Overview: Despite extensive research, brain function and neurological diseases like Huntington disease are still poorly understood. Complexities arise from the vast quantity of neurons in the human brain and from the densely interconnected networks of intermixed cell types. This makes controlling brain function a formidable challenge, and underscores the need for methods that noninvasively probe the underlying micro-circuitry in the brain with single-cell resolution.
Over the last decade, techniques like calcium imaging and optogenetic stimulation—a form of light therapy—have emerged as powerful solutions to this problem. These methods provide all-optical means to monitor and manipulate neuronal activity. Calcium imaging uses indicators that bind with positively charged ions like calcium, altering the fluorescence characteristics of neurons. When a neuron fires, there is an uptake of calcium into the cell membrane, and when illuminated with an excitation light source during the firing event, the fluorescence emission increases. This results in an optical signal that corresponds with brain activity.
Complementary to this is photoactivation, which uses optogenetic tools—including genetically modified cells that express light sensitive proteins, such as microbial opsins derived from Chlamydomonas reinhardtii or engineered proteins like channelrhodopsins—to manipulate neuron firing. This manipulation can activate ion channels or proton pumps, allowing for precise control over membrane potential. This biological technique enables scientists to either cause neurons to fire or silence them, enabling the mapping of neuronal circuits with high temporal precision. Researchers like Karl Deisseroth, Georg Nagel, and institutions like the Max Planck Institute have played pivotal roles in advancing optogenetics research.
Together, calcium imaging and optogenetics provide a means to record the spatiotemporal dynamics of neural circuits, offering insights into how external stimuli influence behavior and how such pathways may be altered in disease. These methods are now widely used in brain stimulation studies, including deep brain stimulation models for neurodegenerative disorders.
Liquid crystal spatial light modulators (LC-SLMs), often used in these setups, function as a programmable lens to manipulate the wavefront of the excitation light. At their core, SLMs redirect light—such as blue light or red light—to specific cells or even specific cells within a 3D volume. This light control allows for precisely defined events like targeting individual neurons or controlling different cell types within neuronal activity studies.
When used in two-photon microscopes, LC-SLMs enable scanless multisite optogenetic stimulation for photoactivation, as well as high-speed volumetric imaging for observing complex brain light responses. This combination gives researchers the ability to explore deep brain regions with remarkable clarity and control. It’s even compatible with experimental setups involving glass bottom dishes and fiber coupled LEDs.
To meet the demands of this market, the ideal SLM must provide high resolution, high phase stability, low optical losses, and high-speed switching. High resolution expands the field of view across neuronal circuits, while low losses ensure adequate light stimulation when dividing beams among many targeted brain cells. Fast switching is essential to match the rate of naturally occurring neural activity.
As optogenetics continues to grow, tools like LC-SLMs—combined with advances in genetic engineering, genetically encoded proteins, and large-scale projects like the Human Connectome Project—are redefining our ability to use light in controlling brain function. Inspired by the vision of pioneers like Francis Crick, optogenetics represents a revolutionary step in understanding how light can influence neuronal circuits, behavior, and disease with precision once unimaginable.
