Abstract
In this study, the role of melanopsin-expressing retinal ganglion cells (mRGCs) in the glaucoma-induced depressive behavioral response pattern was investigated. The CFP-D2 transgenic glaucoma animal model from five age groups was used in this study. Immunohistochemical labeling, quantitative analysis of mRGC morphology, open field test (OFT), and statistical analysis were used. In comparison with C57 BL/6 mice, the age-matched CFP-D2 mice had significantly elevated intraocular pressure (IOP). We observed parallel morphological changes in the retina, including a reduction in the density of cyan fluorescent protein-(CFP) expressing cells (cells mm−2 at 2 months of age, 1309±26; 14 months, 878±30, P<0.001), mRGCs (2 months, 48±3; 14 months, 19±4, P<0.001), Brn3b-expressing RGCs (2 months, 1283±80; 14 months, 950±31, P <0.001), Brn-3b expressing mRGCs (5 months, 50.17%±5.5%; 14 months, 12.61%±3.8%, P<0.001), and reduction in the dendritic field size of mRGCs (mm2 at 2 months, 0.077±0.015; 14 months, 0.065±0.015, P<0.05). CFP-D2 mice had hyperactive locomotor activity patterns based on OFT findings of the total distance traveled, number of entries into the center, and time spent in the center of the testing apparatus. The glaucoma induced hyperactive response pattern could be associated with dysfunctional mRGCs, most likely Brn-3b-positive mRGCs in CFP-D2 mice.
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Quigley H A. Number of people with glaucoma worldwide. Br J Ophthalmol, 1996, 80: 389–393
Quigley H A, Broman A T. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol, 2006, 90: 262–267
Wong A A, Brown R E. A neurobehavioral analysis of the prevention of visual impairment in the DBA/2J mouse model of glaucoma. Invest Ophthalmol Vis Sci, 2012, 53: 5956–5966
Jayawant S S, Bhosle M J, Anderson R T, et al. Depressive symptomatology, medication persistence, and associated healthcare costs in older adults with glaucoma. J Glaucoma, 2007, 16: 513–520
Pappa C, Hyphantis T, Pappa S, et al. Psychiatric manifestations and personality traits associated with compliance with glaucoma treatment. J Psychosom Res, 2006, 61: 609–617
Onen S H, Mouriaux F, Berramdane L, et al. High prevalence of sleep-disordered breathing in patients with primary open-angle glaucoma. Acta Ophthalmol Scan, 2000, 78: 638–641
Kohn A N, Moss A P, Podos S M. Relative afferent pupillary defects in glaucoma without characteristic field loss. Arch Ophthalmol, 1979, 97: 294–296
Warthen D M, Wiltgen B J, Provencio I. Light enhances learned fear. Proc Natl Acad Sci USA, 2011, 108: 13788–13793
Roecklein K A, Wong P M, Miller M A, et al. Melanopsin, photosensitive ganglion cells, and seasonal affective disorder. Neurosci Biobehav Rev, 2013, 37: 229–239
Cumurcu T, Cumurcu B E, Celikel F C, et al. Depression and anxiety in patients with pseudoexfoliative glaucoma. Gen Hosp Psychiatry, 2006, 28: 509–515
Jampel H D, Frick K D, Janz N K, et al. Depression and mood indicators in newly diagnosed glaucoma patients. Am J Ophthalmol, 2007, 144: 238–244
Yochim B P, Mueller A E, Kane K D, et al. Prevalence of cognitive impairment, depression, and anxiety symptoms among older adults with glaucoma. J Glaucoma, 2012, 21: 250–254
Wang S Y, Singh K, Lin S C. Prevalence and predictors of depression among participants with glaucoma in a nationally representative population sample. Am J Ophthalmol, 2012, 154: 436–444
