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Experience regulates synapse formation and function across sensory circuits. How inhibitory synapses in the mammalian retina are sculpted by visual cues remains unclear. By use of a sensory deprivation paradigm, we find that visual cues regulate maturation of two GABA synapse types (GABA A and GABA C receptor synapses), localized across the axon terminals of rod bipolar cells (RBCs)-second-order retinal neurons integral to the night-vision circuit. Lack of visual cues causes GABA A synapses at RBC terminals to retain an immature receptor configuration with slower response profiles and prevents receptor recruitment at GABA C synapses. Additionally, the organizing protein for both these GABA synapses, LRRTM4, is not clustered at dark-reared RBC synapses. Ultrastructurally, the total number of ribbon-output/inhibitory-input synapses across RBC terminals remains unaltered by sensory deprivation, although ribbon synapse output sites are misarranged when the circuit develops without visual cues. Intrinsic electrophysiological properties of RBCs and expression of chloride transporters across RBC terminals are additionally altered by sensory deprivation. Introduction to normal 12-h light-dark housing conditions facilitates maturation of dark-reared RBC GABA synapses and restoration of intrinsic RBC properties, unveiling a new element of light-dependent retinal cellular and synaptic plasticity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Corneal nerves comprise the densest sensory network in the body. Dysfunction of the corneal cold sensitive neurons (CSN) is implicated in ophthalmic disorders, including Dry Eye Disease, the most common ocular surface disorder. The preservative Benzalkonium chloride (BAK) and the mydriatic agent Phenylephrine hydrochloride (PHE) are considered to be inactive at the level of the CSNs. The purpose of this study is to test the impacts of continuous exposures to BAK or PHE at their clinically used concentrations on corneal nerve structure and function., Methods: In vivo extracellular electrophysiology of the rat trigeminal ganglion was used to monitor CSN functional response to stimuli mimicking physiological states and stressors of the cornea. Corneal nerve structure was evaluated by immunostaining., Results: Among the tested stimuli, cold probe receptive field stimulation and hyperosmolar stress were the most sensitive methods of detecting activity changes. CSN activity was attenuated after 30 min exposure to either PHE or BAK. After an hour-long washout period, BAK-treated neurons failed to recover activity while PHE-treated neurons showed signs of functional recovery. Intraepithelial nerve density was reduced and nerve fragmentation was increased in BAK-treated corneas, while PHE exposure left corneal nerves structurally intact., Conclusions: Our study suggests that prolonged ocular instillations of BAK or PHE alter CSN activity through two different processes - irreversible neuronal damage in the case of BAK vs. reversible attenuation in the case of PHE., Competing Interests: Declaration of competing interest The authors have no conflicts to disclose relevant to the production and publication of this work., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Previously we found two types of corneal neurons that we hypothesized to play an important role in tearing. One type is called low threshold-cold sensitive plus dry sensitive (LT-CS + DS), and the other is termed high threshold-cold sensitive plus dry sensitive (HT-CS + DS). The present study examined critical stimuli influencing the activity of these neurons to elucidate environmental factors that may trigger this ocular reflex., Methods: Single corneal neurons were extracellularly recorded from the trigeminal ganglia in response to ocular stimuli that mimic environmental conditions one encounters in daily life. They included an ocular desiccation and slight air currents and were presented while simultaneously monitoring the ocular surface temperatures (OST) in rats., Results: The results showed that the changes in steady state (SS) activity of the neurons closely followed the changes in SS OST: during the sustained ocular desiccation, neural firing displayed numerous small sudden increases in activities ("spiking"); these "spiking" activities of LT-CS + DS neurons were replicated by a minute air current that induced slight ocular surface cooling of approximately 0.2-0.1°C; and the responses of HT-CS + DS neurons showed an inconsistent relationship to the changes in SS OST or exhibited little evidence for "spiking" activities., Conclusions: These results suggest that LT-CS + DS neurons play a role in the afferent trigger of tearing as we face the environment, exposing the cornea to prevailing air currents that produce a slight cooling of the ocular surface. By contrast, HT-CS + DS neurons may serve to protect the eyes from extreme dryness by eliciting nociception-evoked tearing when the OST or osmolarity of tears becomes injurious.

