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Journal of Controlled Release :... Jun 2024Retinal diseases are the leading cause of blindness, resulting in irreversible degeneration and death of retinal neurons. One such cell type, the retinal ganglion cell... (Review)
Review
Retinal diseases are the leading cause of blindness, resulting in irreversible degeneration and death of retinal neurons. One such cell type, the retinal ganglion cell (RGC), is responsible for connecting the retina to the rest of the brain through its axons that make up the optic nerve and is the primary cell lost in glaucoma and traumatic optic neuropathy. To date, different therapeutic strategies have been investigated to protect RGCs from death and preserve vision, yet currently available strategies are restricted to treating neuron loss by reducing intraocular pressure. A major barrier identified by these studies is drug delivery to RGCs, which is in large part due to drug stability, short duration time at target, low delivery efficiency, and undesired off-target effects. Therefore, a delivery system to deal with these problems is needed to ensure maximum benefit from the candidate therapeutic material. Extracellular vesicles (EV), nanocarriers released by all cells, are lipid membranes encapsulating RNAs, proteins, and lipids. As they naturally shuttle these encapsulated compounds between cells for communicative purposes, they may be exploitable and offer opportunities to overcome hurdles in retinal drug delivery, including drug stability, drug molecular weight, barriers in the retina, and drug adverse effects. Here, we summarize the potential of an EV drug delivery system, discussing their superiorities and potential application to target RGCs.
PubMed: 38880332
DOI: 10.1016/j.jconrel.2024.06.029 -
Biomedical Optics Express Jun 2024Accurate segmentation of retinal layers in optical coherence tomography (OCT) images is critical for assessing diseases that affect the optic nerve, but existing...
Accurate segmentation of retinal layers in optical coherence tomography (OCT) images is critical for assessing diseases that affect the optic nerve, but existing automated algorithms often fail when pathology causes irregular layer topology, such as extreme thinning of the ganglion cell-inner plexiform layer (GCIPL). Deep LOGISMOS, a hybrid approach that combines the strengths of deep learning and 3D graph search to overcome their limitations, was developed to improve the accuracy, robustness and generalizability of retinal layer segmentation. The method was trained on 124 OCT volumes from both eyes of 31 non-arteritic anterior ischemic optic neuropathy (NAION) patients and tested on three cross-sectional datasets with available reference tracings: Test-NAION (40 volumes from both eyes of 20 NAION subjects), Test-G (29 volumes from 29 glaucoma subjects/eyes), and Test-JHU (35 volumes from 21 multiple sclerosis and 14 control subjects/eyes) and one longitudinal dataset without reference tracings: Test-G-L (155 volumes from 15 glaucoma patients/eyes). In the three test datasets with reference tracings (Test-NAION, Test-G, and Test-JHU), Deep LOGISMOS achieved very high Dice similarity coefficients (%) on GCIPL: 89.97±3.59, 90.63±2.56, and 94.06±1.76, respectively. In the same context, Deep LOGISMOS outperformed the Iowa reference algorithms by improving the Dice score by 17.5, 5.4, and 7.5, and also surpassed the deep learning framework nnU-Net with improvements of 4.4, 3.7, and 1.0. For the 15 severe glaucoma eyes with marked GCIPL thinning (Test-G-L), it demonstrated reliable regional GCIPL thickness measurement over five years. The proposed Deep LOGISMOS approach has potential to enhance precise quantification of retinal structures, aiding diagnosis and treatment management of optic nerve diseases.
PubMed: 38867777
DOI: 10.1364/BOE.516045 -
Cell Reports Jun 2024In addition to its role in vision, light also serves non-image-forming visual functions. Despite clinical evidence suggesting the antipruritic effects of bright light...
In addition to its role in vision, light also serves non-image-forming visual functions. Despite clinical evidence suggesting the antipruritic effects of bright light treatment, the circuit mechanisms underlying the effects of light on itch-related behaviors remain poorly understood. In this study, we demonstrate that bright light treatment reduces itch-related behaviors in mice through a visual circuit related to the lateral parabrachial nucleus (LPBN). Specifically, a subset of retinal ganglion cells (RGCs) innervates GABAergic neurons in the ventral lateral geniculate nucleus and intergeniculate leaflet (vLGN/IGL), which subsequently inhibit CaMKIIα neurons in the LPBN. Activation of both the vLGN/IGL-projecting RGCs and the vLGN/IGL-to-LPBN projections is sufficient to reduce itch-related behaviors induced by various pruritogens. Importantly, we demonstrate that the antipruritic effects of bright light treatment rely on the activation of the retina-vLGN/IGL-LPBN pathway. Collectively, our findings elucidate a visual circuit related to the LPBN that underlies the antipruritic effects of bright light treatment.
