Combining Wireless Optogenetics and Fiber Photometry for Closed-Loop Experiments

Optogenetic stimulation and fiber photometric recording have played crucial, yet distinct, roles in in vivo behavioral neuroscience. These tools allow researchers to directly link the activity of specific cell types and brain regions to observable behaviors, helping to understand how brain circuitry drives learning and emotion, among other functions.

Optogenetics and fiber photometry have developed significantly in the past couple of decades, including integrating components into a wireless headstage mounted on the head of a subject. Wireless headstages greatly improve mobility and reduce stress, thus increasing the reliability and reproducibility of behavioral data. 

Only recently, however, has technology advanced to the point of consolidating optogenetics and fiber photometry into one wireless headstage. This has reduced experimental design complexity and surgical invasiveness, which allows researchers to simultaneously explore the circuitry connecting inputs and outputs in closed-loop experiments while observing behavior.

Wireless Optogenetics Offers Freedom anda Precise Control

With optogenetics, researchers modulate defined cell populations that express opsins sensitive to specific wavelengths of light, which in turn activate or inhibit these cells when exposed to these wavelengths. Optogenetics offers precise, millisecond-level temporal control over cellular activity. This level of control has made it possible to probe the neural underpinnings of fear, motivation, and learning among other functions of the brain, and to model neurological and psychiatric conditions with remarkable specificity. 

Yet, the flexibility of optogenetic setups has been limited by tethering of the subject to transmit light from a light source to the brain. Tethered optic fibers can restrict movement, increase stress, and interfere with behavior, especially in confined settings, when integrating other tethered technology, or during social interaction trials. Wireless optogenetic systems solve this problem by freeing subjects to move, explore, and interact, modeling natural behaviors more closely.

However, researchers observing the effects of stimulation with wireless optogenetics still rely on less direct readouts, such as behavioral outcomes or postmortem histological analysis, to infer what is happening in the brain. This is where fiber photometry comes in.

Wireless Fiber Photometry Helps Capture Cellular Activity in Real Time

Real-time responses of specific cell populations in the brain, expressed as light emissions from genetically encoded fluorescent biosensors (such as GCaMP, GRABDA, and RCaMP), are captured through fiber photometry. Unlike histological or behavioral readouts, fiber photometry delivers high temporal and cell-type specific resolution, making it possible to see how neural activity unfolds in milliseconds. 

Example fiber photometry signal trace showing changes in fluorescence over time that reflect real-time neural activity.

Wireless options for fiber photometry have also been developed, reducing animal stress and addressing noise,artifacts, and signal loss in data from optic fiber tether twisting or light having to pass through rotary joints and commutators. Wireless fiber photometry offers cleaner, more reliable data. In fact, modern wireless fiber photometry can simultaneously record from two wavelengths and/or two brain regions, enabling researchers to examine the dynamic relationships between distinct cell populations such as excitatory and inhibitory neurons, glial cells, or to compare