Journal of Neuroscience最新文献

Neurons in the cerebral cortex and hippocampus discharge synchronously in brain state-dependent manner to transfer information. Published studies have highlighted the temporal coordination of neuronal activities between the hippocampus and a neocortical area, however, how the spatial extent of neocortical activity relates to hippocampal activity remains partially unknown. We imaged mesoscopic neocortical activity while recording hippocampal local field potentials in anesthetized and unanesthetized GCaMP-expressing transgenic mice. We found that neocortical activity elevates around hippocampal sharp wave ripples (SWR). SWR-associated neocortical activities occurred predominantly in vision-related regions including visual, retrosplenial and frontal cortex. While pre-SWR neocortical activities were frequently observed in awake and natural sleeping states, post-SWR neocortical activity decreased significantly in the latter. Urethane anesthetized mice also exhibited SWR-correlated calcium elevation, but in longer time scale than observed in natural sleeping mice. During hippocampal theta oscillation states, phase-locked oscillations of calcium activity were observed throughout the entire neocortical areas. In addition, possible environmental effects on neocortico-hippocampal dynamics were assessed in this study by comparing mice reared in ISO (isolated condition) and ENR (enriched environment). In both SWR and theta oscillations, mice reared in ISO exhibited clearer brain state-dependent dynamics than those reared in ENR. Our data demonstrate that the neocortex and hippocampus exhibit heterogeneous activity patterns that characterize brain states, and postnatal experience plays a significant role in modulating these patterns.Significant Statement The hippocampus is a center for memory formation. However, the memory formed in the hippocampus is not stored forever, but gradually transferred into the cerebral cortex synchronized activities between the neocortex and hippocampus has been hypothesized (for hippocampus-independent memory see (Sutherland and Rudy, 1989)). However, spatio-temporal dynamics between hippocampus and whole neocortical areas remains partially unexplored. We measured cortical calcium activities with hippocampal electroencephalogram (EEG) simultaneously and found that the activities of widespread neocortical areas are temporally associated with hippocampal EEG. The neocortico-hippocampal dynamics is primarily regulated by animal awake/sleep state. Even if similar EEG patters were observed, temporal dynamics between the neocortex and hippocampus exhibit distinct patterns between awake and sleep period. In addition, animals' postnatal experience modulates the dynamics.

How the prefrontal cortex contributes to working memory remains controversial, as theories differ in their emphasis on its role in storing memories versus controlling their content. To adjudicate between these competing ideas, we tested how perturbations to the human (both sexes) lateral prefrontal cortex impact the storage and control aspects of working memory during a task that requires human subjects to allocate resources to memory items based on their behavioral priority. Our computational model made a strong prediction that disruption of this control process would counterintuitively improve memory for low-priority items. Remarkably, transcranial magnetic stimulation of retinotopically-defined superior precentral sulcus, but not intraparietal sulcus, unbalanced the prioritization of resources, improving memory for low-priority items as predicted by the model. Therefore, these results provide direct causal support for models in which the prefrontal cortex controls the allocation of resources that support working memory, rather than simply storing the features of memoranda.Significance statement Although higher-order cognition depends on working memory, the resources that support our memory are severely limited in capacity. To mitigate this limitation, we allocate memory resources according to the behavioral relevance of items. Nonetheless, the neural basis of these abilities remains unclear. Here, we tested the hypothesis that a region in lateral prefrontal cortex controls prioritization in working memory. Indeed, perturbing this region with transcranial magnetic stimulation disrupted the prioritization of working memory resources. Our results provide causal evidence for the hypothesis that prefrontal cortex primarily controls the allocation of memory resources, rather than storing the contents of working memory.

