The neuropeptide Pth2 dynamically senses others via mechanosensation

This is the author accepted manuscript. The final version is available from nature Research via the DOI in this recordData availability: All data are provided in this paper or the accompanying Supplementary Information files. All sequencing data have been made available under the Sequence Read Archive BioProject PRJNA627056. Gene annotation was performed using the publicly available ENSEMBL database (https://www.ensembl.org/Danio_rerio/Info/Index). The Z-Brain atlas can be downloaded from https://github.com/owenrandlett/Z-Brain60. Gene expression data from Raj et al.23 are available under the Gene Expression Omnibus accession number GSE105010.Code availability: All relevant code is available under the public repository https://github.com/Anneser/SensingOthers/Species that depend on membership in social groups for survival exhibit changes in neuronal gene expression and behaviour when they face restricted social interactions or isolation1,2,3. Here we show that, across the lifespan of zebrafish (Danio rerio), social isolation specifically decreased the level of transcription of pth2, the gene that encodes the vertebrate-specific neuropeptide Pth2. However, 30 minutes of exposure to conspecifics was sufficient to initiate a significant rescue of pth2 transcript levels in previously isolated zebrafish. Transcription of pth2 exhibited bidirectional dynamics; following the acute isolation of socially reared fish, a rapid reduction in the levels of pth2 was observed. The expression of pth2 tracked not only the presence of other fish but also the density of the group. The sensory modality that controls the expression of pth2 was neither visual nor chemosensory in origin but instead was mechanical, induced by the movements of neighbouring fish. Chemical ablation of the mechanosensitive neuromast cells within the lateral line of fish prevented the rescue of pth2 levels that was induced by the social environment. In addition, mechanical perturbation of the water at frequencies similar to the movements of the zebrafish tail was sufficient to rescue the levels of pth2 in previously isolated fish. These data indicate a previously underappreciated role for the relatively unexplored neuropeptide Pth2 in both tracking and responding to the population density of the social environment of an animal.DFG CRC 1193Max Planck Societ

The effects of ocular magnification on Spectralis spectral domain optical coherence tomography scan length

Purpose The purpose of this study was to assess the effects of incorporating individual ocular biometry measures of corneal curvature, refractive error, and axial length on scan length obtained using Spectralis spectral domain optical coherence tomography (SD-OCT). Methods Two SD-OCT scans were acquired for 50 eyes of 50 healthy participants, first using the Spectralis default keratometry (K) setting followed by incorporating individual mean-K values. Resulting scan lengths were compared to predicted scan lengths produced by image simulation software, based on individual ocular biometry measures including axial length. Results Axial length varied from 21.41 to 29.04 mm. Spectralis SD-OCT scan lengths obtained with default-K ranged from 5.7 to 7.3 mm, and with mean-K from 5.6 to 7.6 mm. We report a stronger correlation of simulated scan lengths incorporating the subject’s mean-K value (ρ = 0.926, P < 0.0005) compared to Spectralis default settings (ρ = 0.663, P < 0.0005). Conclusions Ocular magnification appears to be better accounted for when individual mean-K values are incorporated into Spectralis SD-OCT scan acquisition versus using the device’s default-K setting. This must be considered when taking area measurements and lateral measurements parallel to the retinal surface

Repeatability of Foveal Measurements Using Spectralis Optical Coherence Tomography Segmentation Software

