Faculty Bibliography

Temporal focusing (TF) multiphoton systems constitute a powerful solution for cellular resolution optogenetic stimulation and recording in three-dimensional, scattering tissue. Here, we address two fundamental aspects in the design of such systems: first, we examine the design of TF systems with specific optical sectioning by comparatively analyzing previously published results. Next, we develop a solution for obtaining TF in a flexible three-dimensional pattern of cell-matched focal spots. Our solution employs spatio-temporal focusing (SSTF) in a unique optical system design that can be integrated before essentially any multiphoton imaging or stimulation system.

In addition to the widely-used ability to selectively target specific cell types, optogenetics combined with other neurophotonic strategies also offer an exciting path towards spatio-temporally-controlled targeting: projected patterns of light can be used to selectively and flexibly control and image activity patterns distributed across entire populations of neurons. When natural photoreception is disrupted, as in outer-retinal degenerative diseases, stimulation of surviving nerve cells offers a potential strategy for bypassing compromised neural circuits, inspiring early development of optogenetic retinal prostheses. Selectively exciting large neural populations is essential for eliciting meaningful perceptions in the brain. Here, we present our recent work on distributed neuronal interfacing with large populations of optically accessible, optogenetically transduced neurons in two-dimensions (retinas) and three-dimensions (bioengineered brain-like 'optonets'). Our results demonstrate that patterned computer-generated Holographic Optical Neural Stimulation (HONS) can achieve millisecond temporal precision and cellular resolution as a path towards simultaneously controlling populations of retinal ganglion cells, and that new adaptations of multiphoton temporal-focusing holography provides a powerful tool for distributed 3D imaging & control. HONS pattern projection combined with high resolution imaging provides a path towards all-optical bidirectional interfacing, and is also being translate towards in vivo applications.

The Optics and the Brain conference brought together leaders in the neuroscience optics field whose contributions are significantly advancing the state of the art in biological and medical research through the development and implementation of innovative optical technologies. In this conference, the latest advances in neurophotonic imaging, novel optical modulation approaches and applications across scales from small organisms to clinical settings were presented.

Azobenzene photoresponsive elements can be installed on sulfonylureas, yielding optical control over pancreatic beta cell function and insulin release. An obstacle to such photopharmacological approaches remains the use of ultraviolet-blue illumination. Herein, we synthesize and test a novel yellow light-activated sulfonylurea based on a heterocyclic azobenzene bearing a push-pull system.

Light is a fascinating phenomenon that ties together physics, chemistry, and biology. It is unmatched in its ability to confer information with temporal and spatial precision and has been used to map objects on the scale of tens of nanometers (10(-8) m) to light years (10(16) m). This information, gathered through super-resolution microscopes or space-based telescopes, is ultimately funneled through the human visual system, which is a miracle in itself. It allows us to see the Andromeda galaxy at night, an object that is 2.5 million light years away and very dim, and ski the next day in bright sunlight at an intensity that is 12 orders of magnitude higher. Human vision is only one of many photoreceptive systems that have evolved on earth and are found in all kingdoms of life. These systems rely on molecular photoswitches, such as retinal or tetrapyrrols, which undergo transient bond isomerizations or bond formations upon irradiation. The set of chromophores that have been employed in Nature for this purpose is surprisingly small. Nevertheless, they control a wide variety of biological functions, which have recently been significantly increased through the rapid development of optogenetics. Optogenetics originated as an effort to control neural function with genetically encoded photoreceptors that use abundant chromophores, in particular retinal. It now covers a variety of cellular functions other than excitability and has revolutionized the control of biological pathways in neuroscience and beyond. Chemistry has provided a large repertoire of synthetic photoswitches with highly tunable properties. Like their natural counterparts, these chromophores can be attached to proteins to effectively put them under optical control. This approach has enabled a new type of synthetic photobiology that has gone under various names to distinguish it from optogenetics. We now call it photopharmacology. Here we trace our involvement in this field, starting with the first light-sensitive potassium channel (SPARK) and concluding with our most recent work on photoswitchable fatty acids. Instead of simply providing a historical account of our efforts, we discuss the design criteria that guided our choice of molecules and receptors. As such, we hope to provide a roadmap to success in photopharmacology and make a case as to why synthetic photoswitches, properly designed and made available through well-planned and efficient syntheses, should have a bright future in biology and medicine.

One hundred years after his Nobel Prize, Richard Willstatter's achievements and the fascinating role he played in 20th century chemistry are discussed in this Essay. Several of his discoveries, such as the anthocyanidins, cyclooctatetraene, the ortho-quinones, and the structure of cocaine, will forever be associated with his name.