The Light–Eye–Brain Axis: Neurobiological Links Between Mood Disorders and Myopia—A Narrative Review

Abstract

Light is a major environmental signal that shapes circadian rhythms, mood regulation, and ocular growth through a network of non-visual photoreceptive pathways. Increasing evidence suggests that photic information, particularly as decoded by intrinsically photosensitive retinal ganglion cells (ipRGCs), converges on central circuits governing both affective states and refractive development. To integrate these cross-system interactions, we propose the conceptual framework of a “light–eye–brain axis,” which outlines how environmental light cues are encoded by the retina and subsequently modulate neuroendocrine, autonomic, and inflammatory processes. Within this framework, mood disturbances may contribute to myopic progression through altered light-exposure behaviors, neurotransmitter imbalance, hypothalamic–pituitary–adrenal axis instability, and impaired neuroplasticity, whereas high myopia may increase vulnerability to anxiety or depressive symptoms through shared neural and immune pathways. Taken together, this integrative perspective highlights how light-dependent signaling shapes both emotional and refractive outcomes, and provides a conceptual foundation for future mechanistic studies as well as evidence-informed approaches to optimizing light exposure in the context of mood and visual health.

Key Summary Points

Light regulates circadian, mood, and ocular developmental pathways through non-visual photoreception, forming the foundation of the light–eye–brain axis.

Mood disorders and myopia share overlapping neurobiological mechanisms, including neurotransmitter imbalance, CCL2-mediated neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and impaired neuroplasticity.

Disruptions in light timing, spectrum, or intensity can induce mood disturbances and concurrently shift ocular growth signaling, influencing refractive development.

Refining light-exposure patterns and stabilizing mood regulation may offer dual mechanistic targets for future myopia prevention and intervention strategies.

Introduction

Light is not only a carrier of visual information but also a fundamental environmental cue regulating biological rhythms, mood, and development [1]. Increasing evidence shows that light exposure profoundly affects the central nervous system [2], emotional states [3], and metabolic rhythms [4]. As the major photosensitive organ, the eye transmits photic signals to the brain, influencing circadian synchronization, autonomic (particularly sympathetic) regulation, and affective processing. These effects depend strongly on the wavelength, intensity, and timing of light exposure.

In recent years, how light regulates ocular development and influences refractive status has become a research focus. However, it remains unclear how light, after being encoded by the retina, influences refractive development via central mechanisms. Emerging evidence suggests that light-induced modulation of circadian and emotional systems may alter ocular growth through dopamine signaling, sympathetic tone, and neuroimmune balance [5]. To conceptualize these interactions, we propose the “light–eye–brain axis”, a neurophysiological circuit integrating environmental light rhythms, retinal photoreception, and brain regulation.

Short-wavelength light around 480 nm is especially potent in driving non-visual (NV) physiological responses, corresponding to the spectral sensitivity of intrinsically photosensitive retinal ganglion cells (ipRGCs) [6]. Notably, blind individuals (lacking classical visual photoreceptors) also show this response, further confirming the crucial role of ipRGCs in non-visual functions [7]. These melanopsin-expressing neurons project to the suprachiasmatic nucleus, hypothalamus, and limbic structures, acting as a primary conduit between environmental light and central neuroendocrine control [8]. Research also indicates that classical visual photoreceptors (like rods and cones) play a role in these light-dependent responses [9].

This review synthesizes current evidence linking light-mediated non-visual pathways with emotional regulation and refractive development. We particularly focus on three convergent mechanisms: the sympathetic neurotransmitter axis, hypothalamic–pituitary–adrenal (HPA) neuroplasticity coupling, and immune-inflammatory signaling, as potential molecular bridges between mood disorders and myopia, thereby providing an integrative framework for future interdisciplinary research.

Ethical Compliance

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Basic Structure of the Light–Eye–Brain Axis

Light affects the brain not only through image-forming pathways but also through specialized non-visual photic circuits originating in the retina. To delineate how environmental light is converted into central regulatory signals that influence both mood and ocular growth, we propose the term “light–eye–brain axis” as a conceptual framework. This axis emphasizes that ipRGCs project directly to mood-related and circadian centers, including the suprachiasmatic nucleus (SCN), amygdala-related regions, and hypothalamic nuclei, thereby linking photic input to neurotransmitter regulation, HPA-axis dynamics, and emotional homeostasis. Within this framework, the eye acts as the photoreceptive gateway, and the brain functions as the integrative hub that transforms retinal irradiance signals into downstream autonomic, endocrine, and inflammatory outputs. This organization provides a biological basis for understanding why alterations in light exposure may simultaneously affect mood states and refractive development.

At its core, this axis is mediated by ipRGCs, a small subset of retinal neurons (1–3% of total RGCs in humans) that express melanopsin (Opn4 encoded)—a light-sensitive pigment with maximal responsiveness around 480 nm [10]. Through melanopsin-dependent phototransduction, ipRGCs generate sustained depolarization in response to ambient light intensity and spectral composition, distinct from the transient responses of rods and cones [11]. These cells encode global light information and convey it to multiple brain nuclei, linking retinal photoreception to central neuroendocrine and autonomic regulation [12].

Melanopsin (a G-protein-coupled receptor) responds to light by activating the Gq/11-PLCβ4-TRPC6/7 pathway [13]. Unlike rods and cones (transient responses), it produces sustained depolarization dependent on irradiance and spectrum [14]. Beyond phototransduction, ipRGCs express several neuropeptides such as PACAP and Brn3b, which facilitate signal amplification and target specificity [15]. Single-cell RNA sequencing has delineated multiple ipRGC subtypes (M1–M6), each exhibiting distinct molecular signatures and projection patterns [16].

M1 cells primarily project to SCN and adjacent hypothalamic or habenular regions to regulate circadian rhythms [17, 18]. M2 cells contribute to the pupillary light reflex and visual–nonvisual integration via the SCN and lateral geniculate complex. The M3 subtype likely bridges ON and OFF pathways, featuring large somata and dendrites that extend across both retinal layers [19, 20]. The M4–M6 subtypes mainly mediate image-forming vision, including contrast and motion detection [21]. The M4 has the largest soma and complex dendrites [22], M5 is densely branched [23], and M6 is smallest yet highly ramified [16]. Collectively, these diverse ipRGC populations encode global light information and relay it to multiple brain nuclei, forming the fundamental conduit of the light–eye–brain axis.

