Journal of Neuroscience最新文献

Baker-Gordon syndrome (BAGOS) is a neurodevelopmental disorder (NDD) linked to a series of de novo mutations in the synaptic vesicle protein, Synaptotagmin-1 (SYT1). SYT1 is the major calcium sensor for synaptic transmission, and therefore a key molecule in neuronal communication. Several approaches have been used to reveal the underlying molecular mechanisms that lead to BAGOS pathology. While the murine genetic deletion, loss-of-function approach has proven valuable for modeling human diseases, human-induced pluripotent stem cells (hiPSCs) offer a powerful new strategy. In this study, we compare the phenotypes of BAGOS-associated SYT1 mutant variants in murine and human neuron models of either sex. In the well-established murine SYT1 knock-out (KO) model, we found that although all SYT1 mutant variants were correctly localized to the synaptic compartment, none could effectively rescue synaptic transmission. To examine the phenotype of BAGOS-associated SYT1 mutations in the context of human neurons, we generated a SYT1 KO hiPSC line via CRISPR/Cas9 gene editing and used this to derive neurons. As in mouse neurons, SYT1 KO in hiPSCs-derived human neurons strongly impairs synchronous release. Surprisingly, fast synaptic transmission could be rescued to varying extents in the human SYT1 KO model using BAGOS SYT1 mutants. However, overexpression of BAGOS SYT1 mutants in either WT mouse neurons or hiPSC-derived human neurons, a condition closer to the heterozygotic genotype of patients, revealed a dominant-negative effect of the mutant proteins. Our findings suggest that impaired neurotransmitter release efficacy caused by mutations in synaptic proteins may contribute to NDD pathophysiology.

Our visual system can recognize patterns across many spatial scales. A fundamental assumption in visual neuroscience is that this ability relies on the putative scale-invariant properties of receptive fields (RFs) in early vision, whereby the spatial area over which a visual neuron responds is proportional to the spatial scale of information it can encode (i.e., spatial frequency, SF). In other words, the resolution of spatial sampling of a RF is assumed to be constant in the visual cortex. However, this assumption has gone untested in the human visual cortex. To address this, we leveraged model-based fMRI techniques that characterize the spatial tuning and SF preferences of cortical subpopulations sampled within a voxel across eight participants (five females, three males). We find that the voxel-wise ratio between peak SF tuning and RF size-expressed as "cycles per RF"-remains constant across visual areas V1, V2, and V3, suggesting that, at the population level, SF preferences are inversely proportional to the RF size, a tenet of scale invariance in early human vision.

Visuospatial attention is key for parsing visual information and selecting targets to look at. Based on regimented laboratory tasks, it is now well-established that three types of mechanism determine when and where attention is deployed; these are stimulus-driven (exogenous), goal-driven (endogenous), and history-driven (reflecting recent experience). It is unclear, however, how these distinct attentional signals interact and contribute in visual environments that are more akin to natural scanning, when stimuli may change rapidly and no fixation requirements are imposed. Here, we investigate this via a gamified task in which participants (male and female) make continuous saccadic choices at a rapid pace-and yet, perceptual performance can be accurately tracked over time as the choice process unfolds. The results reveal unequivocal markers of exogenous capture toward salient stimuli; endogenous guidance toward valuable targets and relevant locations; and history-driven effects, which produce large, involuntary modulations in processing capacity. Under dynamic conditions, success probability is dictated by temporally precise interplay between different forms of spatial attention, with recent history making a particularly prominent contribution.

Reading is a fundamental skill for communication, learning, and daily life. Alexia, an acquired reading disorder typically caused by left hemisphere stroke, impairs both oral and silent word reading. However, most research and clinical assessments focus on oral reading. Functional imaging studies in typical readers suggest partly shared and partly distinct neural bases of oral versus silent reading, but this has never been assessed in a lesion study. We examined oral word reading and silent word recognition, measured by a lexical decision task, in 85 chronic left hemisphere stroke survivors (46 males, 39 females), comparing efficiency scores combining speed and accuracy to those of 69 neurologically healthy adults (36 males, 33 females). The stroke group had greater deficits in oral reading than lexical decision. Performance on the two tasks was highly correlated suggesting shared substrates, albeit with considerable unexplained variance. Support vector regression-based lesion-symptom mapping localized lesions associated with deficits in the two tasks. Oral reading deficits were associated with lesions to the superior temporal and supramarginal gyri, and the rolandic operculum after controlling for lexical decision performance. Lexical decision deficits were linked to lesions in angular gyrus, even after controlling for oral reading performance. A novel conjunction analysis found that lesions of angular and middle temporal gyri, extending into ventral occipitotemporal cortex, affected performance on both tasks, suggesting shared neural substrates. These findings suggest that neurocognitive bases of silent reading and reading aloud are partly shared and partly distinct. Alexia assessments should include both silent and oral reading tasks.Significance Statement Silent reading is essential for daily life, but has received less attention than oral reading in research on acquired reading deficits, i.e., alexia. While functional imaging suggests partially distinct activation patterns for oral and silent reading, lesion-symptom mapping offers a critical method for identifying brain regions necessary for task performance. This is the first lesion mapping study to compare oral and silent reading within the same individuals. Using lexical decision as a proxy for silent reading, we found partly shared and partly distinct neural substrates for silent versus oral reading. These findings reveal overlapping but differentially weighted neural systems and underscore the need to assess silent reading alongside oral reading when assessing alexia.