Animal models are commonly used to investigate developmental processes and disease risk, but humans and model systems (e.g., mice) differ substantially in the pace of development and aging. The timeline of human developmental circuits is well known, butit is unclear how such timelines compare to those in mice. We lack age alignments across the lifespan of mice and humans. Here, we build upon our Translating Time resource, which is a tool that equates corresponding ages during development. We collected 1,125 observations from age-related changes in body, bone, dental, and brain processes to equate corresponding ages across humans, mice, and rats to boost power for comparison across humans and mice. We acquired high-resolution diffusion MR scans of mouse brains (n=16) of either sex at sequential stages of postnatal development (postnatal day 3, 4, 12, 21, 60) to track brain circuit maturation (e.g., olfactory association, transcallosal pathways). We found heterogeneity in white matter pathway growth. Corpus callosum growth largely ceases days after birth while the olfactory association pathway grows through P60. We found that a P3-4 mouse equates to a human at roughly GW24, and a P60 mouse equates to a human in teenage years. Therefore, white matter pathway maturation is extended in mice as it is in humans, but there are species-specific adaptations. For example, olfactory-related wiring is protracted in mice, which is linked to their reliance on olfaction. Our findings underscore the importance of translational tools to map common and species-specific biological processes from model systems to humans.Significance statement Mice are essential models of human brain development, but we currently lack precise age alignments across their lifespan. Here, we equate corresponding ages across mice and humans. We utilize high-resolution diffusion mouse brain scans to track the growth of brain white matter pathways, and we use our cross-species age alignments to map the timeline of these growth patterns from mouse to humans. In mice, olfactory association pathway growth continues well into the equivalent of human teenage years. The protracted development of olfactory association pathways in mice aligns with their specialized sense of smell. The generation of translational tools bridges the gap between animal models and human biology while enhancing our understanding of developmental processes generating variation across species.

The brain's activity fluctuations have different temporal scales across the brain regions, with associative regions displaying slower timescales than sensory areas. This so-called hierarchy of timescales has been shown to correlate with both structural brain connectivity and intrinsic regional properties. Here, using publicly available human resting-state fMRI and dMRI data it was found that, while more structurally connected brain regions presented activity fluctuations with longer timescales, their activity fluctuations presented lower variance. The opposite relationships between the structural connectivity and the variance and temporal scales of resting-state fluctuations, respectively, were not trivially explained by simple network propagation principles. To understand these structure-function relationships, two commonly used whole-brain models were studied, namely the Hopf and Wilson-Cowan models. These models use the brain's connectome to coupled local nodes (representing brain regions) displaying noise-driven oscillations. The models show that the variance and temporal scales of activity fluctuations can oppositely relate to connectivity within specific model's parameter regions, even when all nodes have the same intrinsic dynamics -but also when intrinsic dynamics are constrained by the myelinization-related macroscopic gradient. These results show that, setting aside intrinsic regional differences, connectivity and network state are sufficient to explain the regional differences in fluctuations' scales. State-dependence supports the vision that structure-function relationships can serve as biomarkers of altered brain states. Finally, the results indicate that the hierarchies of timescales and variances reflect a balance between stability and responsivity, with greater and faster responsiveness at the network periphery, while the network core ensures overall system robustness.Significance Statement Brain regions exhibit activity fluctuations at different temporal scales, with associative areas displaying slower timescales than sensory areas. This hierarchical organization is shaped by both large-scale connectivity and local properties. The present study demonstrates that the variance of fluctuations is also hierarchically organized but, in contrast to timescales, it decreases as a function of structural connectivity. Whole-brain models show that the hierarchies of timescales and variances jointly emerge within specific parameter regions, indicating a state-dependence that could serve as a biomarker for brain states and disorders. Furthermore, these hierarchies link to the responsivity of different network parts, with greater and faster responsiveness at the network periphery and more stable dynamics at the core, achieving a balance between stability and responsiveness.

We appraise other people's emotions by combining multiple sources of information, including somatic facial/body reactions and the surrounding context. Wealthy literature revealed how people take into account contextual information in the interpretation of facial expressions, but the mechanisms mediating such influence still need to be duly investigated. Across two experiments, we mapped the neural representations of distinct (but comparably unpleasant) negative states, pain, and disgust, as conveyed by naturalistic facial expressions or contextual sentences. Negative expressions led to shared activity in the fusiform gyrus and superior temporal sulcus. Instead, pain contexts recruited the supramarginal, postcentral, and insular cortex, whereas disgust contexts triggered the temporoparietal cortex and hippocampus/amygdala. When pairing the two sources of information together, we found a higher likelihood of classifying an expression according to the sentence preceding it. Furthermore, networks specifically involved in processing contexts were re-enacted whenever a face followed said context. Finally, the perigenual medial prefrontal cortex (mPFC) showed increased activity for consistent (vs inconsistent) face-context pairings, suggesting that it integrates state-specific information from the two sources. Overall, our study reveals the heterogeneous nature of face-context information integration, which operates both according to a state-general and state-specific principle, with the latter mediated by the perigenual medial prefrontal cortex.

