Nogo-66 receptors (NgR1-3) are glycosylphosphatidyl inositol-linked proteins that belong to the leucine-rich repeat superfamily. Through binding to myelin-associated inhibitors, NgRs contribute to the inhibition of axonal regeneration after spinal cord injury. Their role in limiting synaptic plasticity and axonal outgrowth in the adult CNS has been described previously, but not much is known about their role during the development of the nervous system. Here, we show that NgR1 and NgR3 mRNAs are expressed during spinal cord development of the chicken embryo. In particular, they are expressed in the dI1 subpopulation of commissural neurons during the time when their axons navigate toward and across the floorplate, the ventral midline of the spinal cord. To assess a potential role of NgR1 and NgR3 in axon guidance, we downregulated them using in ovo RNAi and analyzed the trajectory of commissural axons by tracing them in open-book preparations of spinal cords. Our results show that loss of either NgR1 or NgR...

Nociceptive information is detected and transmitted by neurons in the DRG. Recently, single-cell RNA sequencing has revealed the molecular profile of various cell types, including fibroblasts in the DRG. However, the role of molecules in fibroblasts needs to be elucidated in nociceptive regulation. Here, we found that secreted modular calcium-binding protein 2 (SMOC2) was secreted by fibroblasts to become a component of basement membrane and envelop the unit consisting of DRG neurons and attached satellite glial cells. KO of Smoc2 in both sexes of mice led to increased neuronal clusters and decreased mechanical threshold, but unchanged noxious thermal response. Knockdown of Smoc2 in the DRG phenocopied the behavioral performance by Smoc2 KO in both sexes of mice. In vivo calcium imaging showed that Smoc2 KO increased coupled activation of adjacent DRG neurons induced by nociceptive mechanical stimuli, which was reversed by DRG injection of SMOC2. Importantly, SMOC2 interacted with P2X7 receptor (P2X7R) and...

Brain aging is a natural process that involves structural and functional changes that lead to cognitive decline, even in healthy subjects. This detriment has been associated with N-methyl-D-aspartate receptor (NMDAR) hypofunction due to a reduction in the brain levels of D-serine, the endogenous NMDAR co-agonist. However, it is not clear if D-serine supplementation could be used as an intervention to reduce or reverse age-related brain alterations. In the present work, we aimed to analyze the D-serine effect on aging-associated alterations in cellular and large-scale brain systems that could support cognitive flexibility in rats. We found that D-serine supplementation reverts the age-related decline in cognitive flexibility, frontal dendritic spine density, and partially restored large-scale functional connectivity without inducing nephrotoxicity; instead, D-serine restored the thickness of the renal epithelial cells that were affected by age. Our results suggest that D-serine could be used as a therapeuti...

The generation of surrogate data, i.e., the modification of data to destroy a certain feature, can be considered as the implementation of a null-hypothesis whenever an analytical approach is not feasible. Thus, surrogate data generation has been extensively used to assess the significance of spike correlations in parallel spike trains. In this context, one of the main challenges is to properly construct the desired null-hypothesis distribution and to avoid altering the single spike train statistics. A classical surrogate technique is uniform dithering (UD), which displaces spikes locally and uniformly distributed, to destroy temporal properties on a fine timescale while keeping them on a coarser one. Here we compare UD against five similar surrogate techniques in the context of the detection of significant spatio-temporal spike patterns. We evaluate the surrogates for their performance, first on spike trains based on point process models with constant firing rate, and second on modeled non-stationary arti...

The neural processes that enable healthy humans to orient attention to sudden visual events are poorly understood because they are tightly intertwined with purely sensory processes. Here we isolated visually guided orienting activity from sensory activity using event-related potentials (ERPs). By recording ERPs to a lateral stimulus and comparing waveforms obtained under conditions of attention and inattention, we identified an early positive deflection over the ipsilateral visual cortex that was associated with the covert orienting of visual attention to the stimulus. Across five experiments with male and female adult participants, this ipsilateral visual orienting activity (VOA) could be distinguished from purely sensory-evoked activity and from other top-down spatial attention effects. The VOA was linked with behavioral measures of orienting, being significantly larger when the stimulus was detected rapidly than when it was detected more slowly, and its presence was independent of saccadic eye movements...

Spatial memory and reward processing are known to be disrupted in schizophrenia. Since the lateral septum (LS) may play an important role in the integration of location and reward, we examined the effect of maternal immune activation (MIA), a known schizophrenia risk factor, on spatial representation in the rat LS. In support of a previous study, we found that spatial location is represented as a phase code in the rostral LS of adult male rats, so that LS cell spiking shifts systematically against the phase of the hippocampal, theta-frequency, local field potential as an animal moves along a track toward a reward (phase precession). Whereas shallow precession slopes were observed in control group cells, they were steeper in the MIA animals, such that firing frequently precessed across several theta cycles as the animal moved along the length of the apparatus, with subsequent ambiguity in the phase representation of location. Furthermore, an analysis of the phase trajectories of the control group cells reve...

Shuo Zhang, Bing Cai, Zhen Li, Kaikai Wang, Lan Bao, et al. (see pages [4069–4086][1]) It is now well established that glia contribute to neural transmission. For example, oligodendrocytes form myelin to speed action potential conduction; microglia prune synapses; and astrocytes enwrap synapses

Human apolipoprotein E receptor 2 (APOER2) is a type I transmembrane protein with a large extracellular domain (ECD) and a short cytoplasmic tail. APOER2-ECD contains several ligand-binding domains (LBDs) that are organized into exons with aligning phase junctions, which allows for in-frame exon cassette splicing events. We have identified 25 human APOER2 isoforms from cerebral cortex using gene-specific APOER2 primers, where the majority are exon-skipping events within the N-terminal LBD regions compared with six identified in the heart. APOER2 undergoes proteolytic cleavage in response to ligand binding that releases a C-terminal fragment (CTF) and transcriptionally active intracellular domain (ICD). We tested whether the diversity of human brain-specific APOER2 variants affects APOER2 cleavage. We found isoforms with differing numbers of ligand-binding repeats generated different amounts of CTFs compared with full-length APOER2 (APOER2-FL). Specifically, APOER2 isoforms lacking exons 5–8 (Δex5–8) and la...

In “This Week in the Journal,” which appeared on page [2613][1] of the March 30, 2022 issue, the first title appeared incorrectly. “Role of Calretinin at High-Frequency Calyx-of-Held Synapses” should instead read “Role of Calretinin at High-Frequency Endbulb of Held Synapses.” The online