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The vascular and the nervous systems share similarities in addition to their complex role in providing oxygen and nutrients to all cells. Both are highly branched networks that frequently grow close to one another during development. Vascular patterning and neural wiring share families of guidance cues and receptors. Most recently, this relationship has been investigated in terms of peripheral nervous system (PNS) regeneration, where nerves and blood vessels often run in parallel so endothelial cells guide the formation of the Büngner bands which support axonal regeneration. Here, we characterized the vascular response in regenerative models of the central and peripheral nervous system. After sciatic nerve crush, followed by axon regeneration, there was a significant increase in the blood vessel density 7 days after injury. In addition, the optic nerve crush model was used to evaluate intrinsic regenerative potential activated with a combined treatment that stimulated retinal ganglion cells (RGCs) regrowth. We observed that a 2-fold change in the total number of blood vessels occurred 7 days after optic nerve crush compared to the uncrushed nerve. The difference increased up to a 2.7-fold change 2 weeks after the crush. Interestingly, we did not observe differences in the total number of blood vessels 2 weeks after crush, compared to animals that had received combined treatment for regeneration and controls. Therefore, the vascular characterization showed that the increase in vascular density was not related to the efficiency of both peripheral and central axonal regeneration.

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Ouabain is a classic Na+K+ATPase ligand and it has been described to have neuroprotective effects on neurons and glial cells at nanomolar concentrations. In the present work, the neuroprotective and immunomodulatory potential of ouabain was evaluated in neonatal rat retinal cells using an optic nerve axotomy model in vitro. After axotomy, cultured retinal cells were treated with ouabain (3 nM) at different periods. The levels of important inflammatory receptors in the retina such as TNFR1/2, TLR4, and CD14 were analyzed. We observed that TNFR1, TLR4, and CD14 were decreased in all tested periods (15 min, 45 min, 24 h, and 48 h). On the other hand, TNFR2 was increased after 24 h, suggesting an anti-inflammatory potential for ouabain. Moreover, we showed that ouabain also decreased Iba-1 (microglial marker) density. Subsequently, analyses of retrograde labeling of retinal ganglion cells (RGC) were performed after 48 h and showed that ouabain-induced RGC survival depends on autophagy. Using an autophagy inhibitor (3-methyladenine), we observed a complete blockage of the ouabain effect. Western blot analyses showed that ouabain increases the levels of autophagy proteins (LC3 and Beclin-1) coupled to p-CREB transcription factor and leads to autophagosome formation. Additionally, we found that the ratio of cleaved/pro-caspase-3 did not change after ouabain treatment; however, p-JNK density was enhanced. Also, ouabain decreased reactive oxygen species production immediately after axotomy. Taken together, our results suggest that ouabain controls neuroinflammation in the retina following optic nerve axotomy and promotes RGC neuroprotection through activation of the autophagy pathway.

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BACKGROUND: Ultrasound of the optic nerve sheath diameter (ONSD) has been used as a non-invasive and cost-effective bedside alternative to invasive intracranial pressure (ICP) monitoring. However, ONSD time-lapse behavior in intracranial hypertension (ICH) and its relief by means of either saline infusion or surgery are still unknown. The objective of this study was to correlate intracranial pressure (ICP) and ultrasonography of the optic nerve sheath (ONS) in an experimental animal model of ICH and determine the interval needed for ONSD to return to baseline levels. METHODS: An experimental study was conducted on 30 pigs. ONSD was evaluated by ultrasound at different ICPs generated by intracranial balloon inflation, saline infusion, and balloon deflation, and measured using an intraventricular catheter. RESULTS: All variables obtained by ONS ultrasonography such as left, right, and average ONSD (AON) were statistically significant to estimate the ICP value. ONSD changed immediately after balloon inflation and returned to baseline after an average delay of 30 min after balloon deflation (p = 0.016). No statistical significance was observed in the ICP and ONSD values with hypertonic saline infusion. In this swine model, ICP and ONSD showed linear correlation and ICP could be estimated using the formula: -80.5 + 238.2 × AON. CONCLUSION: In the present study, ultrasound to measure ONSD showed a linear correlation with ICP, although a short delay in returning to baseline levels was observed in the case of sudden ICH relief.

