Seizure-Related Gene 6 (Sez-6) in Amacrine Cells of the Rodent Retina and the Consequence of Gene Deletion

Background: Seizure-related gene 6 (Sez-6) is expressed in neurons of the mouse brain, retina and spinal cord. In the cortex, Sez-6 plays a role in specifying dendritic branching patterns and excitatory synapse numbers during development. Methodology/Principal Findings: The distribution pattern of Sez-6 in the retina was studied using a polyclonal antibody that detects the multiple isoforms of Sez-6. Prominent immunostaining was detected in GABAergic, but not in All glycinergic, amacrine cell subpopulations of the rat and mouse retina. Amacrine cell somata displayed a distinct staining pattern with the Sez-6 antibody: a discrete, often roughly triangular-shaped bright spot positioned between the nucleus and the apical dendrite superimposed over weaker general cytoplasmic staining. Displaced amacrines in the ganglion cell layer were also positive for Sez-6 and weaker staining was occasionally observed in neurons with the morphology of alpha ganglion cells. Two distinct Sez-6 positive strata were present in the inner plexiform layer in addition to generalized punctate staining. Certain inner nuclear layer cells, including bipolar cells, stained more weakly and diffusely than amacrine cells, although some bipolar cells exhibited a perinuclear "bright spot" similar to amacrine cells. In order to assess the role of Sez-6 in the retina, we analyzed the morphology of the Sez-6 knockout mouse retina with immunohistochemical markers and compared ganglion cell dendritic arbor patterning in Sez-6 null retinae with controls. The functional importance of Sez-6 was assessed by dark-adapted paired-flash electroretinography (ERG). Conclusions: In summary, we have reported the detailed expression pattern of a novel retinal marker with broad cell specificity, useful for retinal characterization in rodent experimental models. Retinal morphology, ganglion cell dendritic branching and ERG waveforms appeared normal in the Sez-6 knockout mouse suggesting that, in spite of widespread expression of Sez-6, retinal function in the absence of Sez-6 is not affected

Outcome Feedback Effects on Risk Propensity in an MCPLP Task

In this experimental analysis, the effects of outcome feedback on risk propensity were assessed within the multiple-cue-probability-learning-paradigm (MCPLP). The individual decision maker in this task received outcome feedback on a decision-by-decision basis. It was hypothesized that information on his/her success or lack of success (outcome feedback) on each decision would influence the decision to risk (commit) resources. Hierarchical regression results revealed that after all other performance effects had been partialled out, current outcome feedback explained much of the commitment decision.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Pregnancy and neonatal outcomes of COVID-19: The PAN-COVID study

Objective To assess perinatal outcomes for pregnancies affected by suspected or confirmed SARS-CoV-2 infection. Methods Prospective, web-based registry. Pregnant women were invited to participate if they had suspected or confirmed SARS-CoV-2 infection between 1st January 2020 and 31st March 2021 to assess the impact of infection on maternal and perinatal outcomes including miscarriage, stillbirth, fetal growth restriction, pre-term birth and transmission to the infant. Results Between April 2020 and March 2021, the study recruited 8239 participants who had suspected or confirmed SARs-CoV-2 infection episodes in pregnancy between January 2020 and March 2021. Maternal death affected 14/8197 (0.2%) participants, 176/8187 (2.2%) of participants required ventilatory support. Pre-eclampsia affected 389/8189 (4.8%) participants, eclampsia was reported in 40/ 8024 (0.5%) of all participants. Stillbirth affected 35/8187 (0.4 %) participants. In participants delivering within 2 weeks of delivery 21/2686 (0.8 %) were affected by stillbirth compared with 8/4596 (0.2 %) delivering ≥ 2 weeks after infection (95 % CI 0.3–1.0). SGA affected 744/7696 (9.3 %) of livebirths, FGR affected 360/8175 (4.4 %) of all pregnancies. Pre-term birth occurred in 922/8066 (11.5%), the majority of these were indicated pre-term births, 220/7987 (2.8%) participants experienced spontaneous pre-term births. Early neonatal deaths affected 11/8050 livebirths. Of all neonates, 80/7993 (1.0%) tested positive for SARS-CoV-2. Conclusions Infection was associated with indicated pre-term birth, most commonly for fetal compromise. The overall proportions of women affected by SGA and FGR were not higher than expected, however there was the proportion affected by stillbirth in participants delivering within 2 weeks of infection was significantly higher than those delivering ≥ 2 weeks after infection. We suggest that clinicians’ threshold for delivery should be low if there are concerns with fetal movements or fetal heart rate monitoring in the time around infection

Altered speeds and trajectories of neurons migrating in the ventricular and subventricular zones of the reeler neocortex

The Reelin signaling pathway is essential for proper cortical development, but it is unclear to whether Reelin function is primarily important for cortical layering or neuron migration. It has been proposed that Reelin is perhaps required only for somal translocation but not glial-dependent locomotion. This implies that the location of neurons responding to Reelin is restricted to the outer regions of the cortical plate (CP). To determine whether Reelin is required for migration outside of the CP, we used time-lapse imaging to track the behavior of cells undergoing locomotion in the germinal zones. We focused on the migratory activity in the ventricular/subventricular zones where the first transition of bipolar to multipolar migration occurs and where functional Reelin receptors are known to be expressed. Despite Reelin loss, neurons had no difficulty in undergoing radial migration and indeed displayed greater migratory speed. Additionally, compared with the wild-type, reeler neurons displayed altered trajectories with greater deviation from a radial path. These results suggest that Reelin loss has early consequences for migration in the germinal zones that are portrayed as defective radial trajectories and migratory speeds. Together, these abnormalities can give rise to the increased cell dispersion observed in the reeler cortex