Popescu M L, Boisjoly H, Schmaltz H, et al. Explaining the relationship between three eye diseases and depressive symptoms in older adults. Invest Ophthalmol Vis Sci, 2012, 53: 2308–2313
Do M T, Yau K W. Intrinsically photosensitive retinal ganglion cells. Physio Rev, 2010, 90: 1547–1581
Chen S K, Badea T C, Hattar S. Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs. Nature, 2011, 476: 92–95
Lucas R J, Hattar S, Takao M, et al. Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science, 2003, 299: 245–247
LeGates T A, Altimus C M, Wang H, et al. Aberrant light directly impairs mood and learning through melanopsin-expressing neurons. Nature, 2012, 491: 594–598
Ren C, Luan L, Lau B W, et al. Direct retino-raphe projection alters serotonergic tone and affective behavior. Neuropsychopharmacology, 2013, doi: 10.1038/npp.2013.35
Allcutt D, Berry M, Sievers J. A qualitative comparison of the reactions of retinal ganglion cell axons to optic nerve crush in neonatal and adult mice. Brain Res, 1984, 318: 231–240
Kielczewski J L, Pease M E, Quigley H A. The effect of experimental glaucoma and optic nerve transection on amacrine cells in the rat retina. Invest Ophthalmol Vis Sci, 2005, 46: 3188–3196
Villegas-perez M P, Salvador-silva M, Ruiz-gomez J M, et al. Retinal ganglion cell death after different transient periods of pressure-induced ischemia and survival intervals. A quantitative in vivo study. Invest Ophthalmol Vis Sci, 2002, 37: 2002–2014
Yu S, Tanabe T, Yoshimura N. A rat model of glaucoma induced by episcleral vein ligation. Exp Eye Res, 2006, 83: 758–770
Nair K S, Hmani-Aifa M, Ali Z, et al. Alteration of the serine protease PRSS56 causes angle-closure glaucoma in mice and posterior microphthalmia in humans and mice. Nat Genet, 2011, 43: 579–584
John S W, Smith R S, Savinova O V, et al. Essential iris atrophy, pigment dispersion, and glaucoma in DBA/2J mice. Invest Ophthalmol Vis Sci, 1998, 39: 951–962
Chang B, Smith R S, Hawes N L, et al. Interacting loci cause severe iris atrophy and glaucoma in DBA/2J mice. Nature Genet, 1999, 21: 405–409
Anderson M G, Smith R S, Hawes N L, et al. Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice. Nature Genet, 2002, 30: 81–85
Feng G, Mellor R H, Bernstein M, et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron, 2000, 28: 41–51
Raymond I D, Pool A L, Vila A, et al. A Thy1-CFP DBA/2J mouse line with cyan fluorescent protein expression in retinal ganglion cells. Vis Neurosci, 2009, 26: 453–465
Luan L, Ren C, Lau B W, et al. Y-like retinal ganglion cells innervate the dorsal raphe nucleus in the Mongolian gerbil (Meriones unguiculatus). PLoS ONE, 2011, 6: e18938
Bouwknecht J A, Paylor R. Behavioral and physiological mouse assays for anxiety: a survey in nine mouse strains. Behav Brain Res, 2002, 136: 489–501
Leahy K M, Ornberg R L, Wang Y, et al. Quantitative ex vivo detection of rodent retinal ganglion cells by immunolabeling Brn-3b. Exp Eye Res, 2004, 79: 131–140
Goz D, Studholme K, Lappi D A, et al. Targeted destruction of photosensitive retinal ganglion cells with a saporin conjugate alters the effects of light on mouse circadian rhythms. PLoS ONE, 2008, 3: e3153
Sholl D A. Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat, 1953, 87: 387–406
Raymond I D, Vila A, Huynh U C, et al. CFP expression in ganglion and amacrine cells in a thy1-CFP transgenic mouse retina. Mol Vis, 2008, 14: 1559–1574
Feigl B, Mattes D, Thomas R, et al. Intrinsically photosensitive (melanopsin) retinal ganglion cell function in glaucoma. Invest Ophthalmol Vis Sci, 2011, 52: 4362–4367
