Current theories of visual consciousness disagree about whether it emerges during early stages of processing in sensory brain regions or later when a widespread fronto-parietal network becomes involved. Moreover, disentangling conscious perception from task-related post-perceptual processes (e.g., report) and integrating results across different neuroscientific methods remain ongoing challenges. The present study addressed these problems using simultaneous EEG-fMRI and a specific inattentional-blindness paradigm with three physically identical phases in female and male human participants. In phase 1, participants performed a distractor task during which line drawings of faces and control stimuli were presented centrally. While some participants spontaneously noticed the faces in phase 1, others remained inattentionally blind. In phase 2, all participants were made aware of the task-irrelevant faces, but continued the distractor task. In phase 3, the faces became task-relevant. Bayesian analysis of brain re...

Aging, disease and trauma can lead to loss of vestibular hair cells and permanent vestibular dysfunction. Previous work showed that, following acute destruction of ∼95% of vestibular hair cells in adult mice, ∼20% regenerate naturally (without exogenous factors) through supporting cell transdifferentiation. There is, however, no evidence for recovery of vestibular function. To gain insight into the lack of functional recovery, we assessed functional differentiation in regenerated hair cells for up to 15 months, focusing on key stages in stimulus transduction and transmission: hair bundles, voltage-gated conductances, and synaptic contacts. Regenerated hair cells had many features of mature type II vestibular hair cells, including polarized mechanosensitive hair bundles with zone-appropriate stereocilia heights, large voltage-gated potassium currents, basolateral processes, and afferent and efferent synapses. Regeneration failed, however, to recapture the full range of properties of normal populations, and ...

Astrocytes provide neurons with diffusible factors that promote synapse formation and maturation. In particular, glypican-4/GPC4 released from astrocytes promotes the maturation of excitatory synapses. Unlike other secreted factors, GPC4 contains the C-terminal GPI-anchorage signal. However, the mechanism by which membrane-tethered GPC4 is released from astrocytes is unknown. Using mouse primary astrocyte cultures and a quantitative luciferase-based release assay, we show that GPC4 is expressed on the astrocyte surface via a GPI-anchorage. Soluble GPC4 is robustly released from the astrocytes largely by proteolytic shedding and, to a lesser extent, by GPI-anchor cleavage, but not by vesicular release. Pharmacological, overexpression, and loss of function screens showed that ADAM9 in part mediates the release of GPC4 from astrocytes. The released GPC4 contains the heparan sulfate side chain, suggesting that these release mechanisms provide the active form that promotes synapse maturation and function. Overa...

Here we report the independent discovery and validation of Stearoyl-CoA desaturase (SCD) as a modulator of alpha-synuclein (αSyn) induced pathology and toxicity in cell-based Parkinson’s Disease models (PD). We identified SCD as top altered gene from transcriptional profiling in primary neurons exogenously expressing αSyn with the amplified familial PD mutation 3K. Thus, we sought to further explore SCD as a therapeutic target in neurodegeneration. We report that SCD inhibitors are toxic to early human and rat neuron cultures while displaying minimal toxicity to late cultures. The fatty acid product of SCD, oleic acid, fully rescues this toxicity in early cultures, suggesting on-target toxicity. Furthermore, SCD inhibition rescues αSyn 3K induced toxicity in late primary neurons. We also confirm that SCD inhibitors reduce formation of αSyn accumulations while oleic acid increases these accumulations in an αSyn 3K neuroblastoma model. However, we identify a caveat with this model where αSyn 3K levels can be...

Learning in sensorimotor adaptation tasks has been viewed as an implicit learning phenomenon. The implicit process affords recalibration of existing motor skills so that the system can adjust to changes in the body or environment without relearning from scratch. However, recent findings suggest that the implicit process is heavily constrained, calling into question its utility in motor learning and the theoretical framework of sensorimotor adaptation paradigms. These inferences have been based mainly on results from single bouts of training, where explicit compensation strategies, such as explicitly re-aiming the intended movement direction, contribute a significant proportion of adaptive learning. It is possible, however, that the implicit process supersedes explicit compensation strategies over repeated practice sessions. We tested this by dissociating the contributions of explicit re-aiming strategies and the implicit process in human participants over five consecutive days of training. Despite a substa...

The capacity of human brain to sustain complex cortical dynamics appears to be strongly associated with conscious experience and consistently drops when consciousness fades. For example, several recent studies in humans found a remarkable reduction of the spatiotemporal complexity of cortical responses to local stimulation during dreamless sleep, general anesthesia, and coma. However, this perturbational complexity has never been directly estimated in non-human animals in vivo previously, and the mechanisms that prevent neocortical neurons to engage in complex interactions are still unclear. Here, we quantify the complexity of electroencephalographic responses to intracranial electrical stimulation in rats, comparing wakefulness to propofol, sevoflurane, and ketamine anesthesia. The evoked activity changed from highly complex in wakefulness to far simpler with propofol and sevoflurane. The reduced complexity was associated with a suppression of high frequencies that preceded a reduced phase-locking, and di...

Cortical oscillations have been proposed to play a functional role in speech and music perception, attentional selection and working memory, via the mechanism of neural entrainment. One of the properties of neural entrainment that is often taken for granted is that its modulatory effect on ongoing oscillations outlasts rhythmic stimulation. We tested the existence of this phenomenon by studying cortical neural oscillations during and after presentation of melodic stimuli in a passive perception paradigm. Melodies were composed of ∼60 and ∼80 Hz tones embedded in a 2.5 Hz stream. Using intracranial and surface recordings in male and female humans, we reveal persistent oscillatory activity in the high-gamma band in response to the tones throughout the cortex, well beyond auditory regions. By contrast, in response to the 2.5 Hz stream, no persistent activity in any frequency band was observed. We further show that our data are well-captured by a model of damped harmonic oscillator and can be classified into t...

Primary cilia exhibit a distinct complement of proteins, including G-protein-coupled receptors (GPCRs) that mediate sensory and developmental signals. The localization of GPCRs to the ciliary membrane involves ciliary localization sequences (CLSs), but it is not known how CLSs might relate to cilium type. Here, we studied the localization of two RHO-like GPCRs, SSTR3 and RHO, in three types of cilia: from IMCD3 cells, hTERT-RPE1 cells (possessing pocket cilia), and rod photoreceptors (whose cilia grow into elaborate phototransductive outer segments). SSTR3 was localized specifically to all three types of cilia, whereas RHO showed more selectivity for the photoreceptor cilium. Focusing on C-terminal CLSs, we characterized a novel CLS in the SSTR3 C-terminus, which was required for the robust ciliary localization of SSTR3. Replacing the C-terminus of RHO with this SSTR3 CLS enhanced ciliary localization, compared with full-length RHO, in IMCD3 and hTERT-RPE1 cells. Addition of the SSTR3 CLS to the single tra...

Human language learning differs significantly across individuals in the process and ultimate attainment. Although decades of research exploring the neural substrates of language learning have identified distinct and overlapping neural networks subserving learning of different components, the neural mechanisms that drive the large inter-individual differences are still far from being understood. Here we examine to what extent the neural dynamics of multiple brain networks in men and women across sessions of training contribute to explaining individual differences in learning multiple linguistic components (i.e., vocabulary, morphology, and phrase and sentence structures) of an artificial language in a seven-day training and imaging paradigm with functional Magnetic Resonance Imaging. With machine-learning and predictive modeling, neural activation patterns across training sessions were highly predictive of individual learning success profiles derived from the four components. We identified four neural learn...