The mammalian striatum is divided into two types of anatomical structures: the island-like, μ-opioid receptor (MOR)-rich striosome compartment and the surrounding matrix compartment. Both compartments have two types of spiny projection neurons (SPNs), dopamine receptor D1 (D1R)-expressing direct pathway SPNs (dSPNs) and dopamine receptor D2 (D2R)-expressing indirect pathway SPNs. These compartmentalized structures have distinct roles in the development of movement disorders, although the functional significance of the striosome compartment for motor control and dopamine regulation remains to be elucidated. The aim of this study was to explore the roles of striosome in locomotion and dopamine dynamics in freely moving mice. We targeted striosomal MOR-expressing neurons with male MOR-CreER mice, which express tamoxifen-inducible Cre recombinase under MOR promoter, and Cre-dependent adeno-associated virus vector. The targeted neuronal population consisted mainly of dSPNs. We found that the Gq-coupled designer receptor exclusively activated by designer drugs (DREADD)-based chemogenetic stimulation of striatal MOR-expressing neurons caused a decrease in the number of contralateral rotations and total distance traveled. Wireless fiber photometry with a genetically encoded dopamine sensor revealed that chemogenetic stimulation of striatal MOR-expressing neurons suppressed dopamine signals in the dorsal striatum of freely moving mice. Furthermore, the decrease in mean dopamine signal and the reduction of transients were associated with ipsilateral rotational shift and decrease of average speed, respectively. Thus, a subset of striosomal dSPNs inhibits contralateral rotation, locomotion, and dopamine release in contrast to the role of pan-dSPNs. Our results suggest that striatal MOR-expressing neurons have distinct roles in motor control and dopamine regulation.

Layer 4 (L4) of rabbit V1 contains fast-spike GABAergic interneurons (suspected inhibitory interneurons, SINs) that receive potent synaptic input from the LGN and generate fast, local feedforward inhibition. These cells display receptive fields with overlapping ON/OFF subregions, nonlinear spatial summation, very broad orientation/directional tuning, and high spontaneous and visually driven firing rates. Fast-spike interneurons are also found in Layer 5 (L5), which receives a much sparser input from the LGN, but the response properties and thalamocortical connectivity of L5 SINs are relatively unstudied. Here, we study L5 SINs in awake rabbits (both sexes) and compare their response properties with previously studied SINs of L4. We also assess thalamocortical connectivity of L5 SINs, examining cross-correlation of retinotopically aligned LGN-SIN spike trains and L5 SIN responses to electrical stimulation of the LGN. These analyses confirmed that many L5 SINs, like L4 SINs, receive a strong, fast monosynaptic drive from the LGN. Moreover, these LGN-connected L5 SINs had response properties similar to those of L4 SINs and were predominantly found in the upper half of L5. In contrast, L5 SINs with longer synaptic latencies to LGN stimulation displayed (1) sharper orientation tuning, (2) longer visual response latencies, (3) lower spontaneous and (4) visually driven firing rates, and (5) were found in the deeper half of L5. We suggest that the long-latency synaptic responses in such L5 SINs reflect a multisynaptic intracortical pathway that generates a different constellation of response properties than seen in L5 SINs that are driven directly by LGN input.

Amplitude compression is an indispensable feature of contemporary audio production and especially relevant in modern hearing aids. The cortical fate of amplitude-compressed speech signals is not well-studied, however, and may yield undesired side effects: We hypothesize that compressing the amplitude envelope of continuous speech reduces neural tracking. Yet, leveraging such a 'compression side effect' on unwanted, distracting sounds could potentially support attentive listening if effectively reducing their neural tracking. In this study, we examined 24 young normal-hearing (NH) individuals, 19 older hearing-impaired (HI) individuals, and 12 older normal-hearing individuals. Participants were instructed to focus on one of two competing talkers while ignoring the other. Envelope compression (1:8 ratio, loudness-matched) was applied to one or both streams containing short speech repeats. Electroencephalography (EEG) allowed us to quantify the cortical response function and degree of speech tracking. With compression applied to the attended target stream, HI participants showed reduced behavioural accuracy, and compressed speech yielded generally lowered metrics of neural tracking. Importantly, we found that compressing the ignored stream resulted in a stronger neural representation of the uncompressed target speech. Our results imply that intelligent compression algorithms, with variable compression ratios applied to separated sources, could help individuals with hearing loss suppress distraction in complex multi-talker environments.Significant statement Amplitude compression, integral in contemporary audio production and hearing aids, poses an underexplored cortical challenge. Compressing the amplitude envelope of continuous speech is hypothesized to diminish neural tracking. Yet, capitalizing on this 'compression side effect' for distracting sounds might enhance attentive listening. Studying normal-hearing (NH), older hearing-impaired (HI), and older normal hearing individuals in dual-talker scenarios, we applied envelope compression to speech streams. Both NH and HI participants showed diminished neural tracking with compression on the speech streams. Despite weaker tracking of a compressed distractor, HI individuals exhibited stronger neural representation of the concurrent target. This suggests that adaptive compression algorithms, employing variable ratios for distinct sources, could aid individuals with hearing loss in suppressing distractions in complex multi-talker environments.