IpRGCs connect with multiple brain nuclei to regulate non-visual physiological functions. Their primary role is circadian synchronization, transmitting light signals to the SCN to align internal rhythms with the external light–dark cycle via clock gene regulation (Bmal1, Per1/2) [24]. They also mediate the pupillary light reflex through projections to the olivary pretectal nucleus, functioning even without rods and cones [25]. Beyond these, ipRGC-derived signals influence mood (e.g., reducing depressive-like phenotypes) and cognition (e.g., enhancing attention and memory) through SCN–amygdala–prefrontal cortex pathway [26]. On the metabolic and endocrine level, ipRGCs participate in regulating the sleep/wake cycle by inhibiting melatonin secretion [27]. Collectively, ipRGCs act as the central hub translating ambient light into neural signals that maintain physiological homeostasis.

Effects of Different Light Characteristics on the Light–Eye–Brain Axis

The biological effects of light depend not only on its presence or absence but also on its spectral composition, temporal rhythm, and intensity. Each of these parameters modulates the light–eye–brain axis in distinct yet interconnected ways. Spectral wavelength determines which photoreceptors are activated, temporal patterns of exposure regulate circadian phase and neuroendocrine synchronization, and light intensity shapes the magnitude of ipRGCs signaling and neurotransmitter release. Together, these features define how environmental illumination is encoded and transformed into molecular instructions that influence both central and ocular physiology (Table 1).

Table 1.

Molecules associated with light exposure and refractive development

Molecule	Light condition	Molecular change	Effect on refractive development	References
Dopamine	Bright light (high-intensity white light)	↑	Inhibits myopia	[28]
	Blue light	↑	Inhibits myopia	[29]
	Dark	↓	Promotes myopia	[30]
Melatonin	Dim light–darkness	↑	Promotes myopia	[31]
Serotonin	Flickering light	↑	Promotes myopia	[32]
Vitamin D	Sunlight (outdoor natural light)	↑	Inhibits myopia	[33]
EGR-1	Violet light (380–400 nm)	↑	Inhibits myopia	[34]
OPN5	Violet light (380–400 nm)	Activated	Inhibits myopia	[35]

Impact of Light Wavelength on the Light–Eye–Brain Axis

Wavelength is a key determinant of photic signaling along the light–eye–brain axis. Short-wavelength (“blue”) light around 480 nm most effectively activates melanopsin (Opn4) in ipRGCs, delivering robust input to the SCN and related hypothalamic nuclei. This activation synchronizes circadian rhythms [36], suppresses melatonin release [37], elevates cortisol secretion [38], and boosts sympathetic tone, thus promoting wakefulness and metabolic readiness. In contrast, long-wavelength (“red”) light weakly stimulates melanopsin and exerts limited influence on circadian or hormonal activity under comparable illumination.

Beyond circadian entrainment, wavelength-specific signaling modulates metabolism and neural excitability. Exposure to blue-enriched or natural light reduces glucose tolerance, as reflected by a higher glucose area under the curve, whereas red light elicits no such effect [39]. Mechanistically, ipRGCs can transmit light signals directly to the supraoptic nucleus, bypassing the SCN, where sympathetic activation of brown adipose tissue enhances thermogenesis and glucose utilization [40]. In clinical contexts, individuals with migraine display hypersensitivity to short-wavelength light, which exacerbates cortical spreading depression and triggers photophobic symptoms [41]. Although red light activates ipRGCs less efficiently, sufficiently high intensities (≥ 10 lx) can still alter sleep/wake behavior and retinal signaling in experimental models [42], suggesting an intensity-dependent threshold for long-wavelength effects. Collectively, these findings underscore that short-wavelength light, through Opn4-mediated photoneural pathways, serves as a central regulator of both metabolic and pathological processes.

At the ocular level, wavelength-dependent modulation extends to retinal neurotransmission and refractive control, as reflected by convergent changes in several light-responsive molecules, including dopamine [28–30], melatonin [31], serotonin [32], vitamin D [33], the transcription factor EGR-1 [34], and the violet light-sensitive photopigment OPN5 (Table 1). Bright or short-wavelength-enriched illumination increases retinal dopamine and vitamin D levels and activates EGR-1 and OPN5, collectively suppressing axial elongation and myopia, whereas dim light, darkness, flickering light, or long-wavelength-dominant conditions increase melatonin and serotonin and reduce dopaminergic tone, thereby favoring myopic progression [28]. Animal studies show that exposure to narrow-band blue light or daylight mitigates form-deprivation myopia, whereas red or dim light promotes axial elongation [43]. Overall, short-wavelength light exerts stronger and more comprehensive modulation of the light–eye–brain axis, influencing both central neuroendocrine outputs and local retinal molecular mechanisms that jointly govern refractive development.

Effects of Light Rhythm on the Light–Eye–Brain Axis

The rhythm of light refers to the temporal distribution and variation of illumination across the 24-h cycle, encompassing three major aspects: timing, duration, and frequency of exposure. These temporal characteristics profoundly influence the light–eye–brain axis by modulating circadian synchronization, hormonal secretion, emotional state, and metabolic regulation.

The timing of light exposure plays a pivotal role in maintaining circadian alignment. Morning light promotes synchronization by stimulating melatonin suppression and cortisol elevation, thereby enhancing daytime alertness and neuroendocrine balance. In contrast, nighttime exposure to artificial light (ALAN) delays circadian phase and disrupts melatonin synthesis, increasing vulnerability to insomnia, anxiety, and depressive disorders [44]. Mechanistically, exposure to ALAN activates ipRGCs, which transmit light signals to the SCN and the supraoptic nucleus and suppress melatonin secretion. This disruption of circadian and autonomic regulation increases vulnerability to metabolic syndrome and mood disorders such as anxiety and depression [45].

Epidemiological evidence corroborates these mechanisms: a cohort study in Beijing schoolchildren revealed widespread indoor ALAN exposure, particularly among girls and older students [46]. Clinical studies further link nocturnal light exposure with weight gain [47, 48], obesity [49], and glucose imbalance in adults [50]. In animal models, even dim nighttime light induces anxiety-like and depressive behaviors and reduces dendritic spine density in the hippocampal CA1 region [51]. Together, these findings highlight the timing of light exposure as a decisive factor governing the neuroendocrine and emotional stability mediated by the light–eye–brain axis.

