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Sensorimotor learning requires reorganization of neuronal activity in the premotor cortex (PM) and primary motor cortex (M1). To reveal PM- and M1-specific reorganization in a primate, we conducted calcium imaging in common marmosets while they learned a two-target reaching (pull/push) task after mastering a one-target reaching (pull) task. Throughout learning of the two-target reaching task, the dorsorostral PM (PMdr) showed peak activity earlier than the dorsocaudal PM (PMdc) and M1. During learning, the reaction time in pull trials increased and correlated strongly with the peak timing of PMdr activity. PMdr showed decreasing representation of newly introduced (push) movement, whereas PMdc and M1 maintained high representation of pull and push movements. Many task-related neurons in PMdc and M1 exhibited a strong preference to either movement direction. PMdc neurons dynamically switched their preferred direction depending on their performance in push trials in the early learning stage, whereas M1 neurons stably retained their preferred direction and high similarity of preferred direction between neighbors. These results suggest that in primate sensorimotor learning, dynamic directional motor tuning in PMdc converts the sensorimotor association formed in PMdr to the stable and specific motor representation of M1., (© 2024. The Author(s).)

Neurons decline in their functionality over time, and age-related neuronal alterations are associated with phenotypes of neurodegenerative diseases. In nonneural tissues, an infolded nuclear shape has been proposed as a hallmark of aged cells and neurons with infolded nuclei have also been reported to be associated with neuronal activity. Here, we performed time-lapse imaging in the visual cortex of Nex-Cre;SUN1-GFP mice. Nuclear infolding was observed within 10 min of stimulation in young nuclei, while the aged nuclei were already infolded pre-stimulation and showed reduced dynamics of the morphology. In young nuclei, the depletion of the stimuli restored the nucleus to a spherical shape and reduced the dynamic behavior, suggesting that nuclear infolding is a reversible process. We also found the aged nucleus to be stiffer than the young one, further relating to the age-associated loss of nuclear shape dynamics. We reveal temporal changes in the nuclear shape upon external stimulation and observe that these morphological dynamics decrease with age., (© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

The clustering of neurons with similar response properties is a conspicuous feature of neocortex. In primary visual cortex (V1), maps of several properties like orientation preference are well described, but the functional architecture of color, central to visual perception in trichromatic primates, is not. Here we used two-photon calcium imaging in macaques to examine the fine structure of chromatic representation and found that neurons responsive to spatially uniform, chromatic stimuli form unambiguous clusters that coincide with blobs. Further, these responsive groups have marked substructure, segregating into smaller ensembles or micromaps with distinct chromatic signatures that appear columnar in upper layer 2/3. Spatially structured chromatic stimuli revealed maps built on the same micromap framework but with larger subdomains that go well beyond blobs. We conclude that V1 has an architecture for color representation that switches between blobs and a combined blob/interblob system based on the spatial content of the visual scene.

Integration of information processed separately in distributed brain regions is essential for brain functions. This integration is enabled by long-range projection neurons, and further, concerted interactions between long-range projections and local microcircuits are crucial. It is not well known, however, how this interaction is implemented in cortical circuits. Here, to decipher this logic, using callosal projection neurons (CPNs) in layer 2/3 of the mouse visual cortex as a model of long-range projections, we found that CPNs exhibited distinct response properties and fine-scale local connectivity patterns. In vivo 2-photon calcium imaging revealed that CPNs showed a higher ipsilateral (to their somata) eye preference, and that CPN pairs showed stronger signal/noise correlation than random pairs. Slice recordings showed CPNs were preferentially connected to CPNs, demonstrating the existence of projection target-dependent fine-scale subnetworks. Collectively, our results suggest that long-range projection target predicts response properties and local connectivity of cortical projection neurons., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Resting-state functional connectivity (FC) has become a major functional magnetic resonance imaging method to study network organization of human brains. There has been recent interest in the temporal fluctuations of FC calculated using short time windows ("dynamic FC") because this method could provide information inaccessible with conventional "static" FC, which is typically calculated using the entire scan lasting several tens of minutes. Although multiple studies have revealed considerable temporal fluctuations in FC, it is still unclear whether the fluctuations of FC measured in hemodynamics reflect the dynamics of underlying neural activity. We addressed this question using simultaneous imaging of neuronal calcium and hemodynamic signals in mice and found coordinated temporal dynamics of calcium FC and hemodynamic FC measured in the same short time windows. Moreover, we found that variation in transient neuronal coactivation patterns was significantly related to temporal fluctuations of sliding window FC in hemodynamics. Finally, we show that the observed dynamics of FC cannot be fully accounted for by simulated data assuming stationary FC. These results provide evidence for the neuronal origin of dynamic FC and further suggest that information relevant to FC is condensed in temporally sparse events that can be extracted using a small number of time points., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Although the processing of whisker deflections in the barrel area of the rodent primary somatosensory cortex (S1) has been studied extensively, how cutaneous vibro-tactile stimuli are processed in the rodent S1 outside the barrel area has not been fully examined. Particularly, the cell-type specific representation of multiple vibration frequencies in genetically identified inhibitory cells in the S1 has not been examined. Using two-photon calcium imaging, we examined the responses to vibration stimuli of excitatory and inhibitory neurons in the S1 hind limb area of male and female mice. The excitatory cells showed relatively sharp selectivity to vibration stimuli, whereas the inhibitory cells exhibited less selectivity. The excitatory and inhibitory cells with different preferred stimuli were intermingled in a "salt and pepper" manner. Furthermore, the noise correlation tended to be especially strong in excitatory-inhibitory and inhibitory-inhibitory cell pairs that have similar stimulus selectivity. These results suggest that excitatory cells tend to represent specific stimulus information and work together with similarly tuned inhibitory cells as a functionally connected network.

