Rodents manipulate their vibrissae to actively interact with their environment. The vibrissa area of the primary motor cortex (vM1) is a central player in orchestrating the rhythmic whisker movement, known as "whisking," and previous in vivo electrophysiological studies have revealed the presence of neurons exhibiting activity modulation related to whisking within vM1. vM1 innervates premotoneurons regulating whisking in the reticular nucleus via corticofugal fibers originating exclusively from pyramidal tract (PT) neurons in Layer 5 (L5), while this layer also contains another pyramidal cell subclass, intratelencephalic (IT) neurons, whose axons remain confined within the telencephalon. However, the potential diversity among these morphological subtypes involved in whisking execution remains largely unexplored. Here, we demonstrate functional heterogeneity among both PT and IT neurons in the execution of whisker movement. Juxtacellular recording within L5 of vM1 in head-fixed, awake male mice during self-initiated whisking, followed by post hoc immunohistochemistry, revealed that firing activity in a substantial proportion of neurons was significantly correlated with parameters of whisker movement, such as whisking amplitude and midpoint. Among these, approximately half were activated during whisking, while the rest preferred nonwhisking periods, with these modulation patterns corresponding to their baseline firing properties at rest. Although both types of whisking-related neurons were present within PT and IT populations, whisking-related activation was relatively prevalent in PT neurons, whereas nonwhisking preference was more typical of IT cells. Our findings highlight the functional heterogeneity within morphologically defined neuronal subclasses, providing new insights into the intricate cortical mechanisms underlying various rhythmic movements.
The recent past helps us predict and prepare for the near future. Such preparation relies on working memory (WM) which actively maintains and manipulates information providing a temporal bridge. Numerous studies have shown that recently presented visual stimuli can be decoded from fMRI signals in visual cortex (VC) and the intraparietal sulcus (IPS), suggesting that these areas sustain the recent past. Yet, in many cases, concrete, sensory signals of past information must be transformed into the abstract codes to guide future cognition. However, this process remains poorly understood. Here, human participants of either sex used WM to maintain a separate spatial location in each hemifield wherein locations were embedded in a learned spatial sequence. On each trial, participants made a sequence-match decision to a probe and then updated their WM with the probe. The same abstract sequence guided judgments in each hemifield, allowing the separate detection of concrete spatial locations (hemifield-specific) and abstract sequence positions (hemifield-general) and also tracking of representations of the past (last location/position) and future (next location/position). Consistent with previous reports, concrete past locations held in WM could be decoded from VC and IPS. Moreover, in anticipation of the probe, representations shifted from past to future locations in both areas. Critically, we observed abstract coding of future sequence positions in the IPS whose magnitude related to speeded performance. These data suggest that the IPS sustains abstract codes to facilitate future preparation and reveal a transformation of the sensory past into abstract codes guiding future behavior.
A central question in sensorimotor neuroscience is how sensory inputs are mapped onto motor outputs to enable swift and accurate responses, even in the face of unexpected environmental changes. In this study, we leverage cortico-motor coherence as a window into the dynamics of sensorimotor loops and explore how it relates to online visuomotor control. We recorded brain activity using electroencephalography (EEG) while human participants (of either sex) performed an isometric tracking task involving transient, unpredictable visual perturbations. Our results show that coherence between cortical activity and motor output (force) in the alpha band (8-13 Hz) is associated with faster motor responses, while beta-band coherence (18-30 Hz) promotes more accurate control, in turn linked to a higher likelihood of obtaining rewards. Both effects are most pronounced near the onset of the perturbation, underscoring the predictive value of cortico-motor coherence for sensorimotor performance. Single-trial analyses further reveal that deviations from the preferred cortico-motor phase relationship are associated with longer reaction times and larger errors, and these phase effects are independent of power effects. Thus, beta-band coherence may reflect a cautious, reward-efficient control strategy, while alpha-band coherence enables quicker, though not necessarily efficient, motor responses, indicating a complementary, reactive control mode. These results highlight the finely tuned nature of sensorimotor control, where different aspects of sensory-to-motor transformations are governed by frequency-specific neural synchronization on a moment-to-moment basis. By linking neural dynamics to motor output, this study sheds light on the spectrotemporal organization of sensorimotor networks and their distinct contribution to goal-directed behavior.Significance statement How the brain integrates sensory information with ongoing motor plans to enable quick and accurate responses to unpredictable events remains unclear. By analyzing the oscillatory coupling between brain activity and motor output (force), we identify patterns that selectively govern key attributes of effective behavior. Oscillatory coupling in the alpha band (∼10 Hz) supports rapid reactions, while coupling in the beta band (∼25 Hz) promotes cautious, reward-driven control. These findings enhance our understanding of how the brain organizes sensorimotor processes, allowing us to flexibly adapt to changing environments and goals. This research has potential implications for developing more effective treatments for motor disorders, improving human-machine interactions, and advancing robotic control systems.
