Journal of Neuroscience最新文献

Fast-spiking, non-adaptive inhibitory neurons in the thalamic reticular nucleus (TRN) critically gate the reciprocal communication between the thalamus and the cortex. Parvalbumin (PV) neurons express high levels of PV, the sole role of which appears to be calcium buffering. The significance of the PV protein - and its related high calcium-buffering capacity - under pathological conditions, especially in various neuropsychiatric disorders, is underappreciated. Deficiency of SHANK3, an important neuronal protein containing ankyrin, SH3, and PDZ, three canonical domains for protein recognition, causes behavioral changes relevant to autism spectrum disorders (ASD). Here we report TRN PV neurons of Shank3-/- (exon 4-22 deletion) mice of either sex exhibit pronounced increases in burst firing occurrence, decreased tonic firing frequency, and faster dendritic calcium transient decay. We pinpointed reduced PV expression as the culprit and used the added-buffer approach to confirm the decrease in calcium-buffering capacity in mutant neurons. Conversely, supplementing Shank3-/- PV neurons with extra EGTA reversed the abnormal action potential (AP) firing. In addition, the PV neurons from HCN2-/- mice exhibit consistent changes in neuronal excitability, PV expression, and calcium signaling. Together with the study of dopaminergic (DA) neurons in the ventral tegmental area (VTA), these results uncover reduced PV expression, calcium-buffering capacity, and altered neuronal excitability in Shank3-/- and HCN2-/- mice. This pathway, downstream of Shank3 deficiency and HCN channelopathy, may form an important pathological basis not only for ASD but also other neuropsychiatric disorders.Significance Statement SHANK3 is a scaffolding protein that is highly enriched in the postsynaptic density (PSD) of synapses. Mutations and deletions of the SHANK3 gene are directly connected to Phelan-McDermid syndrome (PMS) and autism spectrum disorders (ASD). However, the links between genetic alterations and abnormalities at the cellular, network, and behavioral levels remain unclear. This study uncovered abnormal physiological changes in inhibitory neurons in the thalamus. A definitive link at the cellular level is established between the Shank3 protein deficiency and the pathological basis of related neuropsychiatric disorders.

Episodic memory retrieval engages both sensory reinstatement and internally transformed representations. Due to modality-specific processing, auditory and visual memories may differ in their reliance on these mechanisms. We used functional magnetic resonance imaging (fMRI) and multivoxel pattern analyses (MVPA) to examine how 25 participants (12 males and 13 females) encoded and retrieved naturalistic sounds and videos. Both auditory and visual targets reinstated event-specific fine activation patterns in the association cortex during retrieval, and reinstatement strength correlates with subjective memory vividness. However, after removing encoding traces, auditory episodes showed a markedly larger reliance on internally transformed traces than visual episodes, quantified by "reinstatement-free" retrieval-retrieval similarity. Sensory reinstatement correlated more with the (detail-related) posterior hippocampus, while internal representations also correlated with the (gist-related) anterior hippocampus. Furthermore, temporal voice areas preserved gist-level (human versus non-human) information from encoding to retrieval, whereas fusiform face representations degraded. These findings reveal that auditory and visual memories share a common sensory reinstatement mechanism, but differ in the neural mechanism that supports retrieval, with participants favoring gist over perceptual details during auditory memory retrieval.Significance Statement How does the brain retrieve memories of sights and sounds, and why do their subjective qualities differ? Behavioral work suggests auditory memories may be less vivid but longer-lasting than visual memories. Using fMRI and multivoxel pattern analysis during the recall of naturalistic soundscapes and videos, we showed that auditory episodes, like visual ones, reinstated item-specific activity patterns in higher-order sensory cortex, and that reinstatement fidelity tracks subjective vividness. Critically, however, auditory retrieval relies more heavily on internally generated, gist-like representations that recruit the anterior hippocampus, whereas visual retrieval preserves richer perceptual details. These findings reveal a shared yet flexibly weighted retrieval architecture across senses, account for behavioral asymmetries in memory, and inform sensory-tailored strategies for education, ageing, and neurorehabilitation.