Schema memory refers to generalized knowledge that is formed across multiple episodes containing regularities. Schema memory is thought to be formed in an active systems consolidation process that transforms individual episodic representations into neocortically anchored schema representations and that is facilitated by sleep. Here we show in rats that sleep is indeed critical for the emergence of a new schema memory. Male rats (n = 20) were trained on an elaborated version of the object-place recognition (OPR) task, which allowed for abstraction of a spatial rule across eight encoding episodes spaced 20 minutes apart without intermittent sleep. During each episode, animals freely explored two objects in an open-field arena. Following the encoding phase, animals either slept or were kept awake for two hours, after which they remained undisturbed for 22 hours before schema memory for the spatial rule was assessed. Only animals that slept during the two-hour post-encoding window exhibited schema memory. Prior knowledge conflicting with the spatial rule prevented schema memory formation. c-Fos expression assessed at retrieval indicated that successful schema recall was supported by a more sparsely activated yet highly interconnected network comprising, amongst others, medial prefrontal cortex and hippocampus. Our findings highlight the critical role of immediate post-encoding sleep in forming new spatial schema memory.Significance Statement Schema representations integrate regularities abstracted from multiple episodes. Whether and how the formation of schema representations benefit from sleep is still unclear, partly because evoking abstraction processes across episodes within a single wake period in animal models is challenging. Using an object-place recognition (OPR) - based schema memory task, we show for the first time in rats that sleep critically supports schema memory formation. Rats that slept, but not those kept awake for 2 hours after encoding the eight task episodes, expressed schema memory 24 hours later. Schema recall after sleep was associated with a sparse but distinctly more coordinated network activation, mainly comprising medial prefrontal cortex and hippocampus. Our findings highlight sleep's role in newly forming distributed spatial schema representations.

Recent studies suggest some hippocampal (HC) neurons respond to passively presented sounds in naive subjects, but the specificity and prevalence of these responses remain unclear. We used Neuropixels probes to record unit activity across layers in mid-ventral HC and auditory cortex (ACtx) of awake, untrained mice (male and female) while presenting diverse sounds at typical environmental levels (65-70 dB SPL). A subset of HC neurons exhibited reliable, short latency responses to passive sounds, including tones and broadband noise. HC units showed evidence of tuning for tone frequency but not spectrotemporal features in continuous dynamic moving ripples. Across sound types, HC responses overwhelmingly occurred at stimulus onset; they quickly adapted to continuous sounds and did not respond at sound offset. Among all sounds tested, broadband noise was most effective at driving HC activity. Spectral manipulations indicated response prevalence scaled with increasing spectral bandwidth and density. Similar responses were also observed for visual flash and contrast-modulated noise movies, although these were less common than for broadband noise. Sound-evoked face movements, quantified by total face motion energy (FME), correlated with population-level HC activity. However, many individual units responded regardless of FME strength, suggesting both auditory and motor-correlated inputs. Together, our results show that abrupt sound onsets are sufficient to activate many HC neurons in the absence of learning or behavioral engagement. This supports a role for HC in detecting salient environmental changes and supports the idea that auditory inputs contribute directly to HC function.

Understanding how pupil-linked arousal couples with cortical state is crucial for uncovering the neural mechanisms underlying brain state-dependent cognitive and sensory processing. Pupil size fluctuations reflect rapid changes of the pupil-linked arousal system, indexing brain states as well as the activity of neuromodulatory systems, including the locus ceruleus-norepinephrine (LC-NE) system. We investigated the relationship among phasic pupil dilation, cortical state, and neuromodulation by combining optogenetic LC stimulation with electroencephalogram (EEG) recordings and pupillometry in awake mice of both sexes. A comparison between EEG signals during spontaneous phasic pupil dilation and those during phasic pupil dilation evoked by LC stimulation revealed distinct cortical states. Using machine learning techniques, we trained a convolutional neural network classifier to distinguish between types of pupil dilation based on the power dynamics of individual EEG frequency bands. The results confirmed that all EEG bands, but most significantly gamma, differ markedly between spontaneous phasic arousal and LC stimulation-evoked arousal. Moreover, pharmacological manipulations to either block α- or β-adrenergic receptors or agonize α-2-adrenergic receptors were employed to explore how adrenergic receptors could influence the coupling between phasic pupil dilation and cortical state. With each manipulation uniquely modulating EEG power and pupil size, our results highlight the differentiated role of adrenergic receptors in moderating the coupling between pupil-linked arousal and cortical state. This study provides new insights into the complex relationship between pupil-linked arousal and cortical arousal state, underscoring the significant role of the LC-NE system in influencing these arousal states.