内在光敏性视网膜神经节细胞在精神疾病的发生与发展中的作用综述

doi:10.3969/j.issn.1674-8115.2025.11.013

摘要/Abstract

摘要：

视网膜作为光线信息的外周感受器，因其与大脑发育同源、结构功能相似，也是中枢神经系统唯一能够直接观察的部分，被誉为“大脑的窗口”。神经视网膜中存在一类特异性表达黑视蛋白、有自感光特性的内在光敏性视网膜神经节细胞（intrinsically photosensitive retinal ganglion cell，ipRGC），其可通过内在光敏性电流以及中介视锥、视杆细胞的输入信号，向大脑传入环境光线变化信号；还可通过广泛的脑区投射影响昼夜节律、情绪、认知、睡眠等重要生物过程。既往研究表明，ipRGC功能异常可直接导致由光线变化诱发的情绪和睡眠觉醒行为出现异常，可能介导失眠、季节性情感障碍、双相障碍、物质滥用及部分继发于躯体疾病的精神症状的发生与发展。因此，了解并进一步探索ipRGC功能有助于发掘潜在的治疗靶点，对于精神疾病的诊治具有较大意义。该文综述了ipRGC的生理特点、功能以及在精神疾病动物模型、患者中的研究现状，以期为后续有针对性地干预ipRGC功能来改善精神疾病方面的研究提供参考。

关键词: 内在光敏性视网膜神经节细胞, 黑视蛋白, 精神障碍

Abstract:

The retina is the peripheral sensor of light information and the only part of the central nervous system accessible to direct observation. It is also regarded as a “window to the brain” due to its developmental and structural similarity to the brain. Intrinsically photosensitive retinal ganglion cells (ipRGCs) within the neural retina transmit signals of environmental light changes to the brain via both intrinsic melanopsin-mediated currents and integrated signals from rod/cone input. ipRGCs project widely to multiple brain regions that regulate circadian rhythm, emotion, cognition and sleep. Numerous studies have indicated that ipRGC dysfunction may impair light-evoked emotional and sleep-wake behavioral changes, and may play a key role in the occurrence and development of insomnia, seasonal affective disorder, bipolar disorder, substance use disorder, and mental disorders associated with physical diseases. Therefore, understanding and futher exploring the function of ipRGCs may help discover potential treatment targets, which is of great value for improving the diagnosis and treatment of mental disorders. This review summarizes the physiological characteristics and functions of ipRGCs, as well as current research findings in animal models of mental disorders and in patients, aiming to provide references for future interventions targeting ipRGC function in mental disorders.

Key words: intrinsically photosensitive retinal ganglion cell (ipRGC), melanopsin, mental disorder

中图分类号:

R749

贾辰希, 朱佳异, 杜江, 赵敏. 内在光敏性视网膜神经节细胞在精神疾病的发生与发展中的作用综述[J]. 上海交通大学学报（医学版）, 2025, 45(11): 1536-1544.

JIA Chenxi, ZHU Jiayi, DU Jiang, ZHAO Min. Review on the role of intrinsically photosensitive retinal ganglion cells in the onset and progression of mental disorders[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(11): 1536-1544.