Neuronal network models have indicated that so-called critical dynamics facilitate efficient information processing, while criticality disruptions were linked to neuropathology through excitation/inhibition (E/I) imbalances. However, there is limited empirical evidence for a relationship between critical brain dynamics and cognition in healthy children and adolescents. Here, we investigate how these dynamics relate to intelligence in a developing cohort. We recorded eyes-open resting EEG in 128 children (6-19 years, 72 female) and quantified near-critical brain dynamics in the alpha band using functional excitation/inhibition ratio (fE/I), and in non-oscillatory activity using the 1/f aperiodic exponent of the power spectrum. We devised models relating intelligence to fE/I and 1/f exponent across seven Yeo7 functional brain networks ranked from lower-order sensorimotor to higher-order association networks. We observed significant correlations between fE/I and 1/f exponent and IQ in association cortices, in contrast to sensorimotor cortices. Children in the high-IQ group had fE/I ratios closer to the theoretical critical value of 1 in association cortices compared to the low-IQ group. The association-sensorimotor axis rank moderated the associations between 1/f exponent and IQ, these associations decreasing on a gradient across the hierarchy of the Yeo7 networks. Age and rank moderated the fE/I-IQ association, with the association-sensorimotor effect size gradient most visible in adolescents. Together, the results suggest that individual variation in criticality-sensitive biomarkers in association networks may be linked to IQ differences in an age-dependent manner, consistent with the hypothesis that developmental modulation of critical dynamics across the cortical hierarchy may support more efficient cognitive processing.Significance statement The healthy brain is posited to operate near a critical transition between a sub-critical state, characterized by excessive neural inhibition, and a super-critical state, marked by excessive neural excitability. Preclinical and computational modelling studies have shown that this critical state is conducive to optimal information processing. The present study provides insight, using electroencephalographic (EEG) brain recordings, into how brain criticality is linked to intelligence during development. The study offers important empirical evidence in agreement with computational studies linking brain criticality to optimal functioning, and may help to better understand the role of criticality in brain disorders.

Our visual world consists of an immense number of unique objects and yet, we are easily able to identify, distinguish, and reason about the things we see within a few hundred milliseconds. Here, we used a large-scale and comprehensively sampled stimulus set and developed an analysis approach to capture how rich, multidimensional object representations unfold over time in the human brain. We modelled time-resolved MEG signals of four humans (2 females and 2 males) viewing single presentations of tens of thousands of object images based on millions of behavioral judgments. Extracting behavior-derived object dimensions from similarity judgments, we developed a data-driven approach to guide our understanding of the neural representation of the object space and found that every dimension is reflected in the neural signal. Studying the temporal profiles for different object dimensions we found that the time courses fell into two broad types, with either a distinct and early peak (∼125 ms) or a slow rise to a late peak (∼300 ms). Further, early effects were stable across participants, in contrast to later effects which showed more variability, suggesting that early peaks may carry stimulus-specific and later peaks more participant-specific information. Dimensions with early peaks appeared to be primarily visual dimensions and those with later peaks more conceptual, suggesting that conceptual representations are more variable across people. Together, these data provide a comprehensive account of how behavior-derived object properties unfold in the human brain and form the basis for the rich nature of object vision.Significance Statement Humans are excellent at identifying, distinguishing, and reasoning about a huge number of objects - all of which requires comparing visual information to internal representations and assign what we see to object categories. Simultaneously, we also process properties relevant to behavior. Seeing a cat, for instance, involves recognizing both its physical properties (fur, size, ears, claws) and many other types of properties (living, moving, playful) that add up to our idea of 'cat.' In our study, we investigated the time course of the neural response using MEG neuroimaging. We found that a diverse array of object properties relevant to behavior contributes to the neural signal and reveal how such rich object representations unfold over time in the human brain.

Economic choice entails computing and comparing the subjective values of different goods. Orbitofrontal cortex (OFC) is thought to contribute to both operations. However, previous work focused almost exclusively on binary choices, raising the question of whether current notions hold for multinary choices. Here we recorded from male rhesus monkeys making trinary choices. Offers varied on three dimensions - juice flavor, quantity, and probability. In these experiments, quantity and probability varied continuously within a preset range. Animal choices were generally risk seeking and satisfied independence of irrelevant alternatives (IIA) - a fundamental assumption in standard economic theory. Different neurons encoded the values of individual offers, the choice outcome, and the chosen value - i.e., the same variables previously identified under binary choices. In addition, other cell groups encoded the chosen probability and the chosen hemifield. The activity of offer value cells reflected the risk attitude and fluctuated from session to session in ways that matched fluctuations observed behaviorally. In other words, the activity of these neurons reflected the subjective nature of value. Importantly, the representation of decision variables in OFC was invariant to changes in menu size - a property that effectively implies IIA.Significance statement Orbitofrontal cortex (OFC) is necessary for the computation and the comparison of subjective values underlying economic choices. However, most previous studies examined choices between two options, and it remains unclear whether current notions apply to multinary choices. Barretto-Garcia and colleagues recorded from the OFC of monkeys choosing between three juice flavors offered in variable quantities and probabilities. Animals' choices were consistent with the independence of irrelevant alternatives (IIA) - a condition necessary for rational behavior. Different neurons in OFC encoded the values of individual offers, the choice outcome, and the chosen value. The activity of value-encoding cells reflected the animals' risk attitude. Importantly, the representation of decision variables was invariant to changes in menu size - a property that effectively implies IIA.