Topics: Animals; Mice; Parabrachial Nucleus; Pruritus; Light; Retinal Ganglion Cells; Visual Pathways; Mice, Inbred C57BL; Male; Antipruritics; GABAergic Neurons; Behavior, Animal; Calcium-Calmodulin-Dependent Protein Kinase Type 2
PubMed: 38865246
DOI: 10.1016/j.celrep.2024.114356 -
Cirugia Y Cirujanos 2024The objective of the study is to compare the optic coherence tomography (OCT) parameters of the healthy and affected sides of patients with idiopathic sudden...
OBJECTIVE
The objective of the study is to compare the optic coherence tomography (OCT) parameters of the healthy and affected sides of patients with idiopathic sudden sensorineural hearing loss (ISSNHL) and to investigate the relationships between these and the improvement in hearing levels.
METHODS
A bilateral eye evaluation of patients diagnosed with ISSNHL was performed with OCT. The ganglion cell complex (GCC) and retina nerve fiber layer (RNFL) thickness values were recorded and the differences between the two eyes were examined.
RESULTS
An evaluation was made of 39 patients with a mean age of 44.82 ± 14.90 years. The RNFL thickness of the eyes was determined to be mean 89.87 ± 3.65 µm on the affected side and 103.87 ± 3.98 µm on the healthy control side (p = 0.0001). The mean GCC was determined to be mean 90.46 ± 3.49 µm on the affected side and 103.77 ± 3.96 µm on the healthy control side (p = 0.0001).
CONCLUSIONS
A statistically significant difference was observed between the healthy and affected eyes of patients with ISSNHL with respect to mean GCC and mean RNFL thickness. OCT could be a useful technique for measuring this neural degeneration.
Topics: Humans; Tomography, Optical Coherence; Adult; Female; Male; Nerve Fibers; Middle Aged; Axons; Retinal Ganglion Cells; Hearing Loss, Sensorineural; Hearing Loss, Sudden; Young Adult
PubMed: 38862104
DOI: 10.24875/CIRU.23000609 -
Pharmacological Research Jul 2024Melatonin, a versatile hormone produced by the pineal gland, has garnered considerable scientific interest due to its diverse functions. In the eye, melatonin regulates... (Review)
Review
Melatonin, a versatile hormone produced by the pineal gland, has garnered considerable scientific interest due to its diverse functions. In the eye, melatonin regulates a variety of key processes like inhibiting angiogenesis by reducing vascular endothelial growth factor levels and protecting the blood-retinal barrier (BRB) integrity by enhancing tight junction proteins and pericyte coverage. Melatonin also maintains cell health by modulating autophagy via the Sirt1/mTOR pathways, reduces inflammation, promotes antioxidant enzyme activity, and regulates intraocular pressure fluctuations. Additionally, melatonin protects retinal ganglion cells by modulating aging and inflammatory pathways. Understanding melatonin's multifaceted functions in ocular health could expand the knowledge of ocular pathogenesis, and shed new light on therapeutic approaches in ocular diseases. In this review, we summarize the current evidence of ocular functions and therapeutic potential of melatonin and describe its roles in angiogenesis, BRB integrity maintenance, and modulation of various eye diseases, which leads to a conclusion that melatonin holds promising treatment potential for a wide range of ocular health conditions.
Topics: Melatonin; Humans; Animals; Eye Diseases; Eye; Blood-Retinal Barrier
PubMed: 38862072
DOI: 10.1016/j.phrs.2024.107253 -
Ophthalmic Research Jun 2024This study aimed to investigate the characteristics of retinal vascular degeneration and the expression of vessel-related Claudin (CLD) proteins in retinal degeneration...
INTRODUCTION
This study aimed to investigate the characteristics of retinal vascular degeneration and the expression of vessel-related Claudin (CLD) proteins in retinal degeneration mouse ( Pde6βrd1/rd1 rd1 mouse).