参考文献 89

[1]	BERSON D M, DUNN F A, TAKAO M. Phototransduction by retinal ganglion cells that set the circadian clock[J]. Science, 2002, 295(5557): 1070-1073.
[2]	HATTAR S, LIAO H W, TAKAO M, et al. Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity[J]. Science, 2002, 295(5557): 1065-1070.
[3]	TSAI N Y, NIMKAR K, ZHAO M, et al. Molecular and spatial analysis of ganglion cells on retinal flatmounts: diversity, topography, and perivascularity[J]. bioRxiv [Preprint], 2024: 2024.12.15.628587.
[4]	LEGATES T A, FERNANDEZ D C, HATTAR S. Light as a central modulator of circadian rhythms, sleep and affect[J]. Nat Rev Neurosci, 2014, 15(7): 443-454.
[5]	MAHONEY H L, SCHMIDT T M. The cognitive impact of light: illuminating ipRGC circuit mechanisms[J]. Nat Rev Neurosci, 2024, 25(3): 159-175.
[6]	CLEYMAET A M, BEREZIN C T, VIGH J. Endogenous opioid signaling in the mouse retina modulates pupillary light reflex[J]. Int J Mol Sci, 2021, 22(2): 554.
[7]	MURE L S. Intrinsically photosensitive retinal ganglion cells of the human retina[J]. Front Neurol, 2021, 12: 636330.
[8]	VIDAL-VILLEGAS B, GALLEGO-ORTEGA A, MIRALLES DE IMPERIAL-OLLERO J A, et al. Photosensitive ganglion cells: a diminutive, yet essential population[J]. Arch Soc Esp Oftalmol (Engl Ed), 2021, 96(6): 299-315.
[9]	BEIER C, ZHANG Z, YURGEL M, et al. Projections of ipRGCs and conventional RGCs to retinorecipient brain nuclei[J]. J Comp Neurol, 2021, 529(8): 1863-1875.
[10]	DACEY D M, LIAO H W, PETERSON B B, et al. Melanopsin-expressing ganglion cells in primate retina signal colour and irradiance and project to the LGN[J]. Nature, 2005, 433(7027): 749-754.
[11]	BROWN T M, GIAS C, HATORI M, et al. Melanopsin contributions to irradiance coding in the thalamo-cortical visual system[J]. PLoS Biol, 2010, 8(12): e1000558.
[12]	凌颖, 毕爱玲, 毕宏生. 内在光敏性视网膜神经节细胞研究现状与展望[J]. 国际眼科杂志, 2023, 23(10): 1648-1652.
	LING Y, BI A L, BI H S. Research status and prospects of intrinsically photosensitive retinal ganglion cells[J]. International Eye Science, 2023, 23(10): 1648-1652.
[13]	ECKER J L, DUMITRESCU O N, WONG K Y, et al. Melanopsin-expressing retinal ganglion-cell photoreceptors: cellular diversity and role in pattern vision[J]. Neuron, 2010, 67(1): 49-60.
[14]	SCHMIDT T M, KOFUJI P. Functional and morphological differences among intrinsically photosensitive retinal ganglion cells[J]. J Neurosci, 2009, 29(2): 476-482.
[15]	CHEN S K, BADEA T C, HATTAR S. Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs[J]. Nature, 2011, 476(7358): 92-95.
[16]	RUPP A C, REN M, ALTIMUS C M, et al. Distinct ipRGC subpopulations mediate light′s acute and circadian effects on body temperature and sleep[J]. eLife, 2019, 8: e44358.
[17]	LI J Y, SCHMIDT T M. Divergent projection patterns of M1 ipRGC subtypes[J]. J Comp Neurol, 2018, 526(13): 2010-2018.
[18]	GAMLIN P D R, MCDOUGAL D H, POKORNY J, et al. Human and macaque pupil responses driven by melanopsin-containing retinal ganglion cells[J]. Vision Res, 2007, 47(7): 946-954.
[19]	GRAHAM D M, WONG K Y, SHAPIRO P, et al. Melanopsin ganglion cells use a membrane-associated rhabdomeric phototransduction cascade[J]. J Neurophysiol, 2008, 99(5): 2522-2532.