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BACKGROUND: Retina and/or optic nerve injury may cause irreversible blindness, due to degeneration of retinal ganglion cells. We and others have previously shown that the intravitreal injection of mesenchymal stem cells (MSCs) protects injured retinal ganglion cells and stimulates their regeneration after optic nerve injury, but the long-term effects of this therapy are still unknown. METHODS: We injected rat MSC (rMSC) intravitreally in adult (3-5 months) Lister Hooded rats of either sex after optic nerve crush. Retinal ganglion cell survival, axonal regeneration, and reconnection were analyzed 60 and 240 days after crush by immunohistochemistry for Tuj1, anterograde labeling with cholera-toxin B and by immunohistochemistry for nerve growth factor-induced gene A (NGFI-A, driven by light stimulation) in the superior colliculus after a cycle of light deprivation-stimulation. Visual behaviors (optokinetic reflex, looming response, and preference for dark) were analyzed 70 days after crush. RESULTS: rMSC treatment doubled the number of surviving retinal ganglion cells, preferentially of a larger subtype, and of axons regenerating up to 0.5 mm. Some axons regenerated to the lateral geniculate nucleus and superior colliculus. NGFI-A+ cells were doubled in rMSC-treated animals 60 days after crush, but equivalent to vehicle-injected animals 240 days after crush, suggesting that newly formed synapses degenerated. Animals did not recover visual behaviors. CONCLUSIONS: We conclude that rMSC-induced neuroprotection is sustained at longer time points. Although rMSCs promoted long-term neuroprotection and long-distance axon regeneration, the reconnection of retinal ganglion cells with their targets was transitory, indicating that they need additional stimuli to make stable reconnections.

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The regenerative capacity of CNS tracts has ever been a great hurdle to regenerative medicine. Although recent studies have described strategies to stimulate retinal ganglion cells (RGCs) to regenerate axons through the optic nerve, it still remains to be elucidated how these therapies modulate the inhibitory environment of CNS. Thus, the present work investigated the environmental content of the repulsive axon guidance cues, such as Sema3D and its receptors, myelin debris, and astrogliosis, within the regenerating optic nerve of mice submitted to intraocular inflammation + cAMP combined to conditional deletion of PTEN in RGC after optic nerve crush. We show here that treatment was able to promote axonal regeneration through the optic nerve and reach visual targets at twelve weeks after injury. The Regenerating group presented reduced MBP levels, increased microglia/macrophage number, and reduced astrocyte reactivity and CSPG content following optic nerve injury. In addition, Sema3D content and its receptors are reduced in the Regenerating group. Together, our results provide, for the first time, evidence that several regenerative repulsive signals are reduced in regenerating optic nerve fibers following a combined therapy. Therefore, the treatment used made the CNS microenvironment more permissive to regeneration.

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Looming-sensitive neurons (LSNs) are motion-sensitive neurons tuned for detecting imminent collision. Their main characteristic is the selectivity to looming (a 2D representation of an object approach), rather than to receding stimuli. We studied a set of LSNs by performing surface extracellular recordings in the optic nerve of Neohelice granulata crabs, and characterized their response against computer-generated visual stimuli with different combinations of moving edges, highlighting different components of the optical flow. In addition to their selectivity to looming stimuli, we characterized other properties of these neurons, such as low directionality; reduced response to sustained excitement; and an inhibition phenomenon in response to visual stimuli with dense optical flow of expansion, contraction, and translation. To analyze the spatio-temporal processing of these LSNs, we proposed a biologically plausible computational model which was inspired by previous computational models of the locust lobula giant motion detector (LGMD) neuron. The videos seen by the animal during electrophysiological experiments were applied as an input to the model which produced a satisfactory fit to the measured responses, suggesting that the computation performed by LSNs in a decapod crustacean appears to be based on similar physiological processing previously described for the LGMD in insects.

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PURPOSE: To investigate the effects of the Valsalva maneuver (VM) on optic disc morphology, choroidal thickness, and anterior chamber parameters. METHODS: This prospective observational study included 60 eyes of 60 healthy subjects. The anterior chamber parameters, including central corneal thickness (CCT), anterior chamber depth (ACD), anterior chamber angle (ACA), anterior chamber volume (ACV), pupil diameter (PD), axial length (AL), subfoveal and peripapillary choroidal thickness, optic disc parameters, and intraocular pressure (IOP), were measured at rest and during VM. RESULTS: VM did not have any significant influence on AL, subfoveal and peripapillary choroidal thickness, optic disc area, rim area, cup area, cup-to-disc area ratio, vertical cup-to-disc ratio, rim volume, cup volume, and nerve head volume measurements (for all; p >0.05). IOP and PD significantly increased during VM (for both; p <0.001). VM significantly decreased CCT, ACD, ACA, and ACV values (for all; p <0.001). Moreover, the optic nerve cup volume decreased and the horizontal cup-to-disc ratio significantly increased during VM (for both; p <0.05). CONCLUSIONS: VM may cause transient changes in IOP, optic disc morphology, and anterior chamber parameters.

