Journal of Neuroscience最新文献

Neonatal hypoxia (Hx) causes white matter (WM) injury, particularly in the cerebellum. We previously demonstrated Hx-induced reduction of cerebellar Purkinje cell (PC) activity results in locomotor deficits. Yet, the mechanism of Hx-induced cerebellar WM injury and associated locomotor abnormalities remains undetermined. Here, we show that the cerebellar WM injury and linked locomotor deficits are driven by PC activity and are reversed when PC activity is restored. Using optogenetics and multielectrode array recordings, we manipulated PC activity and captured the resulting cellular responses in WM oligodendrocyte precursor cells and GABAergic interneurons. To emulate the effects of Hx, we used light activated Halorhodopsin targeted specifically to the PC layer of normal mice. Suppression of PC firing activity at P13 and P21 phenocopied the locomotor deficits observed in Hx. Moreover, histopathologic analysis of the developing cerebellar WM following PC inhibition (P21) revealed a corresponding reduction in oligodendrocyte maturation and myelination, akin to our findings in Hx mice. Conversely, PC stimulation restored PC activity, promoted oligodendrocyte maturation and enhanced myelination, resulting in reversed Hx-induced locomotor deficits. Our findings highlight the crucial role of PC activity in cerebellar WM development and locomotor performance following neonatal injury.Significance statement Adult survivors of prematurity often experience locomotor incoordination secondary to cerebellar dysfunction. The cerebellum develops in the last trimester of pregnancy, a period that preterm neonates miss. Here, we show how neonatal hypoxia alters the crosstalk between neurons and oligodendrocytes in the developing cerebellum. Through loss-of-function and gain-of-function experiments, we unveiled that neuronal activity drives cerebellum-associated white matter injury and locomotor dysfunction after hypoxia. Importantly, restoring neuronal activity using direct neurophysiological stimulation reversed the hypoxia-induced white matter injury and locomotor deficits. Early cerebellar neuronal stimulation could serve as a potential therapeutic intervention for locomotor dysfunction in neonates.

Barn owls enable investigation of neural mechanisms underlying stimulus selection of concurrent stimuli. The audio-visual space map in the optic tectum (OT), avian homologue of the superior colliculus, encodes relative strength of concurrent auditory stimuli through spike response rate and interneuronal spike train synchrony (STS). Open questions remain regarding stimulus selection in downstream forebrain regions lacking topographic coding of auditory space, including the functional consequences of interneuronal STS on interregional signaling. To this end, we presented concurrent stimuli at different locations and manipulated relative strength while simultaneously recording neural responses from OT and its downstream thalamic target, nucleus rotundus (nRt), in awake barn owls of both sexes. Results demonstrated that broadly spatially tuned nRt units exhibit different spike response patterns to competition depending on spatial tuning preferences. Modeling suggests nRt units integrate convergent inputs from distant locations across midbrain map regions. Additionally, STS within nRt reflects the temporal properties of the strongest stimulus. Furthermore, interregional STS between OT and nRt was strongest when spatial tuning overlap between units across regions was large and when the strongest stimulus location during competition was favorable for units in both regions. Additionally, though gamma oscillations synthesized within OT are weakly propagated within nRt, average gamma power across regions correlates with strength of interregional STS. Overall, we demonstrate that nRt integrates inputs across distant areas of OT, retains spatial information through differences in strength of inputs from various locations of the midbrain map across neurons, and prioritizes coding of identity features to the strongest sound.Significance Statement The brain strategically selects and preferentially processes salient stimuli. A critical function to this process involves transferring salient information across regions that may exhibit drastic transformations in coding schemes. Our study in barn owls investigates bottom-up signaling between the midbrain space map and its downstream thalamic target, which lacks spatial topography as also observed in mammalian auditory forebrain regions to elucidate general mechanisms underlying how spatial location information and other properties of the strongest sound are relayed between regions. Results show that the thalamus integrates neural responses widely across the midbrain map, retains coding of spatial location through varying strength of inputs of the map across neurons, and prioritizes further coding of identity features only to the strongest sound.

