A Practical Method for Creating Targeted Focal Ischemic Stroke in the Cortex of Nonhuman Primates.

Ischemic stroke is a major cause of disability among adults worldwide. Despite its prevalence, few effective treatment options exist to alleviate sensory and motor dysfunctions that result from stroke. In the past, rodent models of stroke have been the primary experimental models used to develop stroke therapies. However, positive results in these studies have failed to replicate in human clinical trials, highlighting the importance of nonhuman primate (NHP) models as a preclinical step. Although there are a few NHP models of stroke, the extent of tissue damage is highly variable and dependent on surgical skill. In this study, we employed the photothrombotic stroke model in NHPs to generate controlled, reproducible ischemic lesions. Originally developed in rodents, the photothrombotic technique consists of intravenous injection of a photosensitive dye such as Rose Bengal followed by illumination of an area of interest to induce endothelial damage resulting in the formation of thrombi in the illuminated vasculature. We developed a quantitative model to predict the extent of tissue damage based on the light scattering profile of light in the cortex of NHPs. We then employed this technique in the sensorimotor cortex of two adult male Rhesus Macaques. In vivo optical coherence tomography imaging of the cortical microvasculature and subsequent histology confirmed the formation of focal cortical infarcts and demonstrated its reproducibility and ability to control the sizes and locations of light-induced ischemic lesions in the cortex of NHPs. This model has the potential to enhance our understanding of perilesional neural dynamics and can be used to develop reliable neurorehabilitative therapeutic strategies to treat stroke.

A Quantitative Model for Estimating the Scale of Photochemically Induced Ischemic Stroke.

Photothrombosis is a technique that can induce ischemic cortical infarcts using the photodynamic effect of anionic xanthene dyes, typically Rose Bengal, to cause occlusion of cerebral blood circulation. The ability to quantitatively predict the scale of the lesion in photothrombotic procedures can offer crucial insight in the development and implementation of light-induced stroke models in animals. In this article, we introduced a quantitative model that could estimate the normalized light intensity distribution in tissue which scatters photons from a collimated beam. We simulated the penetration and scattering profile of light of Rose Bengal's characteristic absorption wavelengths in mouse cortex. We further illustrated that our model could estimate the spatial extent of effective region under photothrombotic protocols, and how this model can be used to titrate the intensity and geometry of light beams used to generate infarcts of desired dimensional characteristics.

An integrative approach for analyzing hundreds of neurons in task performing mice using wide-field calcium imaging.

Advances in neurotechnology have been integral to the investigation of neural circuit function in systems neuroscience. Recent improvements in high performance fluorescent sensors and scientific CMOS cameras enables optical imaging of neural networks at a much larger scale. While exciting technical advances demonstrate the potential of this technique, further improvement in data acquisition and analysis, especially those that allow effective processing of increasingly larger datasets, would greatly promote the application of optical imaging in systems neuroscience. Here we demonstrate the ability of wide-field imaging to capture the concurrent dynamic activity from hundreds to thousands of neurons over millimeters of brain tissue in behaving mice. This system allows the visualization of morphological details at a higher spatial resolution than has been previously achieved using similar functional imaging modalities. To analyze the expansive data sets, we developed software to facilitate rapid downstream data processing. Using this system, we show that a large fraction of anatomically distinct hippocampal neurons respond to discrete environmental stimuli associated with classical conditioning, and that the observed temporal dynamics of transient calcium signals are sufficient for exploring certain spatiotemporal features of large neural networks.