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Retinitis pigmentosa (RP) is a family of genetically heterogeneous diseases still without a cure. Despite the causative genetic mutation typically not expressed in cone photoreceptors, these cells inevitably degenerate following the primary death of rods, causing blindness. The reasons for the "bystander" degeneration of cones are presently unknown but decrement of survival factors, oxidative stress, and inflammation all play a role. Targeting these generalized biological processes represents a strategy to develop mutation-agnostic therapies for saving vision in large populations of RP individuals. A classical method to support neuronal survival is by employing neurotrophic factors, such as NGF. This study uses painless human NGF (hNGFp), a TrkA receptor-biased variant of the native molecule with lower affinity for nociceptors and limited activity as a pain inducer; the molecule has identical neurotrophic power of the native form but a reduced affinity for the p75NTR receptors, known to trigger apoptosis. hNGFp has a recognized activity on brain microglial cells, which are induced to a phenotype switch from a highly activated to a more homeostatic configuration. hNGFp was administered to RP-like mice in vivo with the aim of decreasing retinal inflammation and also providing retinal neuroprotection. However, the ability of this treatment to counteract the bystander degeneration of cones remained limited.

Spike-and-wave discharges (SWDs) and sleep spindles are characteristic electroencephalographic (EEG) hallmarks of absence seizures and nonrapid eye movement sleep, respectively. They are commonly generated by the cortico-thalamo-cortical network including the thalamic reticular nucleus (TRN). It has been reported that SWD development is accompanied by a decrease in sleep spindle density in absence seizure patients and animal models. However, whether the decrease in sleep spindle density precedes, coincides with, or follows, the SWD development remains unknown. To clarify this, we exploited Pvalb-tetracycline transactivator (tTA)::tetO-ArchT (PV-ArchT) double-transgenic mouse, which can induce an absence seizure phenotype in a time-controllable manner by expressing ArchT in PV neurons of the TRN. In these mice, EEG recordings demonstrated that a decrease in sleep spindle density occurred 1 week before the onset of typical SWDs, with the expression of ArchT. To confirm such temporal relationship observed in these genetic model mice, we used a gamma-butyrolactone (GBL) pharmacological model of SWDs. Prior to GBL administration, we administered caffeine to wild-type mice for 3 consecutive days to induce a decrease in sleep spindle density. We then administered low-dose GBL, which cannot induce SWDs in normally conditioned mice but led to the occurrence of SWDs in caffeine-conditioned mice. These findings indicate a temporal relationship in which the decrease in sleep spindle density consistently precedes SWD development. Furthermore, the decrease in sleep spindle activity may have a role in facilitating the development of SWDs. Our findings suggest that sleep spindle reductions could serve as early indicators of seizure susceptibility.

Contemporary research has begun to show a strong relationship between movements and the perception of time. More specifically, concurrent movements serve to both bias and enhance time estimates. To explain these effects, we recently proposed a mechanism by which movements provide a secondary channel for estimating duration that is combined optimally with sensory estimates. However, a critical test of this framework is that by introducing "noise" into movements, sensory estimates of time should similarly become noisier. To accomplish this, we had human participants move a robotic arm while estimating intervals of time in either auditory or visual modalities (n = 24, ea.). Crucially, we introduced an artificial "tremor" in the arm while subjects were moving, that varied across three levels of amplitude (1-3 N) or frequency (4-12 Hz). The results of both experiments revealed that increasing the frequency of the tremor led to noisier estimates of duration. Further, the effect of noise varied with the base precision of the interval, such that a naturally less precise timing (i.e., visual) was more influenced by the tremor than a naturally more precise modality (i.e., auditory). To explain these findings, we fit the data with a recently developed drift-diffusion model of perceptual decision-making, in which the momentary, within-trial variance was allowed to vary across conditions. Here, we found that the model could recapitulate the observed findings, further supporting the theory that movements influence perception directly. Overall, our findings support the proposed framework, and demonstrate the utility of inducing motor noise via artificial tremors.

Much of what has been discovered concerning neurophysiological mechanisms can be credited to ex vivo biomedical experiments. Beyond these discoveries, ex vivo research techniques have enhanced the global understanding of human physiology and pathology in almost every biomedical specialty. Naturally, ex vivo experiments are among the most desired methods of research, particularly in the field of neuroscience. Ex vivo experiment platforms may be purchased commercially. However, their substantial cost and sometimes limited availability can render them inaccessible to many research labs. Moreover, these manufactured systems are often rigid in function with no possibility of customization, severely narrowing their capabilities. However, developing essential components for ex vivo laboratory systems with a fused deposition modeling printer provides a practical solution to each of these obstacles. Here, we provide the designs and construction process for an easily accessible, highly adaptable recording stage with modifiable submersion chambers using a 3D printer for a total cost under $15.00. With the versatility afforded by the exchangeable custom chambers, the system may be used to conduct research on a variety of ex vivo tissue preparations, paving the way for novel research.

