Mechanisms of the release of anterogradely transported neurotrophin-3 from axon terminals

Neurotrophins have profound effects on synaptic function and structure. They can be derived from presynaptic, as well as postsynaptic, sites. To date, it has not been possible to measure the release of neurotrophins from axon terminals in intact tissue. We implemented a novel, extremely sensitive assay for the release and transfer of anterogradely transported neurotrophin-3 (NT-3) from a presynaptic to a postsynaptic location that uses synaptosomal fractionation after introduction of radiolabeled NT-3 into the retinotectal projection of chick embryos. Release of the anterogradely transported NT-3 in intact tissue was assessed by measuring the amount remaining in synaptosomal preparations after treatment of whole tecta with pharmacological agents. Use of this assay reveals that release of NT-3 from axon terminals is increased by depolarization, calcium influx via N-type calcium channels, and cAMP analogs, and release is most profoundly increased by excitation with kainic acid or mobilization of calcium from intracellular stores. NT-3 release depends on extracellular sodium, CaM kinase II activity, and requires intact microtubules and microfilaments. Dantrolene inhibits the high potassium-induced release of NT-3, indicating that release of calcium from intracellular stores is required. Tetanus toxin also inhibits NT-3 release, suggesting that intact synaptobrevin or synaptobrevin-like molecules are required for exocytosis. Ultrastructural autoradiography and immunolabel indicate that NT-3 is packaged in presumptive large dense-core vesicles. These data show that release of NT-3 from axon terminals depends on multiple regulatory proteins and ions, including the mobilization of local calcium. The data provide insight in the mechanisms of anterograde neurotrophins as synaptic modulators

Eye Movements, Strabismus, Amblyopia, and Neuro-Ophthalmology Differences in Gene Expression between Strabismic and Normal Human Extraocular Muscles

PURPOSE. Strabismic extraocular muscles (EOMs) differ from normal EOMs in structural and functional properties, but the gene expression profile of these two types of EOM has not been examined. Differences in gene expression may inform about causes and effects of the strabismic condition in humans. METHODS. EOM samples were obtained during corrective surgery from patients with horizontal strabismus and from deceased organ donors with normal EOMs. Microarrays and quantitative PCR identified significantly up-and down-regulated genes in EOM samples. Analysis was performed on probe sets with more than 3-fold differential expression between normal and strabismic samples, with an adjusted P value of 0.05. RESULTS. Microarray analysis showed that 604 genes in these samples had significantly different expression. Expression predominantly was upregulated in genes involved in extracellular matrix structure, and down-regulated in genes related to contractility. Expression of genes associated with signaling, calcium handling, mitochondria function and biogenesis, and energy homeostasis also was significantly different between normal and strabismic EOM. Skeletal muscle PCR array identified 22 (25%) of 87 muscle-specific genes that were significantly down-regulated in strabismic EOMs; none was significantly upregulated. CONCLUSIONS. Differences in gene expression between strabismic and normal human EOMs point to a relevant contribution of the peripheral oculomotor system to the strabismic condition. Decreases in expression of contractility genes and increases of extracellular matrix-associated genes indicate imbalances in EOM structure. We conclude that gene regulation of proteins fundamental to contractile mechanics and extracellular matrix structure is involved in pathogenesis and/or consequences of strabismus, suggesting potential novel therapeutic targets. (Invest Ophthalmol Vis Sci. 2012;53:5168-5177

Neurotrophins in the developing and regenerating visual system

The neurotrophins NGF, BDNF, NT-3 and NT-4 have a wide range of effects in the development and regeneration of neural circuits in the visual system of vertebrates. This review focuses on the localization and functions of neurotrophins in the retina, lateral geniculate nucleus, suprachiasmatic nucleus, superior colliculus/optic tectum, and isthmic nuclei. Research of the past 20 years has shown that neurotrophins and their receptors are localized in numerous visual centers from the retina to the visual cortex, and that neurotrophins influence proliferation, neurite outgrowth and survival of cells in the visual system in vitro and in vivo. A relationship between electrical activity and neurotrophic functions has been established in several visual centers in the CNS, and neurotrophins have been implicated in synaptic plasticity in the visual cortex. Besides functions of neurotrophins as retrograde, target-derived trophic factors, recent data indicate that neurotrophins may have anterograde, afferent as well as local, paracrine actions in the retina, optic nerve and the visual cortex. Some neurotrophins appear to regulate proliferation and survival of glial cells in the optic pathways. Neurotrophins increase the survival of retinal ganglion cells after axotomy or ischemia and they promote the regeneration of retinal ganglion cell axons in some vertebrates. Neurotrophins also rescue photoreceptors from degeneration. These findings implicate the neurotrophins not only as important regulators during development, but also as potential therapeutic agents in degenerative retinal diseases and after optic nerve injury

Prevalence of Olfactory Dysfunction with the Omicron Variant of SARS-CoV-2: A Systematic Review and Meta-Analysis

