Miniature microscopes for manipulating and recording in vivo brain activity.

Here we describe the development and application of miniature integrated microscopes (miniscopes) paired with microendoscopes that allow for the visualization and manipulation of neural circuits in superficial and subcortical brain regions in freely behaving animals. Over the past decade the miniscope platform has expanded to include simultaneous optogenetic capabilities, electrically-tunable lenses that enable multi-plane imaging, color-corrected optics, and an integrated data acquisition platform that streamlines multimodal experiments. Miniscopes have given researchers an unprecedented ability to monitor hundreds to thousands of genetically-defined neurons from weeks to months in both healthy and diseased animal brains.

View from Silicon Valley: Maximizing the Scientific Impact of Global Brain Initiatives through Entrepreneurship.

In this era of technology-driven global neuroscience initiatives, the role of the neurotechnology industry remains woefully ambiguous. Here, we explain why industry is essential to the success of these global initiatives, and how it can maximize the scientific impact of these efforts by (1) scaling and ultimately democratizing access to breakthrough neurotechnologies, and (2) commercializing technologies as part of integrated, end-to-end solutions that accelerate neuroscientific discovery.

Direct Imaging of Hippocampal Epileptiform Calcium Motifs Following Kainic Acid Administration in Freely Behaving Mice.

Prolonged exposure to abnormally high calcium concentrations is thought to be a core mechanism underlying hippocampal damage in epileptic patients; however, no prior study has characterized calcium activity during seizures in the live, intact hippocampus. We have directly investigated this possibility by combining whole-brain electroencephalographic (EEG) measurements with microendoscopic calcium imaging of pyramidal cells in the CA1 hippocampal region of freely behaving mice treated with the pro-convulsant kainic acid (KA). We observed that KA administration led to systematic patterns of epileptiform calcium activity: a series of large-scale, intensifying flashes of increased calcium fluorescence concurrent with a cluster of low-amplitude EEG waveforms.

Miniature microscopes for large-scale imaging of neuronal activity in freely behaving rodents.

Recording neuronal activity in behaving subjects has been instrumental in studying how information is represented and processed by the brain. Recent advances in optical imaging and bioengineering have converged to enable time-lapse, cell-type specific recordings of neuronal activities from large neuronal populations in deep-brain structures of freely behaving rodents. We will highlight these advancements, with an emphasis on miniaturized integrated microscopy for large-scale imaging in freely behaving mice.

Zolpidem reduces hippocampal neuronal activity in freely behaving mice: a large scale calcium imaging study with miniaturized fluorescence microscope.

Therapeutic drugs for cognitive and psychiatric disorders are often characterized by their molecular mechanism of action. Here we demonstrate a new approach to elucidate drug action on large-scale neuronal activity by tracking somatic calcium dynamics in hundreds of CA1 hippocampal neurons of pharmacologically manipulated behaving mice. We used an adeno-associated viral vector to express the calcium sensor GCaMP3 in CA1 pyramidal cells under control of the CaMKII promoter and a miniaturized microscope to observe cellular dynamics.

Long-term dynamics of CA1 hippocampal place codes.

Using Ca(2+) imaging in freely behaving mice that repeatedly explored a familiar environment, we tracked thousands of CA1 pyramidal cells' place fields over weeks. Place coding was dynamic, as each day the ensemble representation of this environment involved a unique subset of cells. However, cells in the ∼15-25% overlap between any two of these subsets retained the same place fields, which sufficed to preserve an accurate spatial representation across weeks.

Miniaturized integration of a fluorescence microscope.

The light microscope is traditionally an instrument of substantial size and expense. Its miniaturized integration would enable many new applications based on mass-producible, tiny microscopes. Key prospective usages include brain imaging in behaving animals for relating cellular dynamics to animal behavior.

Advances in light microscopy for neuroscience.

Since the work of Golgi and Cajal, light microscopy has remained a key tool for neuroscientists to observe cellular properties. Ongoing advances have enabled new experimental capabilities using light to inspect the nervous system across multiple spatial scales, including ultrastructural scales finer than the optical diffraction limit. Other progress permits functional imaging at faster speeds, at greater depths in brain tissue, and over larger tissue volumes than previously possible.