The duration of light exposure influences physiological responses in a dose-dependent but nonlinear manner. In humans, extending high-intensity light exposure (10,000 lx) from 0.2 to 4 h progressively delays the circadian phase, though shorter exposures induce a greater phase shift per minute [52]. Prolonged light exposure can further affect mood and cognition: in mice, acute bright light activates the ipRGCs-CeA (central amygdala) pathway, elevating corticosterone levels and inducing long-term anxiety-like behavior [53]. Conversely, repeated moderate light therapy (3000 lx for 2 h/day over 3 weeks) enhances spatial memory and maintains this improvement for at least 2 weeks after cessation [54]. These results indicate that both the duration and cumulative photic dose determine whether light functions as a beneficial entrainer or a stressor within the light–eye–brain framework.

The frequency of light exposure further influences emotional and cognitive processes, independent of circadian period length. High-frequency alternating illumination (T7 cycle: 3.5-h light–dark transitions) disrupts ipRGC signaling to the amygdala and prefrontal cortex, leading to anxiety and depressive phenotypes [26]. Brn3b-positive ipRGCs project to the lateral dorsal thalamus and activate CeA-related circuits, whereas Brn3b-negative ipRGCs primarily target the SCN and influence learning via downstream hippocampal prefrontal pathways [55]. Pharmacological evidence shows that antidepressants can reverse T7-induced mood abnormalities [56], suggesting that the ipRGC-CeA circuit represents a potential therapeutic target for rhythm-related emotional dysregulation. Ultimately, irregular light rhythms disturb both central circadian coordination and retinal dopaminergic signaling, positioning the eye not only as the initial photoreceptor but also as the effector organ that translates disrupted light timing into ocular and behavioral consequences [57].

Impact of Light Intensity on the Light–Eye–Brain Axis

The intensity of light primarily influences the light–eye–brain axis by modulating the firing amplitude of ipRGCs, which determines the strength of downstream circadian, metabolic, and autonomic signaling. However, this relationship is phase-dependent rather than linear. For example, higher intensity morning light (≈ 1000–1700 lx) enhances vigilance and sustained attention, whereas identical illumination in the afternoon yields little benefit [58, 59]. Conversely, low-intensity morning light (≈ 200 lx) can, under some conditions, produce equal or greater attentional improvement [60], indicating that light intensity interacts with circadian state, rather than exerting uniform effects across time.

Light intensity also influences systemic metabolic regulation through the SCN-paraventricular nucleus (PVN)-autonomic axis [61]. Under circadian disruption, low-intensity light can mitigate metabolic disturbances, whereas high-intensity light potentiates sympathetic activation and worsens glucose-lipid dysregulation in high-fat-fed mice [62]. Thus, light intensity shifts central autonomic regulatory setpoints, linking photic amplitude to metabolic outcome.

These central effects can ultimately return to the eye, where light intensity regulates retinal dopaminergic signaling, a key modifier of axial elongation [63]. Adequate illumination promotes dopamine release, inhibiting myopic progression, while chronically dim environments reduce dopaminergic tone and favor axial elongation [64]. Excessively intense light, however, may impose oxidative or excitatory stress on retinal circuits [65]. Therefore, light intensity acts not only as a circadian and metabolic regulator but also as a direct modulator of ocular growth, reaffirming the eye as both the sensory entry point and the effector site within the light–eye–brain axis [64].

Relationship between Mood Disorders and Refractive Development

Mood disturbances and refractive abnormalities frequently co-occur, and recent evidence suggests a biological coupling rather than a purely psychosocial association. Individuals with high myopia exhibit elevated rates of anxiety and depression [66]. Notably, CCL2-dependent monocyte recruitment contributes to anxiety-like phenotypes in both patients and myopic mouse models, and pharmacologic blockade of CCL2 attenuates these behaviors [67]. In parallel, shifts in Lactobacillaceae composition modulate inflammatory tone and GABAergic neurotransmission, further linking ocular state to emotional regulation [68]. These findings indicate that myopia and mood disorders share convergent immune neurochemical pathways, providing a mechanistic basis for bidirectional interaction (Table 2).

Table 2.

Molecules associated with light exposure and mood disorders

Target	Lighting conditions (wavelength/illuminance/duration)	Molecular/action	Type of mood disorder	References
Dopamine	Bright white light (broad-spectrum, ~ 400–700 nm), 10,000 lx, morning exposure, 30 min/day	Prevents decline in mood and motivation; modulates dopaminergic neurotransmission	Seasonal affective disorder	[69, 70]
Dopamine	Cool-white fluorescent light, 1500–3000 lx, morning or daytime exposure, 45–60 min/day (animal models)	Reverses dopamine-related circadian and molecular disturbances; alters Per2 expression	Circadian and depression-like phenotypes	[71]
GABA	Red light, 50 lx, 2 h	c-fos↑, GABAergic activity↑, nociception	Neuropathic pain	[72]
Melatonin	N/A	WT increase predicts DLMO	Circadian disruptions	[73]
Melatonin	Artificial light at night	Melatonin↓	Worsens depression/anxiety	[74]
Melatonin	Bright morning light	Melatonin↓	Improves depressive symptoms	[75]
Vitamin D	Low sunlight	VitD↓	Increases depression risk	[76]
Cortisol	Night-time light	Abnormal HPA-axis rhythm	Worsens mood	[77]
Cortisol	Artificial light at night	Cortisol↑	Worsens mood	[78]

Anxiety/Depressive-Like Mood on Refractive Development

In adolescents, anxiety and depressive symptoms are frequently observed alongside myopia. Children with myopia tend to engage less in outdoor activity and face higher near-work and academic visual demands, which may contribute to reduced social participation and increased psychological stress [79, 80]. A population-based cohort of 890,000 Israeli adolescents demonstrated that the risk of anxiety increased progressively with myopia severity, independent of visual acuity and comorbidities, with girls showing greater susceptibility to anxiety and depressive symptoms [81]. These findings suggest that refractive status and mood are linked not only through behavioral patterns but also through shared vulnerability to stress-related regulatory alterations.

A similar association is observed in the elderly, where vision impairment markedly elevates the prevalence of depressive and anxiety symptoms. Individuals living with age-related macular degeneration (AMD) are particularly vulnerable, as progressive central vision loss affects not only daily functioning but also autonomy, social engagement, and overall quality of life [82]. Importantly, longitudinal studies further suggest that the onset or progression of AMD may precede and predict subsequent development of depressive symptoms [83]. These support the notion that disrupted visual input can exert a sustained impact on emotional regulation across the lifespan, and highlight the need for early psychological screening and intervention in this population.

