Intelligent behavior and cognitive functions in mammals depend on cortical microcircuits made up of a variety of excitatory and inhibitory cells that form a forest-like complex across six layers. ...Mechanistic understanding of cortical microcircuits requires both manipulation and monitoring of multiple layers and interactions between them. However, existing techniques are limited as to simultaneous monitoring and stimulation at different depths without damaging a large volume of cortical tissue. Here, we present a relatively simple and versatile method for delivering light to any two cortical layers simultaneously. The method uses a tiny optical probe consisting of two microprisms mounted on a single shaft. We demonstrate the versatility of the probe in three sets of experiments: first, two distinct cortical layers were optogenetically and independently manipulated; second, one layer was stimulated while the activity of another layer was monitored; third, the activity of thalamic axons distributed in two distinct cortical layers was simultaneously monitored in awake mice. Its simple-design, versatility, small-size, and low-cost allow the probe to be applied widely to address important biological questions.
Modeling the processes of neuronal progenitor proliferation and differentiation to produce mature cortical neuron subtypes is essential for the study of human brain development and the search for ...potential cell therapies. We demonstrated a novel paradigm for the generation of vascularized organoids (vOrganoids) consisting of typical human cortical cell types and a vascular structure for over 200 days as a vascularized and functional brain organoid model. The observation of spontaneous excitatory postsynaptic currents (sEPSCs), spontaneous inhibitory postsynaptic currents (sIPSCs), and bidirectional electrical transmission indicated the presence of chemical and electrical synapses in vOrganoids. More importantly, single-cell RNA-sequencing analysis illustrated that vOrganoids exhibited robust neurogenesis and that cells of vOrganoids differentially expressed genes (DEGs) related to blood vessel morphogenesis. The transplantation of vOrganoids into the mouse S1 cortex resulted in the construction of functional human-mouse blood vessels in the grafts that promoted cell survival in the grafts. This vOrganoid culture method could not only serve as a model to study human cortical development and explore brain disease pathology but also provide potential prospects for new cell therapies for nervous system disorders and injury.
Most cortical synapses are local and excitatory. Local recurrent circuits could implement amplification, allowing pattern completion and other computations
. Cortical circuits contain subnetworks ...that consist of neurons with similar receptive fields and increased connectivity relative to the network average
. Cortical neurons that encode different types of information are spatially intermingled and distributed over large brain volumes
, and this complexity has hindered attempts to probe the function of these subnetworks by perturbing them individually
. Here we use computational modelling, optical recordings and manipulations to probe the function of recurrent coupling in layer 2/3 of the mouse vibrissal somatosensory cortex during active tactile discrimination. A neural circuit model of layer 2/3 revealed that recurrent excitation enhances sensory signals by amplification, but only for subnetworks with increased connectivity. Model networks with high amplification were sensitive to damage: loss of a few members of the subnetwork degraded stimulus encoding. We tested this prediction by mapping neuronal selectivity
and photoablating
neurons with specific selectivity. Ablation of a small proportion of layer 2/3 neurons (10-20, less than 5% of the total) representing touch markedly reduced responses in the spared touch representation, but not in other representations. Ablations most strongly affected neurons with stimulus responses that were similar to those of the ablated population, which is also consistent with network models. Recurrence among cortical neurons with similar selectivity therefore drives input-specific amplification during behaviour.
The human brain coordinates a wide variety of motor activities. On a large scale, the cortical motor system is topographically organized such that neighboring body parts are represented by ...neighboring brain areas. This homunculus-like somatotopic organization along the central sulcus has been observed using neuroimaging for large body parts such as the face, hands and feet. However, on a finer scale, invasive electrical stimulation studies show deviations from this somatotopic organization that suggest an organizing principle based on motor actions rather than body part moved. It has not been clear how the action-map organization principle of the motor cortex in the mesoscopic (sub-millimeter) regime integrates into a body map organization principle on a macroscopic scale (cm). Here we developed and applied advanced mesoscopic (sub-millimeter) fMRI and analysis methodology to non-invasively investigate the functional organization topography across columnar and laminar structures in humans. Compared to previous methods, in this study, we could capture locally specific blood volume changes across entire brain regions along the cortical curvature. We find that individual fingers have multiple mirrored representations in the primary motor cortex depending on the movements they are involved in. We find that individual digits have cortical representations up to 3 mm apart from each other arranged in a column-like fashion. These representations are differentially engaged depending on whether the digits’ muscles are used for different motor actions such as flexion movements, like grasping a ball or retraction movements like releasing a ball. This research provides a starting point for non-invasive investigation of mesoscale topography across layers and columns of the human cortex and bridges the gap between invasive electrophysiological investigations and large coverage non-invasive neuroimaging.
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•A sub-millimeter fMRI method is developed to image neural microcircuitry in humans.•The method can capture large FOVs with thin slices for ‛columnar’ and ‛laminar’ mapping.•An analysis pipeline is developed to investigate topographical representations that have only been visible in animals so far.•Novel findings include a mirrored finger representation in the human motor cortex.
In the cerebral cortex, local circuits consist of tens of thousands of neurons, each of which makes thousands of synaptic connections. Perhaps the biggest impediment to understanding these networks ...is that we have no wiring diagrams of their interconnections. Even if we had a partial or complete wiring diagram, however, understanding the network would also require information about each neuron's function. Here we show that the relationship between structure and function can be studied in the cortex with a combination of in vivo physiology and network anatomy. We used two-photon calcium imaging to characterize a functional property--the preferred stimulus orientation--of a group of neurons in the mouse primary visual cortex. Large-scale electron microscopy of serial thin sections was then used to trace a portion of these neurons' local network. Consistent with a prediction from recent physiological experiments, inhibitory interneurons received convergent anatomical input from nearby excitatory neurons with a broad range of preferred orientations, although weak biases could not be rejected.