Cerebral amyloid-beta (Aβ) accumulation, a hallmark pathology of Alzheimer's disease (AD), precedes clinical impairment by two to three decades. However, it is unclear whether Aβ contributes to subtle memory deficits observed during the preclinical stage. The heterogenous emergence of Aβ deposition may selectively impact certain memory domains, which rely on distinct underlying neural circuits. In this context, we tested whether specific domains of mnemonic discrimination, a neural computation essential for episodic memory, exhibit specific deficits related to early Aβ deposition. We tested 108 cognitively unimpaired human older adults (66% female) who underwent 18F-florbetapir positron emission tomography (Aβ-PET), and a control group of 35 young adults, on a suite of mnemonic discrimination tasks taxing object, spatial, and temporal domains. We hypothesized that Aβ pathology would be selectively associated with temporal discrimination performance due to Aβ's propensity to accumulate in the basal frontotemporal cortex, which supports temporal processing. Consistent with this hypothesis, we found a dissociation in which generalized age-related deficits were found for object and spatial mnemonic discrimination, while Aβ-PET levels were selectively associated with deficits in temporal mnemonic discrimination. Further, we found that higher Aβ-PET levels in medial orbitofrontal and inferior temporal cortex, regions supporting temporal processing, were associated with greater temporal mnemonic discrimination deficits, pointing to the selective vulnerability of circuits related to temporal processing early in AD progression. These results suggest that Aβ accumulation within basal frontotemporal regions may disrupt temporal mnemonic discrimination in preclinical AD, and future work is needed to determine whether assessing temporal mnemonic discrimination can aid in predicting emerging AD progression.Significance Statement Identifying subtle cognitive changes that reflect emerging Aβ accumulation could lead to the development of cognitive tasks to detect individuals at risk of AD and sensitively assess clinical intervention outcomes for Aβ-lowering therapeutics. Temporal mnemonic discrimination, the ability to distinguish between events occurring at different times, is supported by basal frontotemporal regions which are among the earliest impacted by Aβ. We demonstrate that Aβ-positivity, as well as increased Aβ deposition in basal frontotemporal regions, is selectively associated with deficits in temporal mnemonic discrimination, but not other domains of mnemonic discrimination such as object identity or spatial relationships. These results suggest that Aβ disrupts cortical circuits supporting temporal processing and highlights inclusion of temporal mnemonic discrimination tasks in future clinical assessments.

Eph/ephrin signaling is crucial for organizing retinotopic maps in vertebrates. Unlike other EphAs, which are expressed in the embryonic ventral retina, EphA4 is found in the retinal ganglion cell (RGC) layer at perinatal stages, and its role in mammalian visual system development remains unclear. Using classic in vitro stripe assays, we demonstrate that, while RGC axons are repelled by ephrinB2, they grow on ephrinB1 stripes through EphA4-mediated adhesion. In vivo, retinal axons from EphA4-deficient mice from either sex show impaired arborization in the medial, but not lateral, regions of the superior colliculus that express ephrinB1. Gain-of-function experiments further reveal that ephrinB1-mediated adhesion depends on EphA4 tyrosine kinase activity but it is independent of its sterile alpha motif. Together, our findings suggest that EphA4/ephrinB1 forward signaling likely facilitates adhesion between retinal axon terminals and cells in the medial colliculus, contributing to the establishment of proper connectivity within the visual system.