Despite a rapidly-growing scientific and clinical brain imaging literature based on functional MRI using blood oxygenation level dependent (BOLD)1 signals, it remains controversial if BOLD signals in a particular region can be caused by activation of local excitatory neurons2. This difficult question is central to the interpretation and utility of BOLD, with major significance for fMRI studies in basic research and clinical applications3. Using a novel integrated technology unifying optogenetic4–13 control of inputs with high-field fMRI signal readouts, we show here that specific stimulation of local CaMKIIα-expressing excitatory neurons, either in neocortex or thalamus, elicits positive BOLD signals at the stimulus location with classical kinetics. We also show that optogenetic fMRI (ofMRI) allows visualization of the causal effects of specific cell types defined not only by genetic identity and cell body location, but also by axonal projection target. Finally, we show that ofMRI within the living and intact mammalian brain reveals BOLD signals in downstream targets distant from the stimulus, indicating that this approach can be used to map the global effects of controlling a local cell population. In this respect, unlike both conventional fMRI studies based on correlations14 and fMRI with electrical stimulation which will also directly drive afferent and nearby axons, this ofMRI approach provides causal information about the global circuits recruited by defined local neuronal activity patterns. Together these findings provide an empirical foundation for the widely-employed fMRI BOLD signal, and the features of ofMRI define a potent tool that may be suitable for functional circuit analysis as well as global phenotyping of dysfunctional circuitry.
Functional magnetic resonance imaging (fMRI) has been widely used for imaging brain functions. However, the extent of the fMRI hemodynamic response around the active sites, at submillimeter resolution, remains poorly understood and controversial. With the use of perfusion-based fMRI, we evaluated the hemodynamic response in the cat visual cortex after orientation-specific stimuli. Activation maps obtained by using cerebral blood flow fMRI measurements were predominantly devoid of large draining vein contamination and reproducible at columnar resolution. Stimulusspecific cerebral blood flow responses were spatially localized to individual cortical columns, and columnar layouts were resolved. The periodic spacing of orientation columnar structures was estimated to be 1.1 ؎ 0.2 mm (n ؍ 14 orientations, five animals), consistent with previous findings. The estimated cerebral blood flow response at full width at half-maximum was 470 m under single-stimulus conditions without differential subtraction. These results suggest that hemodynamic-based fMRI can indeed be used to map individual functional columns if large-vessel contributions can be minimized or eliminated.
Optical imaging based on intrinsic signals was used to investigate the functional architecture of cat area 17 and the border between areas 17 and 18. The visual stimuli were gratings of different spatial frequencies moving at different angles, in different directions and with different speeds. In area 17 the iso-orientation domains were usually organized in patches rather than as elongated bands. Patches with different orientation preferences were arranged radially forming 'pinwheels' around 'orientation centres'. The pinwheel density was approximately 1.7-fold higher than in area 18. To explore clustering according to direction of motion, stimuli having the same orientation but moving in opposite directions were used. These two stimuli yielded very similar activity maps giving no indication of robust directionality clustering. Using near infrared light we were able to simultaneously image ocular-dominance and iso-orientation domains. A quantitative assessment of the relative strengths of the two subsystems showed that in upper cortical layers clustering according to orientation preference was three-fold stronger than clustering according to ocular dominance. The functional organization of spatial frequency was also examined. When we compared the activated regions by stimuli having different spatial frequency and moving at different velocities we observed that neurons were clustered also in these respects. We also investigated the functional architecture at the area 17/18 border and found that orientation maps at both sides of the border were not independent of each other. The map of area 17 smoothly blended into that of area 18. Similarly, the preferred spatial frequency of the neurons changed gradually over a distance of approximately 0.8 mm at the region of the area 17/18 border.
Integration of inputs by cortical neurons provides the basis for the complex information processing performed in the cerebral cortex. Here, we have examined how primary visual cortical neurons integrate classical and nonclassical receptive field inputs. The effect of nonclassical receptive field stimuli and, correspondingly, of long-range intracortical inputs is known to be context-dependent: the same long-range stimulus can either facilitate or suppress responses, depending on the level of local activation. By constructing a large-scale model of primary visual cortex, we demonstrate that this effect can be understood in terms of the local cortical circuitry. Each receptive field position contributes both excitatory and inhibitory inputs; however, the inhibitory inputs have greater influence when overall receptive field drive is greater. This mechanism also explains contrast-dependent modulations within the classical receptive field, which similarly switch between excitatory and inhibitory. In order to simplify analysis and to explain the fundamental mechanisms of the model, self-contained modules that capture nonlinear local circuit interactions are constructed. This work supports the notion that receptive field integration is the result of local processing within small groups of neurons rather than in single neurons.