Astrocytes are essential for the formation and maintenance of neural networks. However, a major technical challenge for investigating astrocyte function and disease-related pathophysiology has been the limited ability to obtain functional human astrocytes. Despite recent advances in human pluripotent stem cell (hPSC) techniques, primary rodent astrocytes remain the gold standard in coculture with human neurons. We demonstrate that a combination of leukemia inhibitory factor (LIF) and bone morphogenetic protein-4 (BMP4) directs hPSC-derived neural precursor cells to a highly pure population of astroglia in 28 d. Using single-cell RNA sequencing, we confirm the astroglial identity of these cells and highlight profound transcriptional adaptations in cocultured hPSC-derived astrocytes and neurons, consistent with their further maturation. In coculture with human neurons, multielectrode array recordings revealed robust network activity of human neurons in a coculture with hPSC-derived or rat astrocytes [3.63 ± 0.44 min^-1 (hPSC-derived), 2.86 ± 0.64 min^-1 (rat); p = 0.19]. In comparison, we found increased spike frequency within network bursts of human neurons cocultured with hPSC-derived astrocytes [56.31 ± 8.56 Hz (hPSC-derived), 24.77 ± 4.04 Hz (rat); p < 0.01], and whole-cell patch-clamp recordings revealed an increase of postsynaptic currents [2.76 ± 0.39 Hz (hPSC-derived), 1.07 ± 0.14 Hz (rat); p < 0.001], consistent with a corresponding increase in synapse density [14.90 ± 1.27/100 μm² (hPSC-derived), 8.39 ± 0.63/100 μm² (rat); p < 0.001]. Taken together, we show that hPSC-derived astrocytes compare favorably with rat astrocytes in supporting human neural network activity and maturation, providing a fully human platform for investigating astrocyte function and neuronal-glial interactions.

Contrast sensitivity (CS), which constrains human vision, decreases from fovea to periphery, from the horizontal to the vertical meridian, and from the lower vertical to the upper vertical meridian. It also depends on spatial frequency (SF), and the contrast sensitivity function (CSF) depicts this relation. To compensate for these visual constraints, we constantly make saccades and foveate on relevant objects in the scene. Already before saccade onset, presaccadic attention shifts to the saccade target and enhances perception. However, it is unknown whether and how it modulates the interplay between CS and SF, and if this effect varies around polar angle meridians. CS enhancement may result from a horizontal or vertical shift of the CSF, increase in bandwidth, or any combination. In addition, presaccadic attention could enhance CS similarly around the visual field, or it could benefit perception more at locations with poorer performance (i.e., vertical meridian). Here, we investigated these possibilities by extracting key attributes of the CSF of human observers. The results reveal that presaccadic attention (1) increases CS across SF, (2) increases the most preferred and the highest discernable SF, and (3) narrows the bandwidth. Therefore, presaccadic attention helps bridge the gap between presaccadic and postsaccadic input by increasing visibility at the saccade target. Counterintuitively, this CS enhancement was more pronounced where perception is better-along the horizontal than the vertical meridian-exacerbating polar angle asymmetries. Our results call for an investigation of the differential neural modulations underlying presaccadic perceptual changes for different saccade directions.

When presented shortly after another, discrete pictures are naturally perceived as continuous. The neuronal mechanism underlying such continuous or discrete perception is not well understood. While continuous alpha oscillations are a candidate for orchestrating such neuronal mechanisms, recent evidence is mixed. In this study, we investigated the influence of prestimulus alpha oscillation on visual temporal perception. Specifically, we were interested in whether prestimulus alpha phase modulates neuronal and perceptual processes underlying discrete or continuous perception. Participants had to report the location of a missing object in a visual temporal integration task, while simultaneously MEG data were recorded. Using source reconstruction, we evaluated local phase effects by contrasting phase angle values between correctly and incorrectly integrated trials. Our results show a phase opposition cluster between -0.8 and -0.5 s (relative to stimulus presentation) and between 6 and 20 Hz. These momentary phase angle values were correlated with behavioral performance and event-related potential amplitude. There was no evidence that frequency defined a window of temporal integration.

Alteration of synaptic function in the dorsal horn (DH) has been implicated as a cellular substrate for the development of neuropathic pain, but certain details remain unclear. In particular, the lack of information on the types of synapses that undergo functional changes hinders the understanding of disease pathogenesis from a synaptic plasticity perspective. Here, we addressed this issue by using optogenetic and retrograde tracing ex vivo to selectively stimulate first-order nociceptors expressing Nav1.8 (NRs^Nav1.8) and record the responses of spinothalamic tract neurons in spinal lamina I (L1-STTNs). We found that spared nerve injury (SNI) increased excitatory postsynaptic currents (EPSCs) in L1-STTNs evoked by photostimulation of NRs^Nav1.8 (referred to as Nav1.8-STTN EPSCs). This effect was accompanied by a significant change in the failure rate and paired-pulse ratio of synaptic transmission from NRs^Nav1.8 to L1-STTN and in the frequency (not amplitude) of spontaneous EPSCs recorded in L1-STTNs. However, no change was observed in the ratio of AMPA to NMDA receptor-mediated components of Nav1.8-STTN EPSCs or in the amplitude of unitary EPSCs constituting Nav1.8-STTN EPSCs recorded with extracellular Ca²⁺ replaced by Sr²⁺ In addition, there was a small increase (approximately 10%) in the number of L1-STTNs showing immunoreactivity for phosphorylated extracellular signal-regulated kinases in mice after SNI compared with sham. Similarly, only a small percentage of L1-STTNs showed a lower action potential threshold after SNI. In conclusion, our results show that SNI induces presynaptic modulation at NR^Nav1.8 (consisting of both peptidergic and nonpeptidergic nociceptors) synapses on L1-STTNs forming the lateral spinothalamic tract.