The omicron variant is thought to cause less olfactory dysfunction than previous variants of SARS-CoV-2, but the reported prevalence differs greatly between populations and studies. Our systematic review and meta-analysis provide information regarding regional differences in prevalence as well as an estimate of the global prevalence of olfactory dysfunction based on 62 studies reporting information on 626,035 patients infected with the omicron variant. Our estimate of the omicron-induced prevalence of olfactory dysfunction in populations of European ancestry is 11.7%, while it is significantly lower in all other populations, ranging between 1.9% and 4.9%. When ethnic differences and population sizes are considered, the global prevalence of omicron-induced olfactory dysfunction in adults is estimated to be 3.7%. Omicron’s effect on olfaction is twofold to tenfold lower than that of the alpha or delta variants according to previous meta-analyses and our analysis of studies that directly compared the prevalence of olfactory dysfunction between omicron and previous variants. The profile of the prevalence differences between ethnicities mirrors the results of a recent genome-wide association study that connected a gene locus encoding an odorant-metabolizing enzyme, UDP glycosyltransferase, to the extent of COVID-19-related loss of smell. Our analysis is consistent with the hypothesis that this enzyme contributes to the observed population differences

Dorsomedial telencephalon of lungfishes: A pallial or subpallial structure? criteria based on histology, connectivity, and histochemistry

The dorsomedial telencephalon of lepidosirenid lungfishes has been interpreted in two divergent ways: earlier investigators regarded it as a subpallial (septal) structure; more recently, it has been reinterpreted as the medial pallium (hippocampus). To resolve this question, we identified parameters that are conclusive in their association with either the medial pallium or the septum in anamniotes. The present study examines the position of ependymal thickenings and the distribution of acetylcholinesterase (AchE) in the cerebral hemispheres of the African lungfish Protopterus, the Australian lungfish Neoceratodus, and the amphibian species Xenopusand Ambystoma. In addition, projections from the hypothalamus (paraventricular organ) to the telencephalon are investigated in Protopterus. Ependymal specializations are located dorsally and ventrally in the lateral ventricles of amphibians, but laterally and medially in lungfishes. In Protopterus, the paraventricular organ projects to the medial telencephalic hemisphere, but not to the dorsal roof. High levels of AchE are present in restricted neuropil regions of the medial hemisphere and in the ventral and ventrolateral telencephalon, but they are lacking in the dorsal roof. Intensely AchE‐stained neuronal cell bodies are located in the ventral telencephalon (rostrally) and the dorsomedial telencephalon (at mid‐level). In Neoceratodus, AchE staining is pronounced in the septal area, but absent in the pallium. The terminal nerve proper lacks AchE stain in Protopterus; nerve fibers of the preoptic nerve are AchE‐positive in both lungfish species. In Xenopus, AchE staining of fibers and terminals is restricted to the subpallium (medial septum, tuberculum olfactorium, striatum, nucleus accumbens, and medial amygdala); cell bodies are AchE positive in parts of the subpallium and rostral pallium. Comparison of cytological, histochemical, and “connectional” parameters substantiates the interpretation that the dorsomedial telencephalon of lungfishes represents a subpallial, but not a “medial pallial” structure. The dorsomedial part of the lepidosirenid telencephalon corresponds to the septum in the most plesiomorphic living lungfish, Neoceratodus forsteri, but it differs considerably from the dorsomedial telencephalon (medial pallium) in amphibians

The olfactory nerve is not a likely route to brain infection in COVID-19: a critical review of data from humans and animal models

International audienceOne of the most frequent symptoms of COVID-19 is the loss of smell and taste. Based on the lack of expression of the virus entry proteins in olfactory receptor neurons, it was originally assumed that the new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) does not infect olfactory neurons. Recent studies have reported otherwise, opening the possibility that the virus can directly infect the brain by traveling along the olfactory nerve. Multiple animal models have been employed to assess mechanisms and routes of brain infection of SARS-CoV-2, often with conflicting results. We here review the current evidence for an olfactory route to brain infection and conclude that the case for infection of olfactory neurons is weak, based on animal and human studies. Consistent brain infection after SARS-CoV-2 inoculation in mouse models is only seen when the virus entry proteins are expressed abnormally, and the timeline and progression of rare neuro-invasion in these and in other animal models points to alternative routes to the brain, other than along the olfactory projections. COVID-19 patients can be assured that loss of smell does not necessarily mean that the SARS-CoV-2 virus has gained access to and has infected their brains

Prediction of junior faculty success in biomedical research: comparison of metrics and effects of mentoring programs

Measuring and predicting the success of junior faculty is of considerable interest to faculty, academic institutions, funding agencies and faculty development and mentoring programs. Various metrics have been proposed to evaluate and predict research success and impact, such as the h-index, and modifications of this index, but they have not been evaluated and validated side-by-side in a rigorous empirical study. Our study provides a retrospective analysis of how well bibliographic metrics and formulas (numbers of total, first-and co-authored papers in the PubMed database, numbers of papers in high-impact journals) would have predicted the success of biomedical investigators (n = 40) affiliated with the University of Nevada, Reno, prior to, and after completion of significant mentoring and research support (through funded Centers of Biomedical Research Excellence, COBREs), or lack thereof (unfunded COBREs), in 2000-2014. The h-index and similar indices had little prognostic value. Publishing as mid-or even first author in only one high-impact journal was poorly correlated with future success. Remarkably, junior investigators with >6 first-author papers within 10 years were significantly (p < 0.0001) more likely (93%) to succeed than those with <= 6 first-author papers (4%), regardless of the journal's impact factor. The benefit of COBRE-support increased the success rate of junior faculty approximately 3-fold, from 15% to 47%. Our work defines a previously neglected set of metrics that predicted the success of junior faculty with high fidelity-thus defining the pool of faculty that will benefit the most from faculty development programs such as COBREs