Functional magnetic resonance imaging (fMRI) studies with ultra-high field (UHF, 7+ Tesla) technology enable the acquisition of high-resolution images. In this work, we discuss recent achievements in ...UHF fMRI at the mesoscopic scale, on the order of cortical columns and layers, and examine approaches to addressing common challenges. As researchers push to smaller and smaller voxel sizes, acquisition and analysis decisions have greater potential to degrade spatial accuracy, and UHF fMRI data must be carefully interpreted. We consider the impact of acquisition decisions on the spatial specificity of the MR signal with a representative dataset with 0.8 mm isotropic resolution. We illustrate the trade-offs in contrast with noise ratio and spatial specificity of different acquisition techniques and show that acquisition blurring can increase the effective voxel size by as much as 50% in some dimensions. We further describe how different sources of degradations to spatial resolution in functional data may be characterized. Finally, we emphasize that progress in UHF fMRI depends not only on scientific discovery and technical advancement, but also on informal discussions and documentation of challenges researchers face and overcome in pursuit of their goals. This article is part of the theme issue 'Key relationships between non-invasive functional neuroimaging and the underlying neuronal activity'.
Neocortical regions are organized into columns and layers. Connections between layers run mostly perpendicular to the surface suggesting a columnar functional organization. Some layers have ...long-range excitatory lateral connections suggesting interactions between columns. Similar patterns of connectivity exist in all regions but their exact role remain a mystery. In this paper, we propose a network model composed of columns and layers that performs robust object learning and recognition. Each column integrates its changing input over time to learn complete predictive models of observed objects. Excitatory lateral connections across columns allow the network to more rapidly infer objects based on the partial knowledge of adjacent columns. Because columns integrate input over time and space, the network learns models of complex objects that extend well beyond the receptive field of individual cells. Our network model introduces a new feature to cortical columns. We propose that a representation of location relative to the object being sensed is calculated within the sub-granular layers of each column. The location signal is provided as an input to the network, where it is combined with sensory data. Our model contains two layers and one or more columns. Simulations show that using Hebbian-like learning rules small single-column networks can learn to recognize hundreds of objects, with each object containing tens of features. Multi-column networks recognize objects with significantly fewer movements of the sensory receptors. Given the ubiquity of columnar and laminar connectivity patterns throughout the neocortex, we propose that columns and regions have more powerful recognition and modeling capabilities than previously assumed.
In sensory cortex regions, neurons are tuned to specific stimulus features. For example, in the visual cortex, many neurons fire predominantly in response to moving objects of a preferred ...orientation. However, the characteristics of the synaptic input that cortical neurons receive to generate their output firing pattern remain unclear. Here we report a novel approach for the visualization and functional mapping of sensory inputs to the dendrites of cortical neurons in vivo. By combining high-speed two-photon imaging with electrophysiological recordings, we identify local subthreshold calcium signals that correspond to orientation-specific synaptic inputs. We find that even inputs that share the same orientation preference are widely distributed throughout the dendritic tree. At the same time, inputs of different orientation preference are interspersed, so that adjacent dendritic segments are tuned to distinct orientations. Thus, orientation-tuned neurons can compute their characteristic firing pattern by integrating spatially distributed synaptic inputs coding for multiple stimulus orientations.
Personal space (PS) is the space around the body that people prefer to maintain between themselves and unfamiliar others. Intrusion into personal space evokes discomfort and an urge to move away. ...Physiologic studies in nonhuman primates suggest that defensive responses to intruding stimuli involve the parietal cortex. We hypothesized that the spatial encoding of interpersonal distance is initially transformed from purely sensory to more egocentric mapping within human parietal cortex. This hypothesis was tested using 7 Tesla (7T) fMRI at high spatial resolution (1.1 mm isotropic), in seven subjects (four females, three males). In response to visual stimuli presented at a range of virtual distances, we found two categories of distance encoding in two corresponding radially-extending columns of activity within parietal cortex. One set of columns (P columns) responded selectively to moving and stationary face images presented at virtual distances that were nearer (but not farther) than each subject's behaviorally-defined personal space boundary. In most P columns, BOLD response amplitudes increased monotonically and nonlinearly with increasing virtual face proximity. In the remaining P columns, BOLD responses decreased with increasing proximity. A second set of parietal columns (D columns) responded selectively to disparity-based distance cues (near or far) in random dot stimuli, similar to disparity-selective columns described previously in occipital cortex. Critically, in parietal cortex, P columns were topographically interdigitated (nonoverlapping) with D columns. These results suggest that visual spatial information is transformed from visual to body-centered (or person-centered) dimensions in multiple local sites within human parietal cortex.
Recent COVID-related social distancing practices highlight the need to better understand brain mechanisms which regulate "personal space" (PS), which is defined by the closest interpersonal distance that is comfortable for an individual. Using high spatial resolution brain imaging, we tested whether a map of external space is transformed from purely visual (3D-based) information to a more egocentric map (related to personal space) in human parietal cortex. We confirmed this transformation and further showed that it was mediated by two mutually segregated sets of columns: one which encoded interpersonal distance and another that encoded visual distance. These results suggest that the cortical transformation of sensory-centered to person-centered encoding of space near the body involves short-range communication across interdigitated columns within parietal cortex.
![Double-[mu]Periscope, a too...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/2050-084X/small "Double-[mu]Periscope, a tool for multilayer optical recordings, optogenetic stimulations or both")
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