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ABSTRACT Purpose: To investigate the effects of the Valsalva maneuver (VM) on optic disc morphology, choroidal thickness, and anterior chamber parameters. Methods: This prospective observational study included 60 eyes of 60 healthy subjects. The anterior chamber parameters, including central corneal thickness (CCT), anterior chamber depth (ACD), anterior chamber angle (ACA), anterior chamber volume (ACV), pupil diameter (PD), axial length (AL), subfoveal and peripapillary choroidal thickness, optic disc parameters, and intraocular pressure (IOP), were measured at rest and during VM. Results: VM did not have any significant influence on AL, subfoveal and peripapillary choroidal thickness, optic disc area, rim area, cup area, cup-to-disc area ratio, vertical cup-to-disc ratio, rim volume, cup volume, and nerve head volume measurements (for all; p >0.05). IOP and PD significantly increased during VM (for both; p <0.001). VM significantly decreased CCT, ACD, ACA, and ACV values (for all; p <0.001). Moreover, the optic nerve cup volume decreased and the horizontal cup-to-disc ratio significantly increased during VM (for both; p <0.05). Conclusions: VM may cause transient changes in IOP, optic disc morphology, and anterior chamber parameters.

RESUMO Objetivo: Investigar os efeitos da manobra de Valsalva (VM) sobre a morfologia do disco óptico, a espessura da coroide e parâmetros câmara anterior. Métodos: Estudo observacional, prospectivo incluiu 60 olhos de 60 indivíduos saudáveis. Os parâmetros da câmara anterior, incluindo da espessura central da córnea (CCT), profundidade da câmara anterior (ACD), ângulo da câmara anterior (ACA), volume de câmara anterior (ACV), diâmetro da pupila (PD), comprimento axial (AL), espessura da coroide subfoveal e peripapilar, parâmetros de disco óptico e pressão intraocular (IOP) foram medidos em repouso e durante VM. Resultados: A VM não apresentou influência significativa em AL, espessura da coroide subfoveal e peripapilar, área de disco óptico, área da rima neural, área da escavação, relação da área escavação-disco, a relação vertical escavação-disco, volume da rima neural, volume da escavação, medidas de volume cabeça do nervo (para todos; p >0,05). IOP e PD aumentaram significativamente durante VM (para ambos; p <0,001). A VM diminuiu os valores CCT, ACD, ACA e ACV significativamente (para todos; p <0,001). Além disso, o volume da escavação do nervo óptico diminuiu e a razão horizontal escavação-disco aumentou significativamente durante VM (para ambos; p <0,05). Conclusões: A VM pode causar alterações transitórias na pressão intraocular, na morfologia do disco óptico e em parâmetros câmara anterior.

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This study was designed to investigate the progressive effect of tactile stimulation in the cytoarchitecture of the optic nerve of normal rats during early postnatal development. We used 36 male pups which were randomly assigned to either the tactile-stimulated group (TS-stimulation for 3 min, once a day, from postnatal day (P) 1 to 32) or the non-tactile-stimulated (NTS) group. Morphological analysis were performed to evaluate the alterations caused by tactile stimulation, and morphometric analysis were carried out to determine whether the observed changes in optic nerve cytoarchitecture were significantly different between groups and at three different ages (P18, P22, and P32), thereby covering the entire progression of development of the optic nerve from its start to its completion. The rats of both groups presented similar increase in body weight. The morphometric analysis revealed no difference in the astrocyte density between age-matched groups; however, the oligodendrocyte density of TS group was higher compared to the NTS at P22, and P32, but not at P18. The optic nerve of TS group showed an increase of blood vessels and a reduction of damage fiber density when compared to the age-matched pups of NTS. Taken together, these findings support the view that tactile stimulation, an enriching experience, can positively affects the neuroanatomy of the brain, modifying its cellular components by progressive morphological and morphometric changes.

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