Neurons in primary visual cortex (area 17) respond vigorously to oriented stimuli within their receptive fields; however, stimuli presented outside the suprathreshold receptive field can also influence their responses. Here we describe a fundamental feature of the spatial interaction between suprathreshold center and subthreshold surround. By optical imaging of intrinsic signals in area 17 in response to a stimulus border, we show that a given stimulus generates activity primarily in iso-orientation domains, which extend for several millimeters across the cortical surface in a manner consistent with the architecture of long-range horizontal connections in area 17. By mapping the receptive fields of single neurons and imaging responses from the same cortex to stimuli that include or exclude the aggregate suprathreshold receptive field, we show that intrinsic signals strongly reveal the subthreshold surround contribution. Optical imaging and single-unit recording both demonstrate that the relative contrast of center and surround stimuli regulates whether surround interactions are facilitative or suppressive: the same surround stimulus facilitates responses when center contrast is low, but suppresses responses when center contrast is high. Such spatial interactions in area 17 are ideally suited to contribute to phenomena commonly regarded as part of "higher-level" visual processing, such as perceptual "popout" and "filling-in."A prominent feature of nearly every region of the mammalian cortex is a dense network of patchy, long-range horizontal connections within the superficial cortical layers (1). In primary visual cortex, these connections arise primarily as axonal branches of pyramidal cells in layers 2/3 (2, 3), and link neurons located at distances up to several millimeters away in the superficial cortical layers. Long-range horizontal connections make excitatory synapses on their target neurons (4), but those postsynaptic neurons can be excitatory (spiny stellate or pyramidal cells) or inhibitory (smooth stellate cells, see ref. 5).Although these anatomical features of horizontal connections are by now well established, their physiological role remains only partially understood. Long-range connections in area 17 are clustered into regions with similar orientation preference (6), and form a likely substrate for mediating influences on neurons from outside their "classical" receptive field. (We define the classical receptive field as the region over which a stimulus can evoke a suprathreshold spike response from the cell.) These influences can include modulation of orientation specific responses in area 17 neurons (7,8). Consistent with the anatomy of long-range connections, the effect of electrically stimulating lateral connections in cortical slices can be both excitatory and inhibitory, although the balance between the two can be modified (9). Reducing thalamocortical excitation, either in the long term by a retinal lesion (10) or in the short term by an artificial scotoma (11,12), causes changes in ...
The development of both long-range intracortical and interhemispheric connections depends on visual experience. Previous experiments showed that in strabismic but not in normal cats, clustered horizontal axon projections preferentially connect cell groups activated by the same eye. This indicates that there is selective stabilization of fibers between neurons exhibiting correlated activity. Extending these experiments, we investigated in strabismic cats: (1) whether tangential connections remain confined to columns of similar orientation preference within the subsystems of left and right eye domains; and (2) whether callosal connections also extend predominantly between neurons activated by the same eye and preferring similar orientations. To this end, we analyzed in strabismic cats the topographic relationships between orientation preference domains and both intrinsic and callosal connections of area 17. Red and green latex microspheres were injected into monocular iso-orientation domains identified by optical imaging of intrinsic signals. Additionally, domains sharing the ocular dominance and orientation preference of the neurons at the injection sites were visualized by 2-deoxyglucose (2-DG) autoradiography. Quantitative analysis revealed that 56% of the retrogradely labeled cells within the injected area 17 and 60% of the transcallosally labeled neurons were located in the 2-DG-labeled iso-orientation domains. This indicates: (1) that strabismus does not interfere with the tendency of long-range horizontal fibers to link predominantly neurons of similar orientation preference; and (2) that the selection mechanisms for the stabilization of callosal connections are similar to those that are responsible for the specification of the tangential intrinsic connections.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.