Cortical layer development and orientation is modulated by relative contributions of reelin-negative and-positive neurons in mouse chimeras

Reelin is an important protein that is indispensable for cortical lamination. In the absence of Reelin, cortical layers fail to form due to inappropriate neuron migration and positioning. The inversion of cortical layers is attributed to failure of neurons to migrate past earlier-generated neurons although how Reelin-insufficiency causes this is unclear. The issue is complicated by recent studies showing that very little Reelin is required for cortical layering. To test how variation in the number of Reelin-producing cells is linked to cortical lamination, we have employed Reelin+/+ ↔ Reelin-/- chimeras in which the number of Reelin-expressing neurons is adjusted. We found that the Reeler phenotype was rescued in chimeras with a large contribution of Reelin+/+ neurons; conversely in chimeras with a weak contribution by Reelin+/+ neurons, the mutant phenotype remained. However, increasing the number of Reelin+/+ neurons beyond an unknown threshold resulted in partial rescue, with the formation of a correctly layered secondary cortex lying on top of an inverted mutant cortex. Therefore, the development of cortical layers in the correct order requires a minimal level of Reelin protein to be present although paradoxically, this is insufficient to prevent the simultaneous formation of inverted cortical layers in the same hemisphere

Oligodendrocyte positioning in cerebral cortex is independent of projection neuron layering

The factors affecting normal oligodendrocyte positioning in the cerebral cortex are unknown. Apart from the white matter, the highest numbers of oligodendrocytes in the rodent cortex are found in Layers V/VI, where the infragranular neurons normally reside. Few, if any, oligodendrocytes are normally found in the superficial cortical layers. To test whether or not this asymmetric positioning of oligodendrocytes is linked to the lamina positions of Layer V/VI projection neurons, mutant mice that cause neuronal layer inversion were examined. In three lines of mutant mice (Reeler, disabled-1, and p35) examined, representing two different genetic signaling pathways, the oligodendrocyte distribution was altered from an asymmetric to a symmetric distribution pattern. Unlike cortical neurons that are inverted in these mutant mice, the lack of oligodendrocyte inversion suggests a decoupling of the genetic mechanisms governing neuronal versus oligodendrocyte patterning. We conclude that oligodendrocyte positioning is not linked to the layer positions of V/VI projection neurons

Indicators of dependence and efforts to quit vaping and smoking among youth in Canada, England and the USA.

OBJECTIVE: The current study examined indicators of dependence among youth cigarette smokers and e-cigarette users in Canada, England and the USA, including changes between 2017 and 2019. METHODS: Data are from repeated cross-sectional online surveys conducted in 2017, 2018 and 2019 with national samples of youth aged 16-19 years, in Canada (n=12 018), England (n=11 362) and the USA (n=12 110). Measures included perceived addiction to cigarettes/e-cigarettes, frequency of experiencing strong urges to smoke/use an e-cigarette, plans to quit smoking/using e-cigarettes and past attempts to quit. Logistic regression models were fitted to examine differences between countries and changes over time. RESULTS: The proportion of ever-users who vaped frequently was significantly higher in 2019 compared with 2017 for all outcomes in each country. Between 2017 and 2019, the proportion of past 30-day vapers reporting strong urges to vape on most days or more often increased in each country (Canada: 35.3%; England: 32.8%; USA: 46.1%), along with perceptions of being 'a little' or 'very addicted' to e-cigarettes (Canada: 48.3%; England: 40.1%; USA: 53.1%). Indicators of dependence among smokers were consistently greater than e-cigarette users, although differences had narrowed by 2019, particularly in Canada and the USA. CONCLUSIONS: Prevalence of dependence symptoms among young e-cigarette users increased between 2017 and 2019, more so in Canada and the USA compared with England. Dependence symptom prevalence was lower for e-cigarettes than smoking; however, the gap has narrowed over time

Immunostaining for Sez-6 in the mouse retina reveals labelling in all layers except the outer nuclear layer.

<p>(A) Sez-6 immunostained wild-type mouse retinal section counterstained with bisbenzamide to reveal the morphology of nuclear layers. Layers displaying the strongest staining for Sez-6 are marked by arrows. (B) Sez-6 immunostaining alone on the wild-type section shown in A. (C) Sez-6 knockout (KO) mouse retina immunostained with anti-Sez-6 antiserum and counter-stained with bisbenzamide indicating a low level of non-specific staining in the GCL, INL, OPL and photoreceptor outer segments. The Sez-6 staining alone on the same KO section is shown in (D). (E) Wild-type retina stained for Sez-6 with examples of more weakly stained bipolar cell somata in the INL indicated (arrowheads). (F) Wild-type retina stained for Sez-6 with cells morphologically resembling a horizontal cell and an alpha (or A1) ganglion cell indicated (arrowhead and arrow, respectively). Scale Bar = 50 µm.</p

Paired-flash dark-adapted electroretinogram components in wild-type and Sez-6 knockout mice.

<p>Paired-flash dark-adapted electroretinogram components in wild-type and Sez-6 knockout mice.</p