Kankipati L, Girkin C A, Gamlin P D. The post-illumination pupil response is reduced in glaucoma patients. Invest Ophthalmol Vis Sci, 2011, 52: 2287–2292
La Morgia C, Ross-Cisneros F N, Hannibal J, et al. Melanopsin-expressing retinal ganglion cells: implications for human diseases. Vision Res, 2011, 51: 296–302
Hattar S, Kumar M, Park A, et al. Central projections of melanopsin-expressing retinal ganglion cells in the mouse. J Comp Neurol, 2006, 497: 326–349
Xiang M, Zhou L, Macke J P, et al. The Brn-3 family of POU-domain factors: primary structure, binding specificity, and expression in subsets of retinal ganglion cells and somatosensory neurons. J Neurosci, 1995, 15: 4762–4785
Kaback M B, Burde R M, Becker B. Relative afferent pupillary defect in glaucoma. Am J Ophthalmol, 1976, 81: 462–468
Li R S, Chen B Y, Tay D K, et al. Melanopsin-expressing retinal ganglion cells are more injury-resistant in a chronic ocular hypertension model. Invest Ophthalmol Vis Sci, 2006, 47: 2951–2958
Jakobs T C, Libby R T, Ben Y, et al. Retinal ganglion cell degeneration is topological but not cell type specific in DBA/2J mice. J Cell Biol, 2005, 171: 313–325
Dulawa S C, Holick K A, Gundersen B, et al. Effects of chronic fluoxetine in animal models of anxiety and depression. Neuropsychopharmacology, 2004, 29: 1321–1330
Weiss G A, Goldich Y, Bartov E, et al. Compliance with eye care in glaucoma patients with comorbid depression. IMAJ, 2011, 13: 730–734
Hollo G, Kothy P, Anna G, et al. Personality traits, depression, and objectively measured adherence to once-daily prostaglandin analog medication in glaucoma. J Glaucoma, 2009, 18: 288–292
Wilson M R, Coleman A L, Yu F, et al. Depression in patients with glaucoma as measured by self-report surveys. Ophthalmology, 2002, 109: 1018–1022
Lipkind D, Sakov A, Kafkafi N, et al. New replicable anxiety-related measures of wall vs center behavior of mice in the open field. J Appl Physiol, 2004, 97: 347–359
Can A, Blackwell R A, Piantadosi S C, et al. Antidepressant-like responses to lithium in genetically diverse mouse strains. Genes Brain Behav, 2011, 10: 434–443
Roecklein K A, Rohan K J, Duncan W C, et al. A missense variant (P10L) of the melanopsin (OPN4) gene in seasonal affective disorder. J Affect Disord, 2009, 114: 279–285
Jawahar M C, Brodnicki T C, Quirk F, et al. Behavioral analysis of congenic mouse strains confirms stress-responsive Loci on chromo somes 1 and 12. Behav Genet, 2008, 38: 407–416
Sokoloff G, Parker C C, Lim J E, et al. Anxiety and fear in a cross of C57BL/6J and DBA/2J mice: mapping overlapping and independent QTL for related traits. Genes Brain Behav, 2011, 10: 604–614
Fraser L M, Brown R E, Hussin A, et al. Measuring anxiety- and locomotion-related behaviors in mice: a new way of using old tests. Psychopharmacology (Berl), 2010, 211: 99–112
Hofstetter J R, Hofstetter A R, Hughes A M, et al. Intermittent long-wavelength red light increases the period of daily locomotor activity in mice. J Circadian Rhythms, 2005, 3: 8–15
Hovatta I, Tennant R S, Helton R, et al. Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice. Nature, 2005, 438: 662–666
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Zhang, Q., Vuong, H., Huang, X. et al. Melanopsin-expressing retinal ganglion cell loss and behavioral analysis in the Thy1-CFP-DBA/2J mouse model of glaucoma. Sci. China Life Sci. 56, 720–730 (2013). https://doi.org/10.1007/s11427-013-4493-1
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DOI: https://doi.org/10.1007/s11427-013-4493-1