Dichromatic vision is common in many mammals. However, color processing in the primary visual cortex (V1) of dichromatic mammals is relatively unknown compared to the trichromatic primates. In this study, we investigated the functional organization of color processing in mouse V1. The mouse retina has a graded expression pattern of two opsins along its dorsoventral axis. However, it is not clear whether and how this expression pattern is reflected in the cortical representation at local (several hundred microns) and areal (V1) level. Using in vivo two-photon calcium (Ca 2+ ) imaging and wide-field Ca 2+ imaging, we revealed that V1 neurons responded to S (UV)- and M (green)-opsin isolating stimuli with slightly biased color preference depending on retinotopic position in V1. This was consistent with the distribution of retinal opsins. At the cellular level, preferences for S- and M-opsin isolating stimuli were intermingled in a local region encompassing several hundred microns. These results suggest that functional organizations of color information are locally intermingled, but slightly biased depending on the retinotopic position in mouse V1.

A minicolumn is the smallest anatomical module in the cortical architecture, but it is still in debate whether it serves as functional units for cortical processing. In the rodent primary visual cortex (V1), neurons with different preferred orientations are mixed horizontally in a salt and pepper manner, but vertical functional organization was not examined. In this study, we found that neurons with similar orientation preference are weakly but significantly clustered vertically in a short length and horizontally in the scale of a minicolumn. Interestingly, the vertical clustering is found only in a part of minicolumns, and others are composed of neurons with a variety of orientation preferences. Thus, the mouse V1 is a mixture of vertical clusters of neurons with various degrees of orientation similarity, which may be the compromise between the brain size and keeping the vertical clusters of similarly tuned neurons at least in a subset of clusters.

Resting-state functional connectivity (FC), which measures the correlation of spontaneous hemodynamic signals (HemoS) between brain areas, is widely used to study brain networks noninvasively. It is commonly assumed that spatial patterns of HemoS-based FC (Hemo-FC) reflect large-scale dynamics of underlying neuronal activity. To date, studies of spontaneous neuronal activity cataloged heterogeneous types of events ranging from waves of activity spanning the entire neocortex to flash-like activations of a set of anatomically connected cortical areas. However, it remains unclear how these various types of large-scale dynamics are interrelated. More importantly, whether each type of large-scale dynamics contributes to Hemo-FC has not been explored. Here, we addressed these questions by simultaneously monitoring neuronal calcium signals (CaS) and HemoS in the entire neocortex of mice at high spatiotemporal resolution. We found a significant relationship between two seemingly different types of large-scale spontaneous neuronal activity-namely, global waves propagating across the neocortex and transient coactivations among cortical areas sharing high FC. Different sets of cortical areas, sharing high FC within each set, were coactivated at different timings of the propagating global waves, suggesting that spatial information of cortical network characterized by FC was embedded in the phase of the global waves. Furthermore, we confirmed that such transient coactivations in CaS were indeed converted into spatially similar coactivations in HemoS and were necessary to sustain the spatial structure of Hemo-FC. These results explain how global waves of spontaneous neuronal activity propagating across large-scale cortical network contribute to Hemo-FC in the resting state.

Neuronal activity is important for the functional refinement of neuronal circuits in the early visual system. At the level of the cerebral cortex, however, it is still unknown whether the formation of fundamental functions such as orientation selectivity depends on neuronal activity, as it has been difficult to suppress activity throughout development. Using genetic silencing of cortical activity starting before the formation of orientation selectivity, we found that the orientation selectivity of neurons in the mouse visual cortex formed and matured normally despite a strong suppression of both spontaneous and visually evoked activity throughout development. After the orientation selectivity formed, the distribution of the preferred orientations of neurons was reorganized. We found that this process required spontaneous activity, but not visually evoked activity. Thus, the initial formation and maturation of orientation selectivity is largely independent of neuronal activity, and the initial selectivity is subsequently modified depending on neuronal activity.

Higher order visual areas that receive input from the primary visual cortex (V1) are specialized for the processing of distinct features of visual information. However, it is still incompletely understood how this functional specialization is acquired. Here we used in vivo two photon calcium imaging in the mouse visual cortex to investigate whether this functional distinction exists at as early as the level of projections from V1 to two higher order visual areas, AL and LM. Specifically, we examined whether sharpness of orientation and direction selectivity and optimal spatial and temporal frequency of projection neurons from V1 to higher order visual areas match with that of target areas. We found that the V1 input to higher order visual areas were indeed functionally distinct: AL preferentially received inputs from V1 that were more orientation and direction selective and tuned for lower spatial frequency compared to projection of V1 to LM, consistent with functional differences between AL and LM. The present findings suggest that selective projections from V1 to higher order visual areas initiates parallel processing of sensory information in the visual cortical network.

