Stem cells, through their ability to both self-renew and differentiate, can produce a virtually limitless supply of specialized cells that behave comparably to primary cells. We took advantage of this property to develop an assay for small-molecule-based neuroprotection using stem-cell-derived motor neurons and astrocytes, together with activated microglia as a stress paradigm. Here, we report on the discovery of hit compounds from a screen of more than 10,000 small molecules. These compounds act through diverse pathways, including the inhibition of nitric oxide production by microglia, activation of the Nrf2 pathway in microglia and astrocytes, and direct protection of neurons from nitric-oxide-induced degeneration. We confirm the activity of these compounds using human neurons. Because microglial cells are activated in many neurological disorders, our hit compounds could be ideal starting points for the development of new drugs to treat various neurodegenerative and neurological diseases.
It is generally thought that callosal connections (CCs) in primary visual cortices serve to unify the visual scenery parted in two at the vertical midline (VM). Here, we present evidence that this applies also to visual features that do not cross yet but might cross the VM in the future. During reversible deactivation of the contralateral visual cortex in cats, we observed that ipsilaterally recorded neurons close to the border between areas 17 and 18 receive selective excitatory callosal input on both ongoing and evoked activity. In detail, neurons responding well to a vertical Gabor patch moving away from the deactivated hemifield decreased prestimulus and stimulus-driven activity much more than those preferring motion toward the cooled hemifield. Further, activity of neurons responding to horizontal lines decreased more than the response to vertical lines. Embedding a single Gabor into a collinear line context selectively stabilized responses, especially when the context was limited to the intact hemifield. These findings indicate that CCs interconnect not only neurons coding for similar orientations but also for similar directions of motion. We conclude that CCs anticipate stimulus features that are potentially relevant for both hemifields (i.e., coherent motion but also collinear shape) because already prestimulus activity and activity to stimuli not crossing the VM revealed feature specificity. Finally, we hypothesize that intrinsic and callosal networks processing different orientations and directions are anisotropic close to the VM facilitating perceptual grouping along likely future motion or (shape) trajectories before the visual stimulus arrives.
Neurons in the cerebral cortex are constantly integrating different types of inputs. Dependent on their origin, these inputs can be modulatory in many ways and, for example, change the neuron's responsiveness, sensitivity, or selectivity. To investigate the modulatory role of lateral input from the same level of cortical hierarchy, we recorded in the primary visual cortex of cats while controlling synaptic input from the corresponding contralateral hemisphere by reversible deactivation. Most neurons showed a pronounced decrease in their response to a visual stimulus of different contrasts and orientations. This indicates that the lateral network acts via an unspecific gain-setting mechanism, scaling the output of a neuron. However, the interhemispheric input also changed the contrast sensitivity of many neurons, thereby acting on the input. Such a contrast gain mechanism has important implications because it extends the role of the lateral network from pure response amplification to the modulation of a specific feature. Interestingly, for many neurons, we found a mixture of input and output gain modulation. Based on these findings and the known physiology of callosal connections in the visual system, we developed a simple model of lateral interhemispheric interactions. We conclude that the lateral network can act directly on its target, leading to a sensitivity change of a specific feature, while at the same time it also can act indirectly, leading to an unspecific gain setting. The relative contribution of these direct and indirect network effects determines the outcome for a particular neuron.
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.