Background: To settle the fundamentals of a numerical procedure that relates retinal ganglion-cell density and threshold sensitivity in the visual field. The sensitivity of a generated retina and visual pathways to virtual stimuli are simulated, and the conditions required to reproduce glaucoma-type defects both in the optic-nerve head (ONH) and visual fields are explored.
Methods: A definition of selected structural elements of the optic pathways is a requisite to a translation of clinical knowledge to computer programs for visual field exploration. The program is able to generate a database of normalized visual fields. The relationship between the number of extant receptive fields and threshold sensitivity is plotted for background sensitivity and corresponding automated perimetry. A solution in two planes to the 3D distribution of axons in the ONH is proposed. Visual fields with induced damage in the optic disc are comparable in pattern and quantity to glaucomatous records.
Results: The two-level simulation of the ONH facilitates the analysis of optic-cup/retinal defects. We can generate the virtual optic pathways tailored to the age and morphology of the patient’s eye, and it is possible to reproduce glaucomatous damage by “reverse engineering” engineering. The virtual cortical model renders a quantitative relationship between visual defect and neural damage.
Conclusions: A two-level computing of the retina/optic nerve facilitates the analysis of neuroretinal defects and can be incorporated to automatic perimeters to facilitate visual field analysis.
Abstract: Animals promote their survival by avoiding rapidly approaching objects that indicate threats. It is believed that looming cues are detected by retinal ganglion cells (RGCs) that project to the superior colliculus (SC). However, the exact type of RGC that transmits looming-related signals remains unclear. Here we identify a specific transient type of RGCs that controls mouse looming-evoked defensive response by sending axonal collaterals to the dorsal raphe nucleus (DRN) and SC. Looming signals transmitted by DRN-projecting RGCs activate DRN GABA neurons and in turn inhibit serotonin neurons. Moreover, optogenetically stimulating serotonin neurons reduces looming-evoked defensive behaviors. Thus, a dedicated population of RGCs detects rapidly approaching visual threats and their input to the DRN controls a serotonergic self-gating mechanism that regulates innate defensive responses. Our study provides new insights into how DRN and SC work in concert to extract and translate visual threats into defensive behavioral responses.
Abstract: Axon regeneration capacity declines in mature retinal ganglion cells (RGCs). While a number of transcription factors and signaling molecules have been implicated to the loss of regenerative potential of RGC axon, their upstream regulators are unclear. We investigated the association between developmental decline of RGC regenerative potential and age-related changes in microRNA (miRNA) expression and showed that loss of axon regenerative potential can be partially restored by upregulating miR-19a in RGCs in vitro and in vivo. Regulating miRNA expression represents a new potential therapeutic approach to resuscitate age-related loss of axon growth ability.
Abstract: Pathological retinal neovascularization is the hallmark of primary blinding diseases across all age groups, yet surprisingly little is known about the causative factors. These diseases include diabetic retinopathy and retinopathy of prematurity where progressive decay of retinal vasculature yields zones of neural ischemia. These avascular zones and the hypoxic neurons and glia that reside in them are the source of pro-angiogenic factors that mediate destructive pre-retinal angiogenesis. Central neurons such as retinal ganglion cells (RGCs), which are directly apposed to degenerating vasculature in ischemic retinopathies, require stable metabolic supply for proper function. However, we unexpectedly found that RGCs are resilient to hypoxia/ischemia and a generally compromised metabolic supply and instead of degenerating, trigger protective mechanisms of cellular senescence. Paradoxically, while potentially favoring neuronal survival, the senescent state of RGCs is incompatible with vascular repair as they adopt a senescence-associated secretory phenotype (SASP) that provokes release of a secretome of inflammatory cytokines that drives paracrine senescence and further exacerbates pathological angiogenesis. The mechanisms that lead to retinal cellular senescence and dormancy as well as the therapeutic potential of targeting these pathways will be discussed.
Abstract: Hereditary, metabolic and toxic optic neuropathies cause bilateral, central vision loss and therefore can result in severe impairment in visual function. Accurate, early diagnosis is critical, as nutritional and toxic optic neuropathies may be reversible if identified early, and diagnosis of hereditary optic neuropathies can prevent unnecessary invasive workup, provide prognostic information, and allow for effective genetic counseling. Optical coherence tomography (OCT) is a valuable tool that aids in the diagnosis and prognostication of optic neuropathies as it allows for quantification of changes in the retinal ganglion cells (RGCs) and retinal nerve fiber layer (RNFL) over time. We review the characteristic clinical presentations of hereditary, metabolic and toxic optic neuropathies, with an emphasis on OCT findings.
Background: Axonal degeneration caused by damage to the optic nerve can result in a gradual death of retinal ganglion cells (RGC), leading to irreversible vision loss. An example of such diseases in humans includes optic nerve degeneration in glaucoma. Glaucoma is characterized by the progressive degeneration of the optic nerve and the loss of RGCs that can lead to loss of vision. The different animal models developed to mimic glaucomatous neurodegeneration, all result in RGC loss consequent optic nerve damage.
Methods: The present article summarizes experimental procedures and analytical methodologies related to one experimental model of glaucoma induced by optic nerve crush (ONC). Point-by-point protocol is reported with a particular focus on the critical point for the realization of the model. Moreover, information on the electroretinogram procedure and the immunohistochemical detection of RGCs are described to evaluate the morpho-functional consequences of ONC.
Discussion: Although the model of ONC is improperly assimilated to glaucoma, then the ONC model simulates most of the signaling responses consequent to RGC apoptosis as observed in models of experimental glaucoma. In this respect, the ONC model may be essential to elucidate the cellular and molecular mechanisms of glaucomatous diseases and may help to develop novel neuroprotective therapies.
Background: The complexity of the glaucoma pathophysiology is directly reflected on its experimental modeling for studies about pathological mechanisms and treatment approaches. Currently, a variety of in vivo models are available for the study of glaucoma, although they do not reach an exact reproduction of all aspects characterizing the human glaucoma. Therefore, a comprehensive view of disease onset, progression and treatment efficacy can only be obtained by the integration of outcomes deriving from different experimental models.
Methods: The present article summary experimental procedures and analytical methodologies related with two experimental models of glaucoma belonging to the classes of induced intraocular pressure (IOP)-elevation and genetic models, methyl cellulose (MCE)-induced ocular hypertension and DBA/2J mouse strain. Point-by-point protocols are reported with a particular focus on the critical point for the realization of each model. Moreover, typical strength and drawbacks of each model are described in order to critically handle the outcomes deriving from each model.
Discussion: This paper provides a guideline for the realization, analysis and expected outcomes of two models allowing to study IOP-driven neurodegenerative mechanisms rather than IOP-independent neurodegeneration. The complementary information from these models could enhance the analysis of glaucomatous phenomena from different points of view potentiating the basic and translational study of glaucoma.