Identifying the neuronal ensembles that respond to specific stimuli and mapping their projection patterns in living animals are fundamental challenges in neuroscience. To this end, we engineered a synthetic promoter, the enhanced synaptic activity-responsive element (E-SARE), that drives neuronal activity-dependent gene expression more potently than other existing immediate-early gene promoters. Expression of a drug-inducible Cre recombinase downstream of E-SARE enabled imaging of neuronal populations that respond to monocular visual stimulation and tracking of their long-distance thalamocortical projections in living mice. Targeted cell-attached recordings and calcium imaging of neurons in sensory cortices revealed that E-SARE reporter expression correlates with sensory-evoked neuronal activity at the single-cell level and is highly specific to the type of stimuli presented to the animals. This activity-dependent promoter can expand the repertoire of genetic approaches for high-resolution anatomical and functional analysis of neural circuits.

Neurons in rodent visual cortex are organized in a salt-and-pepper fashion for orientation selectivity, but it is still unknown how this functional architecture develops. A recent study reported that the progeny of single cortical progenitor cells are preferentially connected in the postnatal cortex. If these neurons acquire similar selectivity through their connections, a salt-and-pepper organization may be generated, because neurons derived from different progenitors are intermingled in rodents. Here we investigated whether clonally related cells have similar preferred orientation by using a transgenic mouse, which labels all the progeny of single cortical progenitor cells. We found that preferred orientations of clonally related cells are similar to each other, suggesting that cell lineage is involved in the development of response selectivity of neurons in the cortex. However, not all clonally related cells share response selectivity, suggesting that cell lineage is not the only determinant of response selectivity., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Research on the functional anatomy of visual cortical circuits has recently zoomed in from the macroscopic level to the microscopic. High-resolution functional imaging has revealed that the functional architecture of orientation maps in higher mammals is built with single-cell precision. By contrast, orientation selectivity in rodents is dispersed on visual cortex in a salt-and-pepper fashion, despite highly tuned visual responses. Recent studies of synaptic physiology indicate that there are disjoint subnetworks of interconnected cells in the rodent visual cortex. These intermingled subnetworks, described in vitro, may relate to the intermingled ensembles of cells tuned to different orientations, described in vivo. This hypothesis may soon be tested with new anatomic techniques that promise to reveal the detailed wiring diagram of cortical circuits.

Experience-dependent plasticity is crucial for the precise formation of neuronal connections during development. It is generally thought to depend on Hebbian forms of synaptic plasticity. In addition, neurons possess other, homeostatic means of compensating for changes in sensory input, but their role in cortical plasticity is unclear. We used two-photon calcium imaging to investigate whether homeostatic response regulation contributes to changes of eye-specific responsiveness after monocular deprivation (MD) in mouse visual cortex. Short MD durations decreased deprived-eye responses in neurons with binocular input. Longer MD periods strengthened open-eye responses, and surprisingly, also increased deprived-eye responses in neurons devoid of open-eye input. These bidirectional response adjustments effectively preserved the net visual drive for each neuron. Our finding that deprived-eye responses were either weaker or stronger after MD, depending on the amount of open-eye input a cell received, argues for both Hebbian and homeostatic mechanisms regulating neuronal responsiveness during experience-dependent plasticity.

In the visual cortex of higher mammals, neurons are arranged across the cortical surface in an orderly map of preferred stimulus orientations. This map contains 'orientation pinwheels', structures that are arranged like the spokes of a wheel such that orientation changes continuously around a centre. Conventional optical imaging first demonstrated these pinwheels, but the technique lacked the spatial resolution to determine the response properties and arrangement of cells near pinwheel centres. Electrophysiological recordings later demonstrated sharply selective neurons near pinwheel centres, but it remained unclear whether they were arranged randomly or in an orderly fashion. Here we use two-photon calcium imaging in vivo to determine the microstructure of pinwheel centres in cat visual cortex with single-cell resolution. We find that pinwheel centres are highly ordered: neurons selective to different orientations are clearly segregated even in the very centre. Thus, pinwheel centres truly represent singularities in the cortical map. This highly ordered arrangement at the level of single cells suggests great precision in the development of cortical circuits underlying orientation selectivity.

To plan a serial order behavior, we hold serial sensory information in our minds and convert it to a movement program. We trained monkeys to memorize a sequence of positional cues and to reproduce it by making saccades in either the original or reverse order. The order was determined in the middle of a trial on the basis of an instruction stimulus. Triggered by the instruction stimulus, single neurons in the dorsal premotor cortex became transiently active only when the order needed to be determined. These transient neurons, together with nearby sustained neurons that hold information on cue or movement sequences, appear to mediate the generation of a motor program from the maintained information.