Taken together, mood disturbances and refractive changes demonstrate reciprocal amplification: visual dysfunction increases emotional burden, while emotional stress can modify neural, endocrine, and autonomic pathways that influence ocular growth regulation, a mechanistic relationship elaborated below.

Its Underlying Mechanism

The link between mood regulation and refractive development is mediated by ipRGC projections to limbic and hypothalamic circuits, rather than visual perception itself [84]. Among these pathways, the ipRGC-dpHb-nucleus accumbens (NAc) circuit is central to affective regulation. This pathway is particularly responsive to light at night. When activated, dpHb sends inhibitory output to the NAc, suppressing reward-related signaling and producing depressive-like emotional states [85]. Under natural conditions, such light-driven affective responses likely served as adaptive threat avoidance signals. However, in modern environments characterized by chronic ALAN, this circuit can become persistently activated, leading to sustained negative emotional tone.

Melanopsin activation initiates G-protein-cAMP-PKA signaling in ipRGCs. These signals converge on the PVN and extend through hypothalamus brainstem autonomic networks, engaging both sympathetic output and the HPA axis [53]. Persistent activation elevates noradrenergic tone and cortisol levels, producing a sustained HPA-sympathetic arousal state rather than transient homeostatic responses. This state is characterized by increased metabolic demand, vasoconstrictive bias, and reduced neurotrophic signaling in limbic circuits, reinforcing negative emotional tone.

These systemic changes can reach the eye. Elevated sympathetic activity and cortisol suppress retinal dopamine synthesis and release, a neurotransmitter that normally inhibits axial elongation [86]. Reduced dopamine leads to choroidal thinning, altered scleral extracellular matrix turnover, and progressive axial growth. In this way, emotional dysregulation can act as a biological driver of myopic progression. Thus, mood state and refractive development are coupled through a shared photic input system (ipRGCs) and a common effector mechanism (dopamine-dependent ocular growth control).

Light Signal-Induced Mood Disorders and Their Impact on Myopia

Light Signal-Induced Mood Disorders

The relationship between light signals and mood disorders has a profound historical background and modern scientific validation. As early as ancient Greece, medical literature documented the therapeutic effects of sunlight on physical and mental ailments. Hippocrates’ proposal of “sunlight therapy” laid the foundation for early understandings of the connection between light environments and mood regulation [87]. Modern research indicates that light signals, through non-visual pathways mediated by ipRGCs, directly influence the HPA axis and limbic system, regulating the metabolic balance of neurotransmitters such as serotonin and dopamine. Seasonal affective disorder (SAD), triggered by reduced winter daylight, demonstrates a clear dose–response relationship between light exposure and mood, highlighting that alterations in intensity, duration, or spectral composition can precipitate emotional dysregulation [70].

Basic Role of Light Signals in Mood Regulation

Environmental light modulates emotional states through fast, non-visual signaling pathways. Signals captured by ipRGCs are transmitted to mood-related regions such as the amygdala and lateral habenula (LHb), producing immediate affective responses independent of circadian timing. Bright light suppresses amygdala-driven bottom-up emotional reactivity while enhancing prefrontal top-down control, and this regulatory balance strengthens with increasing illuminance [56, 88]. In parallel, retinal input to the vLGN-LHb pathway reduces LHb excitability, forming a key neural basis for light therapy in depressive disorders.

Light signals regulate mood by influencing the synthesis, secretion, and degradation of neurotransmitters. Studies have shown that light exposure significantly promotes serotonin synthesis, a process that includes increasing tetrahydrobiopterin levels and activating tryptophan hydroxylase, thus elevating serotonin levels [89]. Furthermore, light can impact the expression of serotonin 1A receptors and serotonin transporters, further regulating serotonin neurotransmission. Light also reduces the levels of monoamine oxidase A (MAO-A), which degrades serotonin. MAO-A, a mitochondrial enzyme, significantly decreases in the brain after light exposure, prolonging serotonin’s effects [90]. On the other hand, ultraviolet (UV) radiation, rather than visible light, is responsible for cutaneous vitamin D synthesis [76]. Reduced vitamin D levels can impair the production of dopamine and serotonin, whereas adequate UV exposure supports their biosynthesis [91]. Accordingly, UV-related changes in vitamin D status may indirectly influence neurotransmitter balance and mood regulation. Together, these mechanisms illustrate how photic environments can shape mood through effects on neurotransmitter metabolism.

Light also shapes mood by influencing peripheral hormones and autonomic activity. Through the retinal-hypothalamic pathway, photic input suppresses pineal melatonin and activates the HPA axis, leading to increased cortisol and heightened arousal [92]. At the autonomic level, inappropriate light exposure (e.g., bright LAN) can drive excessive sympathetic nervous system activation, manifesting as elevated heart rate, blood pressure, and metabolic strain [93]. These peripheral physiological changes feed back to the brain via visceral-neural pathways and can intensify underlying mood disturbances. Together with central circuits, these mechanisms form a multilevel framework through which light environments modulate emotional state.

The emotional effects of light are shaped not only by its presence but also by its physical properties, particularly illuminance and color temperature. High illuminance (> 1000 lx) consistently produces a more positive effect [94], likely because robust photic input dampens amygdala-driven bottom-up threat processing while strengthening prefrontal top-down emotional control [88]. Color temperature further modulates these responses. Exposure to high color temperature light, which is enriched in short wavelengths, increases neuronal activity within the paraventricular nucleus, suggesting a greater propensity to trigger stress-related arousal [95]. Consistently, blue-enriched light rapidly enhances activity across cortical and subcortical emotion-processing regions, including the amygdala, hippocampus, and hypothalamus, with stronger functional connectivity during the processing of anger and other salient emotions [96]. Collectively, these findings indicate that specific photic qualities tune the balance between limbic reactivity and cortical regulation, thereby shaping moment-to-moment emotional states.