[20]	WONG K Y. A retinal ganglion cell that can signal irradiance continuously for 10 hours[J]. J Neurosci, 2012, 32(33): 11478-11485.
[21]	PEREZ-LEON J A, WARREN E J, ALLEN C N, et al. Synaptic inputs to retinal ganglion cells that set the circadian clock[J]. Eur J Neurosci, 2006, 24(4): 1117-1123.
[22]	HANNIBAL J, MØLLER M, OTTERSEN O P, et al. PACAP and glutamate are co-stored in the retinohypothalamic tract[J]. J Comp Neurol, 2000, 418(2): 147-155.
[23]	DO M T H. Melanopsin and the intrinsically photosensitive retinal ganglion cells: biophysics to behavior[J]. Neuron, 2019, 104(2): 205-226.
[24]	WENG S J, ESTEVEZ M E, BERSON D M. Mouse ganglion-cell photoreceptors are driven by the most sensitive rod pathway and by both types of cones[J]. PLoS One, 2013, 8(6): e66480.
[25]	RAJA S, MILOSAVLJEVIC N, ALLEN A E, et al. Burning the candle at both ends: intraretinal signaling of intrinsically photosensitive retinal ganglion cells[J]. Front Cell Neurosci, 2023, 16: 1095787.
[26]	VINEY T J, BALINT K, HILLIER D, et al. Local retinal circuits of melanopsin-containing ganglion cells identified by transsynaptic viral tracing[J]. Curr Biol, 2007, 17(11): 981-988.
[27]	BERGUM N, BEREZIN C T, VIGH J. Dopamine enhances GABAA receptor-mediated current amplitude in a subset of intrinsically photosensitive retinal ganglion cells[J]. bioRxiv, 2023: 2023. 12.11.571141.
[28]	CARPENA-TORRES C, SCHILLING T, HUETE-TORAL F, et al. Increased ocular dopamine levels in rabbits after blue light stimulation of the optic nerve head[J]. Exp Eye Res, 2023, 234: 109604.
[29]	SHI Y M, ZHANG J M, LI X Y, et al. Non-image-forming photoreceptors improve visual orientation selectivity and image perception[J]. Neuron, 2025, 113(3): 486-500.e13.
[30]	SONODA T, LEE S K, BIRNBAUMER L, et al. Melanopsin phototransduction is repurposed by ipRGC subtypes to shape the function of distinct visual circuits[J]. Neuron, 2018, 99(4): 754-767.e4.
[31]	BARRIONUEVO P A, SANDOVAL SALINAS M L, FANCHINI J M. Are ipRGCs involved in human color vision? Hints from physiology, psychophysics, and natural image statistics[J]. Vision Res, 2024, 217: 108378.
[32]	FITZPATRICK M J, KRIZAN J, HSIANG J C, et al. A pupillary contrast response in mice and humans: neural mechanisms and visual functions[J]. Neuron, 2024, 112(14): 2404-2422.e9.
[33]	HATORI M, LE H, VOLLMERS C, et al. Inducible ablation of melanopsin-expressing retinal ganglion cells reveals their central role in non-image forming visual responses[J]. PLoS One, 2008, 3(6): e2451.
[34]	GÜLER A D, ECKER J L, LALL G S, et al. Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision[J]. Nature, 2008, 453(7191): 102-105.
[35]	KEENAN W T, RUPP A C, ROSS R A, et al. A visual circuit uses complementary mechanisms to support transient and sustained pupil constriction[J]. eLife, 2016, 5: e15392.
[36]	LUCAS R J, HATTAR S, TAKAO M, et al. Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice[J]. Science, 2003, 299(5604): 245-247.
[37]	ADHIKARI P, ZELE A J, FEIGL B. The post-illumination pupil response (PIPR)[J]. Invest Ophthalmol Vis Sci, 2015, 56(6): 3838-3849.
[38]	KAWASAKI A, UDRY M, EL WARDANI M, et al. Can extra daytime light exposure improve well-being and sleep? A pilot study of patients with glaucoma[J]. Front Neurol, 2021, 11: 584479.