It is widely accepted that the mechanisms for transducing sensory information reside in the nerve terminals. Occasionally, however, studies have appeared demonstrating that similar mechanisms may exist in the axon to which these terminals are connected. We examined this issue in the cornea, where nerve terminals in the epithelial cell layers are easily accessible for debridement, leaving the underlying stromal (axonal) nerves undisturbed. In isoflurane-anesthetized rats, we recorded extracellularly from single trigeminal ganglion neurons innervating the cornea that are excited by ocular dryness and cooling: low-threshold (<2°C cooling) and high-threshold (>2°C) cold-sensitive plus dry-sensitive neurons playing possible roles in tearing and ocular pain. We found that the responses in both types of neurons to dryness, wetness, and menthol stimuli were effectively abolished by the debridement, indicating that their transduction mechanisms lie in the nerve terminals. However, some responses to the cold, heat, and hyperosmolar stimuli in low-threshold cold-sensitive plus dry-sensitive neurons still remained. Surprisingly, the responses to heat in approximately half of the neurons were augmented after the debridement. We were also able to evoke these residual responses and follow the trajectory of the stromal nerves, which we subsequently confirmed histologically. The residual responses always disappeared when the stromal nerves were cut at the limbus, suggesting that the additional transduction mechanisms for these sensory modalities originated most likely in stromal nerves. The functional significance of these residual and enhanced responses from stromal nerves may be related to the abnormal sensations observed in ocular disease. NEW & NOTEWORTHY In addition to the traditional view that the sensory transduction mechanisms exist in the nerve terminals, we report here that the proximal axons (stromal nerves in the cornea from which these nerve terminals originate) may also be capable of transducing sensory information. We arrived at this conclusion by removing the epithelial cell layers of the cornea in which the nerve terminals reside but leaving the underlying stromal nerves undisturbed., (Copyright © 2017 the American Physiological Society.)

Purpose: A population of corneal neurons in rats preferentially sense and monitor the hyperosmolar conditions of tears when the tears begin to evaporate during corneal dryness. The present study exploited this ability in an effort to estimate tear osmolarities by comparing the responses to corneal dryness to their responses to hyperosmolar stimuli., Methods: Extracellular recordings were performed from single neurons in the trigeminal ganglia innervating the corneas of rats. To determine the extent to which the corneal neurons' responses to drying of the cornea were induced via the activation by hyperosmolar stimuli, we assessed the responses to ocular instillation of 500 and 600 mOsm/L, and a graded series of hyperosmolar stimuli ranging from 350 to 1000 mOsm/L., Results: The magnitudes of the responses to drying of the cornea were matched almost exactly to those induced by the ocular instillation of the 600 mOsm/L stimuli but not the 500 mOsm/L solutions. The response magnitudes to a graded series of hyperosmolar solutions were nearly linear from the 350 to the 600 mOsm/L stimuli, but reached a plateau or declined slightly thereafter., Conclusions: Our results demonstrate that the tear osmolarity in rats could reach 600 to 1000 mOsm/L during ocular dryness. Furthermore, a spontaneous eye blink could be generated at a tear osmolarity of approximately 400 mOsm/L if the blink is solely determined by hyperosmolar tears, but ocular surface cooling also can become a major factor if hyperosmolar tears occurring during ocular dryness lower the threshold of activation of the neurons.