The interaction of the limbic system and frontal cortex of the primate brain is important in many affective behaviors. For this reason, it is heavily implicated in a number of psychiatric conditions. This system is often studied in the macaque monkey, the most largely-used non-human primate model species. However, how evolutionary conserved this system is and how well results obtained in any model species translate to the human brain can only be understood by studying its organization across the primate order. Here, we present an investigation of the topology of limbic-frontal connections across seven species, representing all major branches of the primate family tree: humans (13 females, 11 males), chimpanzee (1 female), gorilla (1 male), gibbon (1 male), macaque (1 female, 2 males), squirrel monkey (1 female, 2 males), lemur (3 males). We show that dichotomous organization of amygdalofugal and uncinate connections with frontal cortex is conserved across all species. Subgenual connectivity of the cingulum bundle, however, seems less prominent in prosimian and New World monkey brains. These results inform both translational neuroscience and primate brain evolution.Significance statement The interaction between the limbic system and the frontal cortex is critical for affective behaviors and is implicated in psychiatric conditions. While often studied in macaques, understanding how conserved these circuits are across primates is essential for translational relevance. Here, we investigate limbic-frontal connections across seven primate species, spanning all major evolutionary branches. We demonstrate that the dichotomous organization of amygdalofugal and uncinate pathways is conserved, while subcallosal cingulate connectivity of the cingulum bundle is less prominent in prosimian and New World monkeys. These findings provide key insights into the evolution of primate brains and enhance our understanding of the translational potential of non-human primate models for studying human brain function and disorders.

Chemical synapses are fundamental units for the transmission of information throughout the nervous system. The cytoskeleton allows to build, maintain and transform both pre- and postsynaptic contacts, yet its organization and the role of its unique synaptic nanostructures are still poorly understood. Here we present a presynapse-on-glass model based on cultured neurons from rat pups of either sex. Presynaptic specializations are robustly induced along axons by micropatterned dots of neuroligin, allowing the controlled orientation and easy optical visualization of functional induced presynapses. We demonstrate the relevance and usefulness of this presynapse-on-glass model for the study of presynaptic actin architecture, showing that a majority of induced presynapses are enriched in actin, with this enrichment being correlated to higher synaptic cycling activity. We confirm our previous results on bead-induced presynapses by identifying distinct actin nanostructures within presynapses: corrals, rails and mesh. Furthermore, we leverage the controlled orientation of the presynapse-on-glass model, visualizing the arrangement of these actin structures relative to the active zone nanoclusters using multicolor 3D Single Molecule Localization Microscopy (SMLM), and relative to the sub-diffractive localization exocytic events using a correlative live-cell and SMLM approach.Significance statement The actin cytoskeleton plays important but poorly understood roles at presynapses, fundamental compartments for communication in the nervous system. We developed a presynapse-on-glass model to induce isolated, optically accessible presynaptic specializations along the axon of cultured neurons. This model recapitulates the presynaptic actin enrichment and distinct nanostructures we previously uncovered using presynapses induction by large beads. The controlled orientation of presynapses in our new model allows to go further: we visualized the nanoscale arrangement of actin and presynaptic components by multicolor nanoscopy, and could link actin nanostructures to the precise location of synaptic vesicle release thanks to a correlative live-cell/super-resolution microscopy approach. This demonstrates the relevance of our model for deciphering the nano-architecture of presynapses and understand their molecular functioning.

Bidirectional interactions between sleep, seizures, and epilepsy remain incompletely understood. Evidence from animal models and people with focal epilepsy suggest that seizures may engage mechanisms of memory consolidation during post-ictal sleep to reinforce and strengthen synaptic connections within the pathological networks that generates seizures, termed seizure-related consolidation (SRC). Human studies of post-ictal sleep changes supportive of SRC, however, are limited by small sample size and restricted observations of post-ictal sleep. We investigated the interplay between seizures and sleep by analyzing sleep-wake and seizure catalogs derived from continuous local field potential (LFP) recordings in 11 people (6 males and 5 females) with drug-resistant focal epilepsy implanted with novel investigational devices and living in their natural environments. Our findings demonstrate that post-ictal rapid-eye-movement sleep duration is reduced, whereas slow-wave sleep duration, slow-wave LFP spectral power and waveform slope are increased compared to inter-ictal nights without preceding seizures. The most significant changes localize to the epileptogenic networks generating the participants' habitual seizures. These results reveal parallels between SRC and physiological memory consolidation, providing novel insights into the potential role of post-ictal sleep in strengthening epileptic neural engrams, and may have implications for targeted disruption of post-ictal sleep and SRC in focal epilepsy.Significance Statement This study uses long-term intracranial local field potential (LFP) recordings to investigate the relationship between seizures and sleep in epilepsy. The post-ictal slow-wave sleep duration, spectral power, and waveform slope are increased compared to inter-ictal. Post-ictal rapid-eye-movement sleep duration is reduced. These changes are most significant within the epileptogenic networks that generate the participants habitual seizures. While this study cannot directly elucidate the mechanism involved in post-ictal sleep modulation, the study results are consistent with post-ictal sleep reinforcing pathological seizure networks through a process similar to physiological memory consolidation, here termed seizure-related consolidation (SRC). These results provide novel insights into the potential role of post-ictal sleep in epilepsy, with implications for potential targeted disruption of post-ictal sleep and SRC.