[39]	KELBSCH C, STRASSER T, CHEN Y, et al. Standards in pupillography[J]. Front Neurol, 2019, 10: 129.
[40]	DIBNER C, SCHIBLER U, ALBRECHT U. The mammalian circadian timing system: organization and coordination of central and peripheral clocks[J]. Annu Rev Physiol, 2010, 72: 517-549.
[41]	REPPERT S M, WEAVER D R. Molecular analysis of mammalian circadian rhythms[J]. Annu Rev Physiol, 2001, 63: 647-676.
[42]	CZEISLER C A, SHANAHAN T L, KLERMAN E B, et al. Suppression of melatonin secretion in some blind patients by exposure to bright light[J]. N Engl J Med, 1995, 332(1): 6-11.
[43]	ALTIMUS C M, GÜLER A D, VILLA K L, et al. Rods-cones and melanopsin detect light and dark to modulate sleep independent of image formation[J]. Proc Natl Acad Sci USA, 2008, 105(50): 19998-20003.
[44]	WANG H B, ZHOU D, LUK S H C, et al. Long wavelength light reduces the negative consequences of dim light at night[J]. Neurobiol Dis, 2023, 176: 105944.
[45]	PANDA S, PROVENCIO I, TU D C, et al. Melanopsin is required for non-image-forming photic responses in blind mice[J]. Science, 2003, 301(5632): 525-527.
[46]	WANG Y, YANG W Z, ZHANG P P, et al. Effects of light on the sleep-wakefulness cycle of mice mediated by intrinsically photosensitive retinal ganglion cells[J]. Biochem Biophys Res Commun, 2022, 592: 93-98.
[47]	HUANG L, XI Y, PENG Y F, et al. A visual circuit related to habenula underlies the antidepressive effects of light therapy[J]. Neuron, 2019, 102(1): 128-142.e8.
[48]	FERNANDEZ D C, FOGERSON P M, LAZZERINI OSPRI L, et al. Light affects mood and learning through distinct retina-brain pathways[J]. Cell, 2018, 175(1): 71-84.e18.
[49]	WANG G, LIU Y F, YANG Z, et al. Short-term acute bright light exposure induces a prolonged anxiogenic effect in mice via a retinal ipRGC-CeA circuit[J]. Sci Adv, 2023, 9(12): eadf4651.
[50]	LAZZERINI OSPRI L, ZHAN J J, THOMSEN M B, et al. Light affects the prefrontal cortex via intrinsically photosensitive retinal ganglion cells[J]. Sci Adv, 2024, 10(13): eadh9251.
[51]	周晓明, 刘丹丹. 等效照度描述LED光源下非视觉生物效应的影响[J]. 华南理工大学学报(自然科学版), 2018, 46(8): 134-141.
	ZHOU X M, LIU D D. Impact of nonvisual biological effects with the description of the equivalent illuminance for LED lights[J]. Journal of South China University of Technology(Natural Science Edition), 2018, 46(8): 134-141.
[52]	MENG J J, SHEN J W, LI G, et al. Light modulates glucose metabolism by a retina-hypothalamus-brown adipose tissue axis[J]. Cell, 2023, 186(2): 398-412.e17.
[53]	LUAN L J, REN C R, WANG W Y, et al. Morphological properties of medial amygdala-projecting retinal ganglion cells in the Mongolian gerbil[J]. Sci China Life Sci, 2018, 61(6): 644-650.
[54]	BOERTIEN T M, VAN SOMEREN E J W, COUMOU A D, et al. Compression of the optic chiasm is associated with reduced photoentrainment of the central biological clock[J]. Eur J Endocrinol, 2022, 187(6): 809-821.
[55]	MADSEN H Ø, HAGEMAN I, KOLKO M, et al. Seasonal variation in neurohormones, mood and sleep in patients with primary open angle glaucoma - implications of the ipRGC-system[J]. Chronobiol Int, 2021, 38(10): 1421-1431.