Autosomal dominant mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), underlie spinocerebellar ataxia type 27A (SCA27A), a devastating multisystem disorder resulting in progressive deficits in motor coordination and cognitive function. Mice lacking iFGF14 exhibit similar phenotypes, which have been linked to iFGF14-mediated modulation of the voltage-gated sodium (Nav) channels that regulate high-frequency repetitive firing of cerebellar Purkinje neurons, the main output neurons of the cerebellar cortex. To investigate the in vivo mechanisms underlying SCA27A, we developed a targeted knock-in strategy to introduce the first point mutation identified in FGF14 into the mouse Fgf14 locus (Fgf14F145S ). Current-clamp recordings from Purkinje neurons in acute cerebellar slices from adult male and female Fgf14F145S/+ mice revealed that high-frequency repetitive firing, which is characteristic of wild-type Purkinje neurons, was replaced by prolonged bursts of action potentials. A shift from tonic to burst firing was mimicked in wild-type Purkinje neurons by bath application of the Nav channel toxin, tetrodotoxin. Burst firing was also measured in heterozygous Fgf14 knockout (Fgf14+/- ) Purkinje neurons, suggesting that the impaired firing of Fgf14F145S/+ Purkinje neurons reflects reduced Nav channel availability, owing to the loss of the iFGF14 protein. Western blot analyses confirmed reduced iFGF14 protein expression in cerebellar lysates prepared from Fgf14F145S/+ (and Fgf14+/- ) animals and voltage-clamp experiments revealed a hyperpolarizing shift in the voltage-dependence of closed-state Nav channel inactivation in Fgf14F145S/+ (and Fgf14+/- ) Purkinje neurons. Together, these results indicate that Fgf14 haploinsufficiency and reduced Nav channel availability underlie impaired firing in Fgf14F145S/+ Purkinje neurons.Significance Statement Autosomal dominant mutations in FGF14 underlie spinal cerebellar ataxia 27A (SCA27A), a neurological disorder associated with progressive motor and cognitive deficits. To explore the in vivo functional effects of SCA27A-linked mutations in FGF14, we developed a mouse model with targeted knock-in of the first point mutation identified in FGF14, which results in a single amino acid change (phenylalanine to serine) in the iFGF14 protein, iFGF14F145S The experiments here revealed that spontaneous high-frequency repetitive firing, characteristic of wild-type Purkinje neurons, is impaired iFGF14F145S Purkinje neurons, and that this impairment in firing properties reflects Fgf14 haploinsufficiency, reduced iFGF14 protein expression, and resulting alterations in Nav channel availability.
Visual attention is shaped by statistical regularities in the environment, with spatially predictable distractors being proactively suppressed. The neural mechanisms underpinning this suppression remain poorly understood. In this study, we employed magnetoencephalography (MEG) and multivariate classification analysis to investigate how predicted distractor locations are proactively processed in the human brain. Male and female human participants engaged in a statistical learning visual search task that required them to identify a target stimulus while ignoring a colour-singleton distractor. Critically, the distractor appeared more frequently on one side of the visual field, creating an implicit spatial prediction. Our results revealed that distractor locations were encoded in temporo-occipital brain regions prior to the presentation of the search array, supporting the hypothesis that proactive suppression guides visual attention away from predictable distractors. The neural activity patterns corresponding to this pre-search distractor processing extended to post-search activity during late attentional stages (∼200 ms), suggesting an integrated suppressive mechanism. Notably, this generalization from pre- to post-search phases was absent in the early sensory processing stages (∼100 ms), suggesting that post-search distractor processing is not merely a continuation of sustained proactive processing, but involves re-engagement of the same mechanism at distinct stages. These findings establish a mechanistic link between proactive and reactive processing of predictable distractors, demonstrating both shared and unique contributions to attentional selection.Significance Statement In a world full of distractions, anticipating and ignoring irrelevant stimuli is crucial. The brain suppresses distractions both proactively (by preparing for expected distractions) and reactively (by responding after they appear). Yet, how these processes interact is unclear. In this study, we used MEG and multivariate classification during a visual search task, where distractors appeared more frequently on one side, enabling unconscious learning of their likely location. Our results indicate that the brain encodes the distractor's location even before the search begins, showing proactive processing. Moreover, we found a connection between this early suppression and the brain's later response to the distractors, suggesting that proactive and reactive distractor processing rely on shared mechanisms.