PURPOSE: To investigate repeatability and reproducibility of thickness of eight individual retinal layers at axial and lateral foveal locations, as well as foveal width, measured from Spectralis spectral domain optical coherence tomography (SD-OCT) scans using newly available retinal layer segmentation software. METHODS: High-resolution SD-OCT scans were acquired for 40 eyes of 40 young healthy volunteers. Two scans were obtained in a single visit for each participant. Using new Spectralis segmentation software, two investigators independently obtained thickness of each of eight individual retinal layers at 0°, 2° and 5° eccentricities nasal and temporal to foveal centre, as well as foveal width measurements. Bland-Altman Coefficient of Repeatability (CoR) was calculated for inter-investigator and inter-scan agreement of all retinal measurements. Spearman's ρ indicated correlation of manually located central retinal thickness (RT0) with automated minimum foveal thickness (MFT) measurements. In addition, we investigated nasal-temporal symmetry of individual retinal layer thickness within the foveal pit. RESULTS: Inter-scan CoR values ranged from 3.1μm for axial retinal nerve fibre layer thickness to 15.0μm for the ganglion cell layer at 5° eccentricity. Mean foveal width was 2550μm ± 322μm with a CoR of 13μm for inter-investigator and 40μm for inter-scan agreement. Correlation of RT0 and MFT was very good (ρ = 0.97, P 0.05); however this symmetry could not be found at 5° eccentricity. CONCLUSIONS: We demonstrate excellent repeatability and reproducibility of each of eight individual retinal layer thickness measurements within the fovea as well as foveal width using Spectralis SD-OCT segmentation software in a young, healthy cohort. Thickness of all individual retinal layers were symmetrical at 2°, but not at 5° eccentricity away from the fovea

Expanding the clinical phenotype of IARS2-related mitochondrial disease.

BACKGROUND: IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies. METHODS: Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis. RESULTS: Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein. CONCLUSIONS: This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia

Synaptic Plasticity and NO-cGMP-PKG Signaling Regulate Pre- and Postsynaptic Alterations at Rat Lateral Amygdala Synapses Following Fear Conditioning

In vertebrate models of synaptic plasticity, signaling via the putative “retrograde messenger” nitric oxide (NO) has been hypothesized to serve as a critical link between functional and structural alterations at pre- and postsynaptic sites. In the present study, we show that auditory Pavlovian fear conditioning is associated with significant and long-lasting increases in the expression of the postsynaptically-localized protein GluR1 and the presynaptically-localized proteins synaptophysin and synapsin in the lateral amygdala (LA) within 24 hrs following training. Further, we show that rats given intra-LA infusion of either the NR2B-selective antagonist Ifenprodil, the NOS inhibitor 7-Ni, or the PKG inhibitor Rp-8-Br-PET-cGMPS exhibit significant decreases in training-induced expression of GluR1, synaptophysin, and synapsin immunoreactivity in the LA, while those rats infused with the PKG activator 8-Br-cGMP exhibit a significant increase in these proteins in the LA. In contrast, rats given intra-LA infusion of the NO scavenger c-PTIO exhibit a significant decrease in synapsin and synaptophysin expression in the LA, but no significant impairment in the expression of GluR1. Finally, we show that intra-LA infusions of the ROCK inhibitor Y-27632 or the CaMKII inhibitor KN-93 impair training-induced expression of GluR1, synapsin, and synaptophysin in the LA. These findings suggest that the NO-cGMP-PKG, Rho/ROCK, and CaMKII signaling pathways regulate fear memory consolidation, in part, by promoting both pre- and post-synaptic alterations at LA synapses. They further suggest that synaptic plasticity in the LA during auditory fear conditioning promotes alterations at presynaptic sites via NO-driven “retrograde signaling”

Striatal Proteomic Analysis Suggests that First L-Dopa Dose Equates to Chronic Exposure

L-3,4-dihydroxypheylalanine (L-dopa)-induced dyskinesia represent a debilitating complication of therapy for Parkinson's disease (PD) that result from a progressive sensitization through repeated L-dopa exposures. The MPTP macaque model was used to study the proteome in dopamine-depleted striatum with and without subsequent acute and chronic L-dopa treatment using two-dimensional difference in-gel electrophoresis (2D-DIGE) and mass spectrometry. The present data suggest that the dopamine-depleted striatum is so sensitive to de novo L-dopa treatment that the first ever administration alone would be able (i) to induce rapid post-translational modification-based proteomic changes that are specific to this first exposure and (ii), possibly, lead to irreversible protein level changes that would be not further modified by chronic L-dopa treatment. The apparent equivalence between first and chronic L-dopa administration suggests that priming would be the direct consequence of dopamine loss, the first L-dopa administrations only exacerbating the sensitization process but not inducing it