[56]	BLUME C, MÜNCH M. Effects of light on biological functions and human sleep[J]. Handb Clin Neurol, 2025, 206: 3-16.
[57]	GUO Z Z, JIANG S M, ZENG L P, et al. ipRGCs: possible causation accounts for the higher prevalence of sleep disorders in glaucoma patients[J]. Int J Ophthalmol, 2017, 10(7): 1163-1167.
[58]	PANDI-PERUMAL S R, TRAKHT I, SRINIVASAN V, et al. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways[J]. Prog Neurobiol, 2008, 85(3): 335-353.
[59]	BRAINARD G C, HANIFIN J P, GREESON J M, et al. Action spectrum for melatonin regulation in humans: evidence for a novel circadian photoreceptor[J]. J Neurosci, 2001, 21(16): 6405-6412.
[60]	THAPAN K, ARENDT J, SKENE D J. An action spectrum for melatonin suppression: evidence for a novel non-rod, non-cone photoreceptor system in humans[J]. J Physiol, 2001, 535(Pt 1): 261-267.
[61]	OSTRIN L A, ABBOTT K S, QUEENER H M. Attenuation of short wavelengths alters sleep and the ipRGC pupil response[J]. Ophthalmic Physiol Opt, 2017, 37(4): 440-450.
[62]	CHAN J W Y, LI C T, CHAU S W H, et al. Attenuated melanopsin-mediated post-illumination pupillary response is associated with reduced actigraphic amplitude and mesor in older adults[J]. Sleep, 2025, 48(2): zsae239.
[63]	ZHANG Z, BEIER C, WEIL T, et al. The retinal ipRGC-preoptic circuit mediates the acute effect of light on sleep[J]. Nat Commun, 2021, 12(1): 5115.
[64]	ZHANG Z, LIU W Y, DIAO Y P, et al. Superior colliculus GABAergic neurons are essential for acute dark induction of wakefulness in mice[J]. Curr Biol, 2019, 29(4): 637-644.e3.
[65]	MÜNCH M, KOBIALKA S, STEINER R, et al. Wavelength-dependent effects of evening light exposure on sleep architecture and sleep EEG power density in men[J]. Am J Physiol Regul Integr Comp Physiol, 2006, 290(5): R1421-R1428.
[66]	MEYER N, LOK R, SCHMIDT C, et al. The sleep-circadian interface: a window into mental disorders[J]. Proc Natl Acad Sci USA, 2024, 121(9): e2214756121.
[67]	FISHER P M, MADSEN M K, MAHON B M, et al. Three-week bright-light intervention has dose-related effects on threat-related corticolimbic reactivity and functional coupling[J]. Biol Psychiatry, 2014, 76(4): 332-339.
[68]	YOUNG M A, MEADEN P M, FOGG L F, et al. Which environmental variables are related to the onset of seasonal affective disorder?[J]. J Abnorm Psychol, 1997, 106(4): 554-562.
[69]	MARUANI J, VISSOUZE L, HEBERT M, et al. Pupillary response to blue light as a biomarker of seasonal pattern in major depressive episode: a clinical study using pupillometry[J]. Psychiatry Res, 2025, 344: 116333.
[70]	ROECKLEIN K, WONG P, ERNECOFF N, et al. The post illumination pupil response is reduced in seasonal affective disorder[J]. Psychiatry Res, 2013, 210(1): 150-158.
[71]	ROECKLEIN K A, FRANZEN P L, WESCOTT D L, et al. Melanopsin-driven pupil response in summer and winter in unipolar seasonal affective disorder[J]. J Affect Disord, 2021, 291: 93-101.
[72]	MADSEN H Ø, BA-ALI S, HEEGAARD S, et al. Melanopsin-mediated pupillary responses in bipolar disorder: a cross-sectional pupillometric investigation[J]. Int J Bipolar Disord, 2021, 9(1): 7.
[73]	GEOFFROY P A, BELLIVIER F, SCOTT J, et al. Bipolar disorder with seasonal pattern: clinical characteristics and gender influences[J]. Chronobiol Int, 2013, 30(9): 1101-1107.