The Association Between Abnormal Light Signals and Different Types of Mood Disorders

The association between abnormal light signals and mood disorders has become a research hotspot in neuropsychiatry, with mechanisms involving circadian rhythm regulation, neural circuit remodeling, and molecular pathway changes. Disruption of the normal temporal and spectral structure of light produces a characteristic pattern of emotional dysregulation. Under physiological conditions, daytime illumination strengthens SCN-mediated circadian alignment and maintains serotonin/dopamine balance [97]. When light is mistimed, particularly at night, photic input bypasses circadian pathways and directly engages the ipRGC-dpHb-NAc circuit, which is selectively excitable in the dark phase [85]. Activation of this pathway suppresses reward-related dopamine signaling in the NAc, generating a negative emotional bias that can become persistent under chronic ALAN.

Epidemiological data support these mechanistic observations. A cross-sectional study involving over 85,000 participants further confirmed that greater nighttime illumination is associated with higher risks of major depression, bipolar disorder, and severe mood symptoms, whereas adequate daytime light is linked to reduced incidence and better subjective well-being [98]. These associations are not simply reflections of sleep duration, and they remain significant after adjustment for sleep, suggesting a direct contribution of abnormal light input to affective pathology.

Abnormal light exposure is also closely linked with anxiety-related phenotypes. Clinical data indicate that individuals exposed to > 10 lx at night show higher anxiety scores, and prolonged exposure to short wavelength light throughout the day correlates with elevated Hospital Anxiety and Depression Scale (HADS) anxiety scores [99]. Animal studies further demonstrate that acute, mistimed bright light activates melanopsin-dependent ipRGC inputs to the central amygdala, triggering corticosterone release and producing anxiety-like behavior [53]. These responses may have evolved as adaptive vigilance mechanisms but become pathological when photic misalignment is chronic.

The link between abnormal light exposure and bipolar disorder (BD) is particularly striking, given the strong seasonal pattern of the illness. Rapid shifts in daylight length appear to destabilize mood: increasing light in early spring is associated with peaks in manic episodes, whereas shortened photoperiods in late autumn correspond to higher rates of depressive episodes [100, 101]. Disrupted circadian signaling amplifies this vulnerability through secondary effects on immune activation, endocrine rhythms, and adult neurogenesis. At the molecular level, PER3 length polymorphisms, known to influence acute light responsiveness, including melatonin suppression and alertness, modulate individual susceptibility to these seasonal mood shifts and shape the clinical course of BD [102].

Proposed Mechanistic Links Between Light, Mood Regulation, and Myopia

Neurotransmitter Imbalance

Abnormal lighting activates ipRGCs-driven non-visual circuits, inducing anxiety- and depression-like states [85] through limbic and hypothalamic pathways. These affective disturbances lead to central neurotransmitter disequilibrium, involving dopamine (DA), γ-aminobutyric acid (GABA), serotonin (5-HT), and melatonin (MT). Importantly, these same neurotransmitter systems also regulate ocular growth locally within the retina and sclera. Thus, emotional dysregulation can propagate to the eye through shared molecular pathways (Table 3, Fig. 1).

Table 3.

Shared molecular pathways implicated in light exposure, mood regulation, and refractive development

Molecule	Role in refractive regulation	Role in mood regulation	Mechanism	References (DOI)
Dopamine	Inhibits myopia (light increases retinal DA, limiting axial elongation)	Enhances positive mood (light activates mesolimbic DA reward circuits)	Retino-circadian pathway (DA mediates light signals regulating ocular growth); Reward pathway (light activates the midbrain dopaminergic system to improve mood)	[35, 103]
Melatonin	Promotes myopia (darkness elevates melatonin, antagonizing DA’s anti-myopia effect)	Lowers mood stability (prolonged melatonin secretion during darkness causes SAD)	Circadian rhythm (melatonin conveys light–dark cycle; rhythm disruption affects both axial growth and mood)	[34, 115]
Serotonin (5-HT)	Involved in ocular growth regulation (retinal 5-HT rhythm affects eye development)	Enhances mood (light increases 5-HT, alleviates depression)	Circadian rhythm (5-HT is a precursor of melatonin; light affects both ocular and emotional systems through 5-HT signaling)	[103, 112]
Vitamin D	Suppresses myopia progression (outdoor light increases VitD, reduces scleral remodeling)	Improves mood (higher VitD associated with lower depression risk)	Light-endocrine pathway (UV induces VitD synthesis, influencing scleral metabolism and brain function)	[76, 103]

Fig. 1.

Neurotransmitter signaling pathways implicated in scleral remodeling and myopia development. Abnormal light exposure influences non-visual neural circuits via ipRGCs-mediated pathways and may disrupt circadian and mood-related regulation. Such alterations can lead to imbalances in melatonin, dopamine, GABA, and serotonin, which in turn modulate retinal and scleral signaling involved in the onset and progression of myopia. 5-HT 5-hydroxytryptamine (serotonin), 5-HTR 5-HT receptor, AC adenylyl cyclase, Akt protein kinase B, Ca²⁺ calcium ion, cAMP cyclic adenosine monophosphate, cGMP cyclic guanosine monophosphate, CREB cAMP response element-binding protein, DA dopamine, D1R/D2R dopamine D1/D2 receptor, DAG diacylglycerol, GABA gamma-aminobutyric acid, GABAR GABA receptor, GAGs glycosaminoglycans, GTP guanosine triphosphate, IP3 inositol trisphosphate, MMP-2 matrix metalloproteinase-2, MT1/MT2 melatonin receptor 1/2, nNOS neuronal nitric oxide synthase, NO nitric oxide, PI3K phosphoinositide 3-kinase, PKA protein kinase A, PKC protein kinase C, TGF-β transforming growth factor-beta

DA is central to reward processing in the brain, and reduced DA tone is a hallmark of anxiety and depression [69]. Stress and negative affect decrease mesolimbic DA release, weakening motivation and reward responsiveness, whereas bright or blue-enriched light enhances dopaminergic activity in midbrain reward circuits and is associated with improved mood and reduced depressive symptoms [103]. At the same time, DA functions as a major “stop” signal for ocular growth: light-driven increases in retinal DA, conveyed through retino-circadian pathways and, in part, violet-light-sensitive photoreception, limit axial elongation and protect against myopia [35]. Abnormal or insufficient lighting reduces retinal DA release, weakening this inhibitory brake [104]. In multiple species, form deprivation or minus lens defocus markedly lowers retinal DA/DOPAC levels [105]. Increasing DA bioavailability, either through DA or L-DOPA injections, blocks myopic progression across guinea pigs, rabbits, and mice [106]. Because light stimulation can linearly increase dopamine release across four logarithmic units of light intensity [107], disturbances in emotional state or lighting conditions both funnel into the same dopaminergic pathway and bias the eye toward elongation.