METHODS
Retinas from wild-type (WT) mice and rd1 mice at postnatal day 3 (P3), P5, P8, P11, P13, P15, P18, and P21 were collected. Immunofluorescence staining was used to assess the retinal vascular plexus, cell proliferation, CLD expression, and retinal ganglion cells (RGCs). The distribution of retinal superficial and deep vessels was determined by Isolectin B4 fluorescence staining of retinal flat mounts and frozen sections. Hematoxylin and eosin staining and terminal deoxynucleotidyl transferase-mediated dNTP nick end labeling were used to investigate retinal histological degeneration and apoptosis in rd1 mice respectively. Quantitative real-time PCR and western blot were used to measure the expression of vessel-related CLD-1, 2, 3 and CLD-5, vascular endothelial growth factor A (VEGFA), and vascular endothelial growth factor receptor 2 (VEGFR2) in the retinas.
RESULTS
Compared to the WT mice, the rd1 mice displayed delayed but completed progressive development in the retinal superficial vascular plexuses (SVP) and deep vascular plexuses (DVP). In the rd1 mice, the thickness of retinal layers gradually decreased and the retinas underwent progressive atrophy and degeneration. The deterioration got worse at the late developmental stage. The declined vessel density of SVP and DVP correlated with the decreased thickness of the full and inner parts of the retina and the reduced number of RGCs. DVP degeneration and the thinning of the outer nuclear layer occurred an obvious reduction at P15. The expression levels of CLD-1, CLD-2, CLD-3, CLD-5, VEGFA, and VEGFR2 decreased and were consistently lower in the rd1 mice than in WT mice since P15.
CONCLUSION
Rd1 mice exhibited progressive vascular degeneration of retinal SVP and DVP, the thinning and atrophy of retinal ONL and RGC, and the downregulation of vessel-related CLD proteins during the late developmental period. Thus, the rd1 mouse is a useful model of not only retinal neuro-degeneration but also retinal vascular degeneration.
PubMed: 38857592
DOI: 10.1159/000539605 -
ELife Jun 2024Understanding how different neuronal types connect and communicate is critical to interpreting brain function and behavior. However, it has remained a formidable...
Understanding how different neuronal types connect and communicate is critical to interpreting brain function and behavior. However, it has remained a formidable challenge to decipher the genetic underpinnings that dictate the specific connections formed between neuronal types. To address this, we propose a novel bilinear modeling approach that leverages the architecture similar to that of recommendation systems. Our model transforms the gene expressions of presynaptic and postsynaptic neuronal types, obtained from single-cell transcriptomics, into a covariance matrix. The objective is to construct this covariance matrix that closely mirrors a connectivity matrix, derived from connectomic data, reflecting the known anatomical connections between these neuronal types. When tested on a dataset of , our model achieved a performance comparable to, if slightly better than, the previously proposed spatial connectome model (SCM) in reconstructing electrical synaptic connectivity based on gene expressions. Through a comparative analysis, our model not only captured all genetic interactions identified by the SCM but also inferred additional ones. Applied to a mouse retinal neuronal dataset, the bilinear model successfully recapitulated recognized connectivity motifs between bipolar cells and retinal ganglion cells, and provided interpretable insights into genetic interactions shaping the connectivity. Specifically, it identified unique genetic signatures associated with different connectivity motifs, including genes important to cell-cell adhesion and synapse formation, highlighting their role in orchestrating specific synaptic connections between these neurons. Our work establishes an innovative computational strategy for decoding the genetic programming of neuronal type connectivity. It not only sets a new benchmark for single-cell transcriptomic analysis of synaptic connections but also paves the way for mechanistic studies of neural circuit assembly and genetic manipulation of circuit wiring.
Topics: Animals; Caenorhabditis elegans; Connectome; Mice; Neurons; Single-Cell Analysis; Models, Neurological
PubMed: 38857169
DOI: 10.7554/eLife.91532 -
BioRxiv : the Preprint Server For... Jun 2024The ability of neurons to sense and respond to damage is fundamental to homeostasis and nervous system repair. For some cell types, notably dorsal root ganglia (DRG) and...