[74]	GEOFFROY P A, BELLIVIER F, SCOTT J, et al. Seasonality and bipolar disorder: a systematic review, from admission rates to seasonality of symptoms[J]. J Affect Disord, 2014, 168: 210-223.
[75]	ROGUSKI A, NEEDHAM N, MACGILLIVRAY T, et al. Investigating light sensitivity in bipolar disorder (HELIOS-BD)[J]. Wellcome Open Res, 2024, 9: 64.
[76]	MOON J H, CHO C H, SON G H, et al. Advanced circadian phase in mania and delayed circadian phase in mixed mania and depression returned to normal after treatment of bipolar disorder[J]. EBioMedicine, 2016, 11: 285-295.
[77]	LEWY A J, NURNBERGER J I Jr, WEHR T A, et al. Supersensitivity to light: possible trait marker for manic-depressive illness[J]. Am J Psychiatry, 1985, 142(6): 725-727.
[78]	HALLAM K T, BEGG D P, OLVER J S, et al. Abnormal dose-response melatonin suppression by light in bipolar type Ⅰ patients compared with healthy adult subjects[J]. Acta Neuropsychiatr, 2009, 21(5): 246-255.
[79]	WHALLEY L J, PERINI T, SHERING A, et al. Melatonin response to bright light in recovered, drug-free, bipolar patients[J]. Psychiatry Res, 1991, 38(1): 13-19.
[80]	RITTER P, WIELAND F, SKENE D J, et al. Melatonin suppression by melanopsin-weighted light in patients with bipolar Ⅰ disorder compared to healthy controls[J]. J Psychiatry Neurosci, 2020, 45(2): 79-87.
[81]	BERGUM N, BEREZIN C T, DOOLEY G, et al. Morphine accumulates in the retina following chronic systemic administration[J]. Pharmaceuticals (Basel), 2022, 15(5): 527.
[82]	BERGUM N, BEREZIN C T, VIGH J. A retinal contribution to opioid-induced sleep disorders?[J]. Front Neurosci, 2022, 16: 981939.
[83]	BERGUM N, BEREZIN C T, KING C M, et al. µ-opioid receptors expressed by intrinsically photosensitive retinal ganglion cells contribute to morphine-induced behavioral sensitization[J]. Int J Mol Sci, 2022, 23(24): 15870.
[84]	PEÑA-ZELAYETA L, DELGADO-MINJARES K M, VILLEGAS-ROJAS M M, et al. Redefining non-motor symptoms in Parkinson′s disease[J]. J Pers Med, 2025, 15(5): 172.
[85]	FEIGL B, DUMPALA S, KERR G K, et al. Melanopsin cell dysfunction is involved in sleep disruption in Parkinson′s disease[J]. J Parkinsons Dis, 2020, 10(4): 1467-1476.
[86]	杨健, 郑剑虹, 李继波, 等. 光对自闭症者身心功能的影响及教育干预建议[J].中国特殊教育, 2021(6): 52-58.
	YANG J, ZHENG J H, LI J B, et al. The effects of light on the physical and mental functions of individuals with autism and educational intervention[J]. Chinese Journal of Special Education, 2021(6): 52-58.
[87]	潘苗苗, 陈莉. Smith-Magenis综合征相关的睡眠障碍[J]. 中华医学遗传学杂志, 2021, 38(12): 1262-1265.
	Pan M, Chen L. Sleep disturbance associated with Smith-Magenis syndrome[J]. Chinese Journal of Medical Genetics, 2021, 38(12): 1262-1265.
[88]	连雨峥, 孟庆贺, 蒋建军, 等. 蓝光对大鼠焦虑、抑郁及睡眠的影响[J]. 现代预防医学, 2016, 43(18): 3398-3401, 3405.
	LIAN Y Z, MENG Q H, JIANG J J, et al. The influence of blue light on anxiety, depression, and sleep of rats[J]. Modern Preventive Medicine, 2016, 43(18): 3398-3401, 3405.
[89]	鲁玉红, 王毓蓉, 金尚忠, 等. 不同波长蓝光LED对人体光生物节律效应的影响[J]. 发光学报, 2013, 34(8): 1061-1065.
	LU Y H, WANG Y R, JIN S Z, et al. Influence of Different Wavelength Blue LED on Human Optical Biorhythm Effect[J]. Chinese Journal of Luminescence, 2013, 34(8): 1061-1065.