Cognitive control is engaged by working memory processes and high-demand situations like antisaccade, where one must suppress a prepotent response. While it is known to be supported by the frontoparietal control network, how intra- and inter-areal dynamics contribute to cognitive control processes remain unclear. N-Methyl-D-aspartate glutamate receptors (NMDARs) play a key role in prefrontal dynamics that support cognitive control, and its antagonists, such as ketamine, are known to alter task-related prefrontal activities and impair cognitive performance. However, the role of NMDAR in cognitive control-related frontoparietal dynamics remain underexplored. Here, we simultaneously recorded local field potentials and single unit activities from lateral prefrontal (lPFC) and posterior parietal cortices (PPC) in two male macaque monkeys during a rule-based antisaccade task, with both Rule-Visible (RV) and Rule-Memorized (RM) conditions. In addition to altering the E/I balance in both areas, ketamine had a negative impact on rule-coding in true oscillatory activities. It also reduced frontoparietal coherence in a frequency- and rule-dependent manner. Granger prediction analysis revealed that ketamine induced an overall reduction in bidirectional connectivity. Among antisaccade trials, a greater reduction in lPFC-PPC connectivity during the delay period preceded a greater delay in saccadic onset under the RM condition, and a greater deficit in performance under the RV condition. Lastly, ketamine compromised rule coding in lPFC neurons in both RV and RM conditions, and in PPC neurons only in the RV condition. Our findings demonstrate the utility of acute NMDA receptor antagonist in understanding the mechanisms through which frontoparietal dynamics support cognitive control processes.Significance statement A low dose of ketamine is known to induce a transient cognitive control deficit in healthy humans and animals, but it remains unclear whether this deficit is related to a frontoparietal dysconnection. In macaque monkeys performing a rule-based pro- and anti-saccade task, we found that ketamine impaired information coding in frontoparietal neuron, local oscillations and inter-areal synchrony in a rule- and frequency-dependent manner. Notably, under the antisaccade rule, the amount of impairment in task performance could be predicted by the loss in fronto-parietal connectivity in the period just before the monkeys responded. The observations support the utility of NMDA receptor antagonists like ketamine as a tool to understand the role of frontoparietal dynamics in cognitive control.

Hostility often co-occurs in parents and associates with increased aggression and inattention problems in children. In this population-based cohort of 484 mother-father-child neuroimaging trios, we investigated the degree to which associations of prenatal and childhood parental hostility would be associated with maternal, paternal and child brain structural differences. Also, we examined whether hippocampal volumes of the parents or child mediate the association of prenatal parental hostility with child externalizing behaviors. Maternal and paternal hostility was assessed with the hostility subscale of the Brief-Symptom-Inventory at three time points: prenatally at 30 weeks gestation, and when the child was 3 and 10 years old. During adolescence assessment wave (age 14), maternal, paternal, and offspring assessment included a magnetic-resonance-imaging (MRI). Child externalizing problems were assessed with Youth-Self-Report-Child-Behavior-Checklist.Our findings suggest that maternal and paternal hostility were each associated with smaller gray matter, white matter, and hippocampal volumes of their own and their partner's brain. Prenatal maternal but not paternal hostility was associated with smaller total gray matter, white matter, and hippocampal volumes in the offspring. The child's hippocampal volumes partially mediated the associations of prenatal parental hostility (latent-construct) with adolescent externalizing behavior, even after adjusting for prior child externalizing problems. Moreover, parental psychopathology may have long-lasting neurodevelopmental correlates in children that underlie the intergenerational transmission of behavioral problems. The behavior of family members results from a system of interdependent dyadic relationships over time that associate with specific brain structural differences.Significance statement Parental hostility often co-occurs in the parents. Research suggests that what transpires in one family subsystem, e.g. hostility among parents, is related to what transpires in other subsystems, e.g. mother-child or father-child, and can negatively impact child development. To understand the neurobiological effects of parental hostility on the families, these can best be studied with trio analysis as parents and children may all be affected. Overall, the findings elucidate how hostility of a parent negatively relates to different family subsystems and associated brain characteristic, such as the hippocampal volume. Our findings suggest that the behavior of family members results from a system of interdependent dyadic relationships over time that associate with specific brain structural differences.

From a young age, children have advanced social perceptual and reasoning abilities. However, the neural development of these abilities is still poorly understood. To address this gap, we used fMRI data collected 122 3-12-year-old children (64 females) and 33 adults (20 females) watched an engaging and socially rich movie to investigate how the cortical basis of social processing changes throughout development. We labeled the movie with visual and social features, including motion energy, presence of a face, presence of a social interaction, theory of mind (ToM) events, valence and arousal. Using a voxel-wise encoding model trained on these features, we find that models based on visual (motion energy) and social (faces, social interaction, ToM, valence, and arousal) features can both predict brain activity in children as young as three years old across the cortex, with particularly high predictivity in motion selective middle temporal region (MT) and the superior temporal sulcus (STS). Furthermore, models based on individual social features showed that while there may be some development throughout childhood, social interaction information in the STS is present in children as young as three years old and appears adult-like by age seven. The current study, for the first time, links neural activity in children to pre-defined social features in a narrative movie and suggests social interaction perception is supported by early developing neural responses in the STS.Significance Statement This study investigates the neural basis for social scene perception ability in children using fMRI data collected while participants watch a short, animated movie. Unlike most prior studies with movies, we labeled a range of visual and social features in the movie and used machine learning analyses to link each feature to fMRI responses in adults and children ages 3-12. Notably, our results demonstrate strong evidence that children as young as three years old show significant responses to most visual and social features in the movie, including social interaction responses in the superior temporal sulcus (STS), a region in the brain that is well known to be important in social interaction processing in adults.