GABA contributes to emotional regulation by shaping inhibitory control within limbic circuits [72]. Anxiety and depression are characterized by reduced GABAergic tone and altered receptor function, and converging MR spectroscopy and post-mortem data support a “GABAergic deficit” hypothesis of mood disorders [108]. In the retina, GABA regulates horizontal-cell and amacrine-cell signaling and interacts closely with DA pathways [109]. DA release is inhibited by GABA(A)/GABA(C) receptor activation but increased by their antagonists. GABA(C) receptor blockade strongly suppresses lens-induced myopia [110], reinforcing the concept that reducing inhibitory GABAergic drive can enhance retinal DA release and limit axial elongation [103]. Notably, 2-h bright light exposure (1500 lx) reverses form deprivation-induced enhanced GABAergic inhibition and upregulates D2 DA receptor activity, potentially mediating myopia progression antagonism [111], suggesting that light-dependent tuning of the GABA–DA balance in both retina and limbic circuits provides a shared pathway linking refractive development with vulnerability to mood disorders.

Serotonin (also known as 5-hydroxytryptamine, 5-HT) is a key mediator of stress, mood, and behavioral adaptation. Elevated 5-HT activity is frequently observed in anxiety-like and stress-related states. At the same time, deficiencies in forebrain serotonergic tone are strongly implicated in major depressive disorder, and light-based or pharmacological interventions that enhance 5-HT transmission can alleviate depressive symptoms [103, 112]. Because 5-HT is also the biochemical precursor of melatonin, its light-sensitive circadian rhythm provides a molecular link between mood regulation and the ocular response to the light–dark cycle. In the eye, lens-induced myopia [113] and flicker-light induced myopia [114] both show upregulated retinal 5-HT and increased 5-HT₂A-receptor expression. This phenomenon is also present in the form-deprivation model, accompanied by decreased norepinephrine and epinephrine levels. Mechanistic studies suggest that serotonin may activate the 5-HT2A receptor to enhance extracellular matrix remodeling in scleral cells, thereby accelerating axial elongation [114]. Increased 5-HT therefore acts as a molecular bridge between mood dysregulation and ocular growth: stress-related serotonergic activation enhances scleral remodeling and accelerates axial elongation.

MT, the hormone of darkness, is tightly linked to sleep quality and emotional stability [74]. Reduced MT secretion is associated with insomnia, depression, and heightened stress reactivity, whereas abnormally prolonged or phase-shifted nocturnal MT secretion has been implicated in seasonal affective disorder (SAD) [73, 115]. Nighttime abnormal light exposure causes dual pathological effects by inhibiting melatonin secretion: on one hand, reduced melatonin levels directly disrupt circadian rhythms, leading to decreased sleep quality [116], which has been shown to be bidirectionally associated with depressive-like behavior [117]; on the other hand, experimental and clinical data indicate that disruption of ocular melatonin rhythms and signaling is linked to altered diurnal patterns of axial length and enhanced susceptibility to myopic eye growth [34]. Insufficient sleep accelerates axial elongation, and “late-night” behaviors significantly increase the incidence and progression of myopia [118]. Thus, MT deficiency represents a shared molecular pathway through which nighttime light simultaneously worsens mood and increases myopia susceptibility.

Mood disorders may play multiple roles in the light-neurotransmitter imbalance–refractive error pathway, both as potential influencing factors and as comorbid outcomes: (1) mood disorders exacerbate neurotransmitter homeostasis imbalance: mood disorders (such as anxiety and depression) are typically accompanied by abnormal changes in neurotransmitters (e.g., dopamine, serotonin, GABA, melatonin) [119]. Mood disorders may amplify the effects of abnormal light exposure on refractive errors by exacerbating neurotransmitter imbalance. (2) Mood disorders affect light exposure behavior: depressed individuals tend to reduce outdoor activities, leading to insufficient light exposure [120]; anxious or insomniac individuals may be more inclined to use electronic devices at night, increasing nighttime light exposure [121]. (3) Mood disorders may be comorbid outcomes: abnormal light exposure and neurotransmitter imbalances may not only lead to refractive errors but also directly trigger mood disorders. Abnormal light exposure may induce depressive or anxiety-like behaviors by reducing dopamine and disrupting serotonin systems [74, 122]. Mood disorders may be a direct result of light-neurotransmitter imbalance pathways and form comorbidity with refractive errors.

Light-Driven Sympathetic Activation and HPA Axis Dysregulation

Abnormal light exposure may disrupt HPA axis homeostasis via sympathetic nervous system (SNS) activation, thereby regulating choroidal thickness and scleral matrix metalloproteinases (MMPs) to influence myopia progression [78, 123] (Fig. 2).

Fig. 2.

Dysregulation of the HPA axis and impaired neuroplasticity as potential mechanisms linking abnormal light exposure with refractive development. (1) HPA axis dysfunction: abnormal light exposure induces a dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, leading to abnormal steroid hormone release and sustained HPA autonomic activation. Steroid hormones are related to the MMPs–TIMP axis, which is closely associated with choroidal blood flow, and the MMPs–TIMP axis plays a critical role in the development of myopia. (2) Impaired neuroplasticity: abnormal light exposure inhibits synaptogenesis, dendritic spine formation, and neurogenesis through the BDNF/TrkB pathway, impairing neuroplasticity, which further links emotional disorders with myopia development. ACTH adrenocorticotropic hormone, BDNF brain-derived neurotrophic factor, CRH corticotropin-releasing hormone, HPA hypothalamic–pituitary–adrenal, MMPs matrix metalloproteinases, PVN paraventricular nucleus, SCN suprachiasmatic nucleus, TIMP tissue inhibitor of metalloproteinases, TrkB tropomyosin receptor kinase B

The SCN, as the central circadian pacemaker, integrates photic input from ipRGCs and coordinates cortisol rhythms by regulating corticotropin-releasing hormone and arginine vasopressin release through the PVN and dorsomedial hypothalamus, which subsequently drive pituitary ACTH secretion and adrenal glucocorticoid production [124, 125]. Glucocorticoid concentrations exhibit a typical rhythm, peaking in the morning and dipping at night [126]. When light exposure occurs at biologically inappropriate circadian phases, this coordination becomes disrupted. Experimental studies show that nocturnal or early morning light (even at relatively modest intensities) can elevate cortisol, whereas the same light delivered during daytime has little effect [127]. This time-dependent vulnerability suggests that mistimed light can induce prolonged SCN-HPA axis sympathetic activation, accompanied by glucocorticoid dysregulation.