Functional Characterization of the Dendritically Localized mRNA Neuronatin in Hippocampal Neurons

Local translation of dendritic mRNAs plays an important role in neuronal development and synaptic plasticity. Although several hundred putative dendritic transcripts have been identified in the hippocampus, relatively few have been verified by in situ hybridization and thus remain uncharacterized. One such transcript encodes the protein neuronatin. Neuronatin has been shown to regulate calcium levels in non-neuronal cells such as pancreatic or embryonic stem cells, but its function in mature neurons remains unclear. Here we report that neuronatin is translated in hippocampal dendrites in response to blockade of action potentials and NMDA-receptor dependent synaptic transmission by TTX and APV. Our study also reveals that neuronatin can adjust dendritic calcium levels by regulating intracellular calcium storage. We propose that neuronatin may impact synaptic plasticity by modulating dendritic calcium levels during homeostatic plasticity, thereby potentially regulating neuronal excitability, receptor trafficking, and calcium dependent signaling

Transcriptional Responses of Cultured Rat Sympathetic Neurons during BMP-7-Induced Dendritic Growth

Dendrites are the primary site of synapse formation in the vertebrate nervous system; however, relatively little is known about the molecular mechanisms that regulate the initial formation of primary dendrites. Embryonic rat sympathetic neurons cultured under defined conditions extend a single functional axon, but fail to form dendrites. Addition of bone morphogenetic proteins (BMPs) triggers these neurons to extend multiple dendrites without altering axonal growth or cell survival. We used this culture system to examine differential gene expression patterns in naïve vs. BMP-treated sympathetic neurons in order to identify candidate genes involved in regulation of primary dendritogenesis.To determine the critical transcriptional window during BMP-induced dendritic growth, morphometric analysis of microtubule-associated protein (MAP-2)-immunopositive processes was used to quantify dendritic growth in cultures exposed to the transcription inhibitor actinomycin-D added at varying times after addition of BMP-7. BMP-7-induced dendritic growth was blocked when transcription was inhibited within the first 24 hr after adding exogenous BMP-7. Thus, total RNA was isolated from sympathetic neurons exposed to three different experimental conditions: (1) no BMP-7 treatment; (2) treatment with BMP-7 for 6 hr; and (3) treatment with BMP-7 for 24 hr. Affymetrix oligonucleotide microarrays were used to identify differential gene expression under these three culture conditions. BMP-7 significantly regulated 56 unique genes at 6 hr and 185 unique genes at 24 hr. Bioinformatic analyses implicate both established and novel genes and signaling pathways in primary dendritogenesis.This study provides a unique dataset that will be useful in generating testable hypotheses regarding transcriptional control of the initial stages of dendritic growth. Since BMPs selectively promote dendritic growth in central neurons as well, these findings may be generally applicable to dendritic growth in other neuronal cell types

Heterosynaptic plasticity in the neocortex

Ongoing learning continuously shapes the distribution of neurons’ synaptic weights in a system with plastic synapses. Plasticity may change the weights of synapses that were active during the induction—homosynaptic changes, but also may change synapses not active during the induction—heterosynaptic changes. Here we will argue, that heterosynaptic and homosynaptic plasticity are complementary processes, and that heterosynaptic plasticity might accompany homosynaptic plasticity induced by typical pairing protocols. Synapses are not uniform in their susceptibility for plastic changes, but have predispositions to undergo potentiation or depression, or not to change. Predisposition is one of the factors determining the direction and magnitude of homo- and heterosynaptic changes. Heterosynaptic changes which take place according to predispositions for plasticity may provide a useful mechanism(s) for homeostasis of neurons’ synaptic weights and extending the lifetime of memory traces during ongoing learning in neuronal networks