Lacosamide is an anti-epileptic drug that is also used for the treatment of painful diabetic neuropathy acting through voltage-gated sodium channels. The aim of this work was to evaluate the effects of acute application of lacosamide on the electrical activity of corneal cold nerve terminals in lacrimo-deficient guinea pigs. Four weeks after unilateral surgical removal of the main lachrimal gland in guinea pigs, corneas were excised and superfused in vitro at 34°C for extracellular electrophysiological recording of nerve terminal impulse activity of cold thermosensitive nerve terminals. The characteristics of the spontaneous and the stimulus-evoked (cooling ramps from 34°C to 15°C) activity before and in presence of lacosamide 100µM and lidocaine 100µM were compared. Cold nerve terminals (n=34) recorded from dry eye corneas showed significantly enhanced spontaneous activity (8.0±1.1 vs. 5.2±0.7imp/s; P<0.05) and cold response (21.2±1.7 vs. 16.8±1.3imp/s; P<0.05) as well as reduced cold threshold (1.5±0.1 vs. 2.8±0.2 Δ°C; P<0.05) to cooling ramps compared to terminals (n=58) from control animals. Both lacosamide and lidocaine decreased spontaneous activity and peak response to cooling ramps significantly (P<0.05). Temperature threshold was increased by the addition of lidocaine (P<0.05) but not lacosamide (P>0.05) to the irrigation fluid. In summary, the application of lacosamide results in a significant decrease of the augmented spontaneous activity and responsiveness to cold of corneal sensory nerves from tear-deficient animals. Based on these promising results we speculate that lacosamide might be used to reduce the hyperexcitability of corneal cold receptors caused by prolonged ocular surface dryness due to hyposecretory or evaporative dry eye disease., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Dry eye disease (DED) affects >10% of the population worldwide, and it provokes an unpleasant sensation of ocular dryness, whose underlying neural mechanisms remain unknown. Removal of the main lachrymal gland in guinea pigs caused long-term reduction of basal tearing accompanied by changes in the architecture and density of subbasal corneal nerves and epithelial terminals. After 4 weeks, ongoing impulse activity and responses to cooling of corneal cold thermoreceptor endings were enhanced. Menthol (200 μM) first excited and then inactivated this augmented spontaneous and cold-evoked activity. Comparatively, corneal polymodal nociceptors of tear-deficient eyes remained silent and exhibited only a mild sensitization to acidic stimulation, whereas mechanonociceptors were not affected. Dryness-induced changes in peripheral cold thermoreceptor responsiveness developed in parallel with a progressive excitability enhancement of corneal cold trigeminal ganglion neurons, primarily due to an increase of sodium currents and a decrease of potassium currents. In corneal polymodal nociceptor neurons, sodium currents were enhanced whereas potassium currents remain unaltered. In healthy humans, exposure of the eye surface to menthol vapors or to cold air currents evoked unpleasant sensations accompanied by increased blinking frequency that we attributed to cold thermoreceptor stimulation. Notably, stimulation with menthol reduced the ongoing background discomfort of patients with DED, conceivably due to use-dependent inactivation of cold thermoreceptors. Together, these data indicate that cold thermoreceptors contribute importantly to the detection and signaling of ocular surface wetness, and develop under chronic eye dryness conditions an injury-evoked neuropathic firing that seems to underlie the unpleasant sensations experienced by patients with DED.

Purpose: In an effort to elucidate possible neural mechanisms underlying diminished tearing in dry eye disease, this study sought to determine if hyperosmolar tears, a ubiquitous sign of dry eye disease, produce functional changes in corneal nerve responses to drying of the cornea and if these changes correlate with alterations in corneal nerve morphology., Methods: In vivo extracellular electrophysiological recordings were performed in rat trigeminal ganglion neurons that innervated the cornea before, and up to 3 hours after, the ocular application of continuous hyperosmolar tears or artificial tears. In corollary experiments, immunohistochemical staining was performed to compare corneal nerve morphology in control and in eyes treated with hyperosmolar solutions., Results: Our previous studies identified a population of corneal afferents, dry-sensitive neurons that are strongly excited by corneal dessication ("dry response"), a response thought to trigger the lacrimation reflex. In the present study, we found that the dry responses of corneal dry-sensitive neurons were depressed or even completely abolished by hyperosmolar tears in a time- (30 minutes to 3 hours) and dose (450- to 1000-mOsm solutions)-dependent manner. Furthermore, eyes treated with hyperosmolar tears for 3 hours contained large numbers of morphologically abnormal (granular, fragmented, or prominently beaded) subbasal nerves that appeared to be undergoing degeneration., Conclusions: These results demonstrate that tear hyperosmolarity, considered to be a "core" mechanism of dry eye disease, significantly decreases physiological sensitivity and morphologic integrity of the corneal nerves important in tear production. These alterations might contribute to the diminished tearing seen clinically in dry eye patients.

The paper presents the results of a study of cases judged by the District Court in Piotrków Trybunalski in 2004, in which petitioners sought permanent work-disability benefits on grounds of cardiovascular diseases. The largest group of petitioners included those with hypertension, coronary disease and a history of myocardial infarction. The largest percentage of persons judged to be work-disabled were those having suffered a myocardial infarction, but this was true also for individuals with cardiomyopathies, as well as cardiac rhythm and conduction disturbances. Disorders judged to pose the least limitation on the ability to work encompassed non-specific pain in the thoracic cavity, and hypertension.