HPA axis activation-induced autonomic imbalance may influence myopia development by regulating choroidal blood flow. Sustained sympathetic hyperactivity or reduced parasympathetic tone can cause vasoconstriction in the ophthalmic artery, and its branches in the optic nerve, iris, ciliary body, choroid, and sclera, as well as changes in non-vascular smooth muscle tone in the choroid [128]. Alterations in choroidal blood flow and non-vascular smooth muscle tone may affect choroidal thickness [129]. Furthermore, choroidal thickness has been proposed as a biomarker for predicting future axial growth, with reduced choroidal thickness associated with myopia development [130].

Glucocorticoids secreted by the HPA axis may mediate scleral extracellular matrix remodeling through MMP-TIMP imbalances. Various steroid hormones are known to regulate MMPs, and estrogen has been shown to upregulate MMP-2 and MMP-9 in both mice and humans [131, 132], with MMP-2 overexpression confirmed to participate in scleral remodeling during myopia pathology [133]. Animal experiments have shown that hydrocortisone treatment enhances axial elongation, myopia progression, and scleral thinning, while also upregulating MMP-2 expression, downregulating TIMP-2 expression, and increasing plasma E2 levels, suggesting that HPA axis activation may promote myopia progression by disrupting scleral matrix metabolism [134].

Neuronal Plasticity

Neuronal plasticity enables the brain to adjust to environmental changes through neurogenesis and structural remodeling. Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are key molecular indicators of this process, and both exhibit robust circadian oscillations. In rats, hippocampal BDNF/TrkB mRNA levels fluctuate markedly across the 24-h cycle, with peak-to-trough differences ranging from 3.5- to 17.5-fold [135], demonstrating the tight coupling between light–dark cycles and neuroplasticity.

Disruptions in light exposure patterns significantly impair this plasticity. Hippocampal BDNF levels following continuous light or circadian phase-shifting, accompanied by deficits in learning, memory, and affective behavior [33, 110–112, 136]. Structural changes are also evident: circadian disruption reduces dendritic length and complexity in prefrontal cortical neurons, coinciding with anxiety-like and cognitive impairments [114]. Specific lighting paradigms differentially modulate BDNF-related pathways. Continuous darkness suppresses both spatial memory and rhythmic BDNF/TrkB expression [137], whereas continuous light dampens BDNF/ERK activity and evokes fear-related behaviors in chicks [115]. Even physiologically timed bright light produces sex-dependent modulation of BDNF in limbic circuits, altering BDNF or TrkB expression in CA1 or basolateral amygdala depending on sex [116, 117]. These findings collectively show that abnormal or mistimed lighting weakens plasticity-supporting circuits that are also critical for emotional stability.

Altered neuroplasticity may also influence refractive development. Clinical studies demonstrate that aqueous humor BDNF levels are significantly reduced in patients with high myopia, and lower BDNF concentrations correlate with greater axial length [138], suggesting that neurotrophin availability is linked to ocular growth control. Thus BDNF/TrkB pathways participate in retinal and scleral remodeling, reductions in neurotrophic support, whether driven by light-induced mood disturbances, circadian disruption, or stress-related limbic dysregulation, may weaken neuroprotective signaling within ocular tissues [137]. Such deficits could shift the balance of scleral extracellular matrix turnover and choroidal responsiveness toward a proelongation state, thereby contributing to myopic progression [138].

Immune Homeostasis

Disruption of light rhythms alters the immune system at multiple levels, and this immune imbalance provides an additional biological pathway linking mood disturbances with myopic progression. Under normal conditions, circadian oscillators tightly regulate immune functions, including cytokine secretion, phagocytosis, inflammatory resolution, and pattern-recognition signaling helping maintain baseline immune homeostasis [118–120]. When light rhythms are disturbed, this clock–immune coupling deteriorates, leading to elevated pro-inflammatory cytokines such as TNF-α and altered immune cell activation patterns [118].

These immune changes feed back onto the brain and contribute to mood disturbances. Circadian disruption and sleep fragmentation activate microglia and enhance astrocytic phagocytosis [121], both of which are central mechanisms in anxiety- and depression-related neuroinflammation [122]. This neuroimmune activation amplifies HPA-axis drive, reinforcing prolonged sympathetic activation that further destabilizes mood-related regulation and peripheral immune balance. Through this loop, abnormal light exposure simultaneously affects affective states and systemic immunity.

Immune dysregulation is increasingly recognized as relevant to refractive development. Clinical cohorts show higher rates of myopia in immune-related diseases: children with juvenile idiopathic arthritis exhibit significantly elevated myopia prevalence [123], and acute-onset myopia has been reported in systemic lupus erythematosus [124]. Ocular allergic inflammation also confers risk; children with allergic conjunctivitis show a more than two-fold increase in myopia incidence [125]. Mendelian randomization and observational datasets further link elevated IL-2 and IL-2ra levels with higher myopia risk [126], implying that inflammatory tone modulates ocular growth signaling. Animal evidence provides mechanistic support. In form-deprivation models, pro-inflammatory activation via LPS or peptidoglycan accelerates myopic progression, upregulating c-Fos, NF-κB, IL-6, and TNF-α, whereas cyclosporine A suppresses these pathways and slows axial elongation [126]. These findings highlight that inflammatory cascades alter scleral remodeling and choroidal signaling, thereby influencing refractive outcomes.

Light-induced mood disturbances further strengthen this immune ocular connection. CCL2, a chemokine implicated in anxiety and depressive disorders [127–129], is simultaneously elevated in the aqueous humor of patients with high myopia and correlates with the severity of myopic maculopathy [130, 131]. Clinical and experimental data demonstrate that high myopia and associated visual input changes upregulate CCL2 in both the eye and brain, leading to monocyte/macrophage infiltration, disruption of blood–eye and blood–brain barriers, and worsening neuroinflammatory and ocular inflammatory states [67]. Genetic deletion or pharmacologic neutralization of CCL2 reverses both the anxiety-like behaviors and the inflammatory ocular changes, confirming CCL2 as a shared mediator between emotional dysregulation and myopic pathology.