The ability of neurons to sense and respond to damage is fundamental to homeostasis and nervous system repair. For some cell types, notably dorsal root ganglia (DRG) and retinal ganglion cells (RGCs), extensive profiling has revealed a large transcriptional response to axon injury that determines survival and regenerative outcomes. In contrast, the injury response of most supraspinal cell types, whose limited regeneration constrains recovery from spinal injury, is mostly unknown. Here we employed single-nuclei sequencing in mice to profile the transcriptional responses of diverse supraspinal cell types to spinal injury. Surprisingly, thoracic spinal injury triggered only modest changes in gene expression across all populations, including corticospinal tract (CST) neurons. Moreover, CST neurons also responded minimally to cervical injury but much more strongly to intracortical axotomy, including upregulation of numerous regeneration and apoptosis-related transcripts shared with injured DRG and RGC neurons. Thus, the muted response of CST neuron to spinal injury is linked to the injury's distal location, rather than intrinsic cellular characteristics. More broadly, these findings indicate that a central challenge for enhancing regeneration after a spinal injury is the limited sensing of distant injuries and the subsequent modest baseline neuronal response.
PubMed: 38854133
DOI: 10.1101/2024.05.27.596075 -
BioRxiv : the Preprint Server For... Jun 2024High resolution retinal imaging paired with intravitreal injection of a viral vector coding for the calcium indicator GCaMP has enabled visualization of activity...
High resolution retinal imaging paired with intravitreal injection of a viral vector coding for the calcium indicator GCaMP has enabled visualization of activity dependent calcium changes in retinal ganglion cells (RGCs) at single cell resolution in the living eye. The inner limiting membrane (ILM) is a barrier for viral vectors, restricting transduction to a ring of RGCs serving the fovea in both humans and non-human primates (NHP). We evaluate peeling the ILM prior to intravitreal injection as a strategy to expand calcium imaging beyond the fovea in the NHP eye in vivo. Five Macaca fascicularis eyes (age 3-10y; n=3 individuals; 2M, 1F) underwent vitrectomy and 5 to 6-disc diameter ILM peel centered on the fovea prior to intravitreal delivery of 7m8:SNCG:GCaMP8s. Calcium responses from RGCs were recorded using a fluorescence adaptive optics scanning laser ophthalmoscope. In all eyes GCaMP was expressed throughout the peeled area, representing a mean 8-fold enlargement in area of expression relative to a control eye. Calcium recordings were obtained up to 11 degrees from the foveal center. RGC responses were comparable to the fellow control eye and showed no significant decrease over the 6 months post ILM peel, suggesting that RGC function was not compromised by the surgical procedure. In addition, we demonstrate that activity can be recorded directly from the retinal nerve fiber layer. This approach will be valuable for a range of applications in visual neuroscience including pre-clinical evaluation of retinal function, detecting vision loss, and assessing the impact of therapeutic interventions.
PubMed: 38854047
DOI: 10.1101/2024.06.02.597041 -
BioRxiv : the Preprint Server For... Jun 2024Glaucoma is a neurodegenerative disease that leads to the death of retinal ganglion cells (RGCs). A growing body of literature suggests a role for neuroinflammation in...
Glaucoma is a neurodegenerative disease that leads to the death of retinal ganglion cells (RGCs). A growing body of literature suggests a role for neuroinflammation in RGC death after glaucoma-relevant insults. For instance, it was shown that deficiency of three proinflammatory cytokines, complement component 1, subcomponent q ( ), interleukin 1 alpha ( ), and tumor necrosis factor ( ), resulted in near complete protection of RGCs after two glaucoma-relevant insults, optic nerve injury and ocular hypertension. While TNF and C1Q have been extensively investigated in glaucoma-relevant model systems, the role of IL1A in RGC is not as well defined. Thus, we investigated the direct neurotoxicity of IL1A on RGCs in vivo. Intravitreal injection of IL1A did not result in RGC death at either 14 days or 12 weeks after insult. Consistent with previous studies, TNF injection did not result in significant RGC loss at 14 days but did after 12 weeks. Interestingly, IL1A+TNF resulted in a relatively rapid RGC death, driving significant RGC loss two weeks after injection. JUN activation and SARM1 have been implicated in RGC death in glaucoma and after cytokine insult. Using mice deficient in JUN or SARM1, we show RGC loss after IL1A+TNF insult is JUN-independent and SARM1-dependent. Furthermore, RNA-seq analysis showed that RGC death by SARM1 deficiency does not stop the neuroinflammatory response to IL1A+TNF. These findings indicate that IL1A can potentiate TNF-induced RGC death after combined insult is likely driven by a SARM1-dependent RGC intrinsic signaling pathway.
PubMed: 38854045
DOI: 10.1101/2024.05.28.596328