The human auditory cortex is organized according to the timing and spectral characteristics of speech sounds during speech perception. During listening, the posterior superior temporal gyrus is organized according to onset responses, which segment acoustic boundaries in speech, and sustained responses, which further process phonological content. When we speak, the auditory system is actively processing the sound of our own voice to detect and correct speech errors in real time. This manifests in neural recordings as suppression of auditory responses during speech production compared to perception, but whether this differentially affects onset and sustained temporal profiles is not known. Here we investigated this question using intracranial EEG recorded from seventeen pediatric, adolescent, and adult patients with medication-resistant epilepsy while they performed a reading/listening task. We identified onset and sustained responses to speech in bilateral auditory cortex and observed a selective suppression of onset responses during speech production. We conclude that onset responses provide a temporal landmark during speech perception that is redundant with forward prediction during speech production and are therefore suppressed. Phonological feature tuning in these "onset suppression" electrodes remained stable between perception and production. Notably, auditory onset responses and phonological feature tuning were present in the posterior insula during both speech perception and production, suggesting an anatomically and functionally separate auditory processing zone that we believe to be involved in multisensory integration during speech perception and feedback control.Significance Statement Specific neural populations in the auditory cortex preferentially respond to the onset of speech sounds. These "onset responses" aid in perceiving boundaries in continuous speech. We recorded neural responses from patients with intracranial electrodes during a speaking and listening task to investigate the role of onset responses in speech production. Onset responses were present in the auditory cortex during listening, but absent during speaking. On the other hand, onset responses were observed in the insula during both conditions, suggesting a different functional role for the insula in auditory feedback processing. These findings extend our knowledge of how different parts of the brain involved in feedback control operate during speech production by identifying two functionally and anatomically distinct patterns of activity.

Mutations in human VPS4A are associated with neurodevelopmental defects, including motor delays and defective muscle tone. VPS4A encodes a AAA-ATPase required for membrane scission, but how mutations in VPS4A lead to impaired control of motor function is not known. Here we identified a mutation in zebrafish vps4a, T248I, that affects sensorimotor transformation. Biochemical analyses indicate that the T248I mutation reduces the ATPase activity of Vps4a and disassembly of ESCRT filaments, which mediate membrane scission. Consistent with the role for Vps4a in exosome biogenesis, vps4a^T248I larvae have enlarged endosomal compartments in the CNS and decreased numbers of circulating exosomes in brain ventricles. Resembling the central form of hypotonia in VPS4A patients, motor neurons and muscle cells are functional in mutant zebrafish. Both somatosensory and vestibular inputs robustly evoke tail and eye movements, respectively. In contrast, optomotor responses, vestibulospinal, and acoustic startle reflexes are absent or strongly impaired in vps4a^T248I larvae, indicating a greater sensitivity of these circuits to the T248I mutation. ERG recordings revealed intensity-dependent deficits in the retina, and in vivo calcium imaging of the auditory pathway identified a moderate reduction in afferent neuron activity, partially accounting for the severe motor impairments in mutant larvae. Further investigation of central pathways in vps4a^T248I mutants showed that activation of descending vestibulospinal and midbrain motor command neurons by sensory cues is strongly reduced. Our results suggest that defects in sensorimotor transformation underly the profound yet selective effects on motor reflexes resulting from the loss of membrane scission mediated by Vps4a.Significance Statement Here we present a T248I mutation in vps4a, which causes sensorimotor defects in zebrafish larvae. Vps4a plays a key role in membrane scission. Spanning biochemical to systems level analyses, our study indicates that a reduction in Vps4a enzymatic activity leads to abnormalities in membrane-scission dependent processes such as endosomal protein trafficking and exosome biogenesis, resulting in pronounced deficits in sensorimotor transformation of visual, auditory, and vestibular cues. We suggest that the mechanisms underlying this type of dysfunction in zebrafish may also contribute to the condition seen in human patients with de novo mutations in the human VPS4A orthologue.