Moreover, mechanistic studies further confirmed that visual stimuli in high myopia induce increased CCL2 expression in the eye, promoting inflammatory cell infiltration and barrier dysfunction, and are accompanied by upregulation of a broader panel of inflammatory mediators (such as TNF-α, IL-1β, IL-6, IL-8, MCP-1/CCL2, MMP-2, and complement components) as well as activation of retinal microglia/macrophages, which together drive extracellular matrix remodeling and blood–retinal/blood–ocular barrier breakdown [139–141]. Lack of CCL2 or use of CCL2 neutralizing antibodies significantly alleviated these pathological changes and reduced anxiety-like behavior [67]. These findings suggest that CCL2-mediated inflammatory responses are not only an essential mechanism linking high myopia with anxiety but also a key factor in the impact of light-induced mood disorders on myopia progression. Therefore, CCL2 and related inflammatory pathways may serve as potential targets for intervening in light-induced mood disorders and their myopia complications. In conclusion, light rhythm alterations may participate in myopia development by influencing immune system homeostasis (Fig. 3).

Fig. 3.

Immune dysregulation as a shared mechanism linking circadian disruption, emotion-related pathways, and myopia development. Disrupted light–dark cycles can induce circadian misalignment and heightened pro-inflammatory signaling, leading to altered cytokine levels (e.g., IL-6, TNF-α) that modulate both emotional regulation and autonomic balance. These immune-mediated changes may subsequently influence retinal and scleral remodeling processes and contribute to refractive development. CCL2 C–C motif chemokine ligand 2, CsA cyclosporin A, IL-6 interleukin-6, LPS lipopolysaccharide, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, PG prostaglandin, TNF-α tumor necrosis factor-alpha, c-Fos cellular proto-oncogene Fos

Future Interventions and Challenges

Light exposure influences non-visual functions such as circadian rhythm and emotional regulation via the visual pathway [3], and also has a profound impact on the onset and progression of myopia [142]. Randomized controlled trials have shown that behavioral interventions, such as encouraging parents to engage children in outdoor activities, can significantly slow the progression of myopia in children. Moreover, even after the intervention ends, the effects are often sustained [143]. In addition to simple reminders, using wearable devices to continuously monitor children's eye behaviors, outdoor activity times, and other indicators, while providing real-time feedback, has proven more advantageous in improving poor behavior habits and controlling myopia progression [144].

In recent years, research on how light exposure influences emotions through non-visual pathways and indirectly impacts refractive development has gradually become a hot topic in interdisciplinary fields. With the integration of photobiology and neuroscience, studies have begun to reveal that light signals mediated by ipRGCs can establish potential links between emotional disorders and refractive development through multiple pathways, including neurotransmitter imbalance, immune homeostasis disruption, HPA axis dysfunction, and impaired neuroplasticity. This discovery offers a new perspective on understanding the mechanisms behind the high incidence of myopia and comorbid emotional disorders in adolescents, and it also opens new avenues for myopia prevention strategies based on light environment optimization.

We look forward to collaborative approaches that consider both emotional disturbances and myopia. These efforts will not only focus on extending outdoor activity time or increasing light intensity but may evolve toward more refined, evidence-informed approaches to managing light exposure. In the future, physiology-informed recommendations for natural light exposure may be explored based on factors such as a child’s circadian-related mood characteristics and degree of myopia. For example, morning bright-light treatment (10,000 lx for 30 min) has demonstrated efficacy in SAD [70], illustrating how specific light parameters may modulate mood-related pathways.

However, several challenges remain. First, photic signaling in non-visual circuits exhibits strong temporal and spatial specificity, yet the detailed regulatory mechanisms are not fully understood. Second, evidence linking light-induced immune changes, such as alterations in IL-6 or TNF-α, to scleral remodeling or choroidal blood flow is derived largely from animal studies, with limited validation in humans. Third, the relationship between HPA-axis activation and axial elongation remains debated. Addressing these gaps will be essential for translating mechanistic insights into evidence-based and clinically meaningful light-exposure strategies.

Conclusions

Light exerts broad regulatory effects on circadian physiology, mood states, and ocular growth, mediated by the integration of visual and non-visual photic pathways. Emerging evidence indicates that signals processed by intrinsically photosensitive retinal ganglion cells interface with central circuits governing emotional regulation, autonomic balance, immune activity, and HPA axis function. These interconnected pathways provide a mechanistic basis for understanding why mood disturbances and refractive changes often coexist and how alterations in light exposure may jointly influence emotional well-being and refractive development. By synthesizing current findings, this review outlines a conceptual light–eye–brain framework that highlights the relevance of cross-system interactions in mood and myopia research.

Despite growing interest in these relationships, many mechanistic links remain incompletely defined. Key questions include how specific photic environments shape central and ocular signaling, how individual susceptibility modifies these responses, and to what extent emotional states contribute to refractive outcomes across development. Addressing these gaps will require coordinated efforts across ophthalmology, neuroscience, psychophysiology, and photobiology. As evidence accumulates, an integrated understanding of these pathways may guide the development of evidence-based approaches to optimizing light exposure that support both visual health and psychological well-being.

Author Contributions

Cong-Ying Li: Conceptualization, Investigation, Collection data, Methodology, Visualization, Validation, Writing-original draft; Qian-qian Song: Collection data, Visualization, Writing-original draft; Wen-Jun Xu & Xin-Yu Li & Ying Huang: Collection data; Ning-Li Wang: Conceptualization, Visualization; Shi-Ming Li: Conceptualization, Visualization, Funding acquisition, Writing-review & editing, Project administration, Supervision, Resources. All authors read and approved the final version of the manuscript.

Funding

This work was supported by grants of National Natural Science Foundation of China (82471113, 82071000), The Excellent Youth Talents Program of Capital Medical University (A2307), and the Beijing Natural Science Foundation (L248023) to Shi-Ming Li. These funding sources supported the conceptualization and preparation of this review. The Rapid Service Fee was funded by the authors.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Ningli Wang is an Editorial Board member of Ophthalmology and Therapy. Ning-Li Wang was not involved in the selection of peer reviewers for this manuscript nor in any of the subsequent editorial decisions. Cong-Ying Li, Qian-Qian Song, Wen-Jun Xu, Xin-Yu Li, Ying Huang, and Shi-Ming Li have nothing to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.