In addition to providing outputs from the cerebellar cortex, Purkinje cell (PC) axon collaterals target other PCs, molecular layer interneurons (MLIs), and Purkinje layer interneurons (PLIs). It was assumed that PC collateral to MLI synapses provide positive feedback to PCs via the PC-MLI-PC pathway, because it was thought that MLIs primarily inhibit PCs. However, it was recently shown that MLIs consist of two subtypes: MLI1s primarily inhibit PCs, whereas MLI2s mainly inhibit MLI1s and disinhibit PCs. Clarifying PC connectivity onto these MLI subtypes is vital to understanding the influence of feedback from PC collaterals. Here we use a combination of serial EM and optogenetic studies to characterize PC synapses onto MLI subtypes in mice of either sex. EM reconstructions show that PCs make 53% of their synapses onto other PCs, 32% onto PLIs, 6% onto MLI1s and 7% onto MLI2s. Since there are far more MLI1s than MLI2s, each MLI2 is expected to receive many more synapses than each MLI1. In slice experiments, optogenetic activation of PCs evokes inhibitory currents in most MLI2s, but primarily disinhibits MLI1s. We also find that candelabrum cells, a type of PLI, form many more synapses onto MLI1s than MLI2s. These findings suggest that PC-MLI synapses do not primarily disinhibit PCs, and that the PC-MLI2-MLI1-PC and PC-PLI-MLI1-PC pathways might provide negative feedback to PCs that acts in concert with PC-PC synapses to counter elevations in PC firing.Significance Statement Purkinje cells (PCs) influence processing by inhibiting neurons in the cerebellar cortex, including other PCs, molecular layer interneurons (MLIs) and Purkinje layer interneurons (PLIs). The influence of PC-MLI synapses is not known because there are recently identified MLI subtypes with opposing effects: MLI1s inhibit PCs whereas MLI2s inhibit MLI1s and disinhibit PCs. We used serial EM and optogenetic studies to characterize PC synapses onto MLI subtypes and found that PCs preferentially inhibit MLI2s and disinhibit MLI1s. We also found that candelabrum cells (a type of PLI) preferentially inhibit MLI1s. These findings suggest that PC-PC synapses, the PC-MLI2-MLI1-PC pathway and the PC-candelabrum cell-MLI1-PC pathway act together to allow alterations in PC firing to provide negative feedback to other PCs.
How aging affects brain-body connections can be investigated through changes in the coupling between functional magnetic resonance imaging (fMRI) signals and bodily autonomic processes across the adult lifespan. Recent studies using univariate approaches have identified age-related changes in the association between fMRI signals from multiple individual brain regions and low-frequency respiratory and cardiac activity. Here, we investigate if whole-brain spatial fMRI patterns associated with low-frequency physiological processes (heart rate and respiratory volume fluctuations) present generalizable changes with age. Data from human participants of both sexes are included in the analysis. We find that chronological age can be predicted statistically beyond chance from patterns of low-frequency fMRI-physiology coupling, even after accounting for individual differences in physiological signal characteristics and brain anatomy. Notably, brain areas implicated in central autonomic regulation, including nodes within salience and ventral attention networks (e.g., insula and middle cingulate cortex), are amongst the strongest contributors to age prediction. Further, we observe that after removing physiological effects from fMRI data, the residual blood oxygen level-dependent (BOLD) signal variability is still a reliable indicator of age. Together, these findings underscore the close integration between brain and body physiology, and highlight this interaction as a potential biomarker of the aging process.Significance Statement The association between brain activity and respiratory or cardiac activity is often dismissed as "noise" in functional magnetic resonance imaging (fMRI) studies. However, emerging evidence suggests that coupling between fMRI and peripheral physiological signals can provide valuable insight into the brain-body connection. In this study, we show that whole brain patterns of coupling between fMRI signals and low-frequency respiratory and cardiac processes can reliably predict age across the adult lifespan. Brain regions involved in autonomic regulation, such as insula and cingulate cortex, were among the most informative predictors of age. These findings suggest that fMRI-physiology coupling may capture aging-related changes in brain vascular health and autonomic function and may have broader relevance for tracking disease-related disruptions in brain-body interaction.
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