Crowding, the phenomenon of impaired visual discrimination due to nearby objects, has been extensively studied and linked to cortical mechanisms. Traditionally, crowding has been studied extrafoveally; its underlying mechanisms in the central fovea, where acuity is highest, remain de-bated. While low-level oculomotor factors are not thought to play a role in crowding, this study shows that they are key factors in defining foveal crowding. Here we investigate the influence of fixational behavior on foveal crowding and provide a comprehensive assessment of the magnitude and extent of this phenomenon (N=13 human participants, 4 males). Leveraging on a unique blend of tools for high-precision eyetracking and retinal stabilization, we show that removing the retinal motion introduced by oculomotor behavior with retinal stabilization, diminishes the negative effects of crowding. Ultimately, these results indicate that ocular drift contributes to foveal crowding re-sulting in the same pooling region being stimulated both by the target and nearby objects over the course of time, not just in space. The temporal aspect of this phenomenon is peculiar to crowding at this scale and indicates that the mechanisms contributing to foveal and extrafoveal crowding differ.Significance Statement: Foveated stimuli are often crowded. The effects of crowding have been extensively studied in the visual periphery and are thought to have a cortical origin. Nonetheless, foveal crowding mechanisms remain elusive. Here we show that acuity drops by two lines on a Snellen Chart when flankers surround a stimulus presented at the very center of gaze. Further, at this scale, crowding cannot be regarded as a purely cortical phenomenon. Because foveal neurons' receptive fields are the smallest, eye jitter during fixation introduces spatial uncertainty by sweeping target and surrounding distractors over the same cortical pooling region even during short fixation periods, exacerbating crowding effects.

Age-related changes in the BOLD response could reflect neuro-vascular coupling modifications rather than simply impairments in neural functioning. In this study, we propose the use of a sparse dynamic causal model (sDCM) to decouple neuronal and vascular factors in the BOLD signal, with the aim of characterizing the whole-brain spatial pattern of hemodynamic sensitivity to healthy aging, as well as to test the role of hemodynamic features as independent predictors in an age-classification model. sDCM was applied to the resting-state fMRI data of a cohort of 126 healthy individuals in a wide age range (31 females), providing reliable estimates of the hemodynamic response function (HRF) for each subject and each region of interest. Then, some features characterizing each HRF curve were extracted and used to fit a multivariate logistic regression model predicting the age class of each individual. Ultimately, we tested the final predictive model on an independent dataset of 338 healthy subjects (173 females) selected from the Human Connectome Project Aging (HCP-A) and Development (HCP-D) cohorts. Our results entail the spatial heterogeneity of the age effects on the hemodynamic component, since its impact resulted to be strongly region- and population-specific, discouraging any space-invariant corrective procedures that attempt to correct for vascular factors when carrying out functional studies involving groups with different ages. Moreover, we demonstrated that a strong interaction exists between some specific hemodynamic features and age, further supporting the essential role of the hemodynamic factor as independent predictor of biological aging, rather than a simple confounding variable.Significance statement By inferring region-wise hemodynamic profiles at the individual level, this is the first study providing an exhaustive whole-brain characterization of the hemodynamic sensitivity to healthy aging, reporting further evidence of the vascular changes across the adult lifespan. Using a predictive framework, we analysed the statistical influence of advancing age on individual regional hemodynamic attributes, offering a quantitative evaluation of the diverse hemodynamic bias across different brain regions. We then unveiled a specific set of hemodynamic predictors to discriminate young from elderly people, mainly describing vascular properties of right-hemispheric areas. This suggests the asymmetric nature of vascular degeneration processes affecting the human brain at the latest stage of life, other than a potential biomarker that could be relevant for brain-age prediction.

While humans typically saccade every ∼250 ms in natural settings, studies on vision tend to prevent or restrict eye movements. As it takes ∼50 ms to initiate and execute a saccade, this leaves only ∼200 ms to identify the fixated object and select the next saccade goal. How much detail can be derived about parafoveal objects in this short time interval, during which foveal processing and saccade planning both occur? Here, we had male and female human participants freely explore a set of natural images while we recorded magnetoencephalography and eye movements. Using multivariate pattern analysis, we demonstrate that future parafoveal images could be decoded at the feature and category level with peak decoding at ∼110 ms and ∼165 ms respectively, while the decoding of fixated objects at the feature and category level peaked at ∼100 ms and ∼145 ms. The decoding of features and categories was contingent on the objects being saccade goals. In sum, we provide insight on the neuronal mechanism of pre-saccadic attention by demonstrating that feature and category specific information of foveal and parafoveal objects can be extracted in succession within a ∼200 ms intersaccadic interval. These findings rule out strict serial or parallel processing accounts but are consistent with a pipeline mechanism in which foveal and parafoveal objects are processed in parallel but at different levels in the visual hierarchy.Significance Statement We provide neural evidence that future parafoveal saccade goals are processed surprisingly quickly at the feature and the category level before we saccade to them. Specifically, using multivariate pattern analysis applied to magnetoencephalography and eye-tracking data, we found that information about the colour and the category of parafoveal objects emerged at ∼110 ms and ∼165 ms respectively, with the same information about foveal objects emerging ∼100 ms and ∼145 ms. Our findings provide novel insight into the neuronal dynamics of parafoveal previewing during free visual exploration. The dynamics rule out strict serial or parallel processing, but are consistent with a pipelining mechanism in which foveal and parafoveal objects are processed in parallel but at different levels in the visual hierarchy.