an adjunct to antidepressant pharmacotherapy for nonseasonal depression was not effective (five studies; effect size=-0.01, 95% CI=-0.36 to 0.34). Many reports of the efficacy of light therapy are not based on rigorous study designs. This analysis of randomized, controlled trials suggests that bright light treatment and dawn simulation for seasonal affective disorder and bright light for nonseasonal depression are efficacious, with effect sizes equivalent to those in most antidepressant pharmacotherapy trials. Adopting standard approaches to light therapy's specific issues (e.g., defining parameters of active versus placebo conditions) and incorporating rigorous designs (e.g., adequate group sizes, randomized assignment) are necessary to evaluate light therapy for mood disorders.
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                Author and article information

                Journal
                Neuropsychopharmacology
                Neuropsychopharmacology
                Neuropsychopharmacology
                Nature Publishing Group
                0893-133X
                1740-634X
                June 2013
                31 January 2013
                27 February 2013
                1 June 2013
                : 38
                : 7
                : 1163-1175
                Affiliations
                [1 ]Department of Anatomy, School of Basic Medical Sciences, Peking University , Beijing, China
                [2 ]Key Laboratory on Machine Perception (Ministry of Education), Peking University , Beijing, China
                [3 ]Key Laboratory for Visual Impairment and Restoration (Ministry of Education), Peking University , Beijing, China
                [4 ]Department of Anatomy and Research Center of Heart, Brain, Hormone and Healthy Aging, LKS Faculty of Medicine , Pokfulam, Hong Kong, China
                [5 ]The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong , Pokfulam, Hong Kong, China
                [6 ]GHM Institute of CNS Regeneration, Jinan University , Guangzhou, China
                [7 ]Department of Machine Intelligence, Peking University , Beijing, China
                [8 ]School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln Lincoln, NE, USA
                [9 ]Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center , Omaha, NE, USA
                Author notes
                [* ]LKS Faculty of Medicine , 21 Sassoon Road, Pokfulam, Hong Kong, China, Tel: +852 2819 9216, Fax: +852 2817 6821, E-mail: hrmaskf@ 123456hku.hk
                [* ]Anatomy/Embryology, School of Basic Medical Sciences; Key Laboratory on Machine Perception; Key Laboratory for Visual Impairment and Restore, Peking University , 38 Xueyuan Road, Beijing 100191, China, Tel: +8610 8280 2972, Fax +8610 8280 2877, E-mail: mpu@ 123456hsc.pku.edu.cn
                [10]

                These authors contributed equally to this work.

                Article
                npp201335
                10.1038/npp.2013.35
                3656380
                23370156
                Copyright © 2013 American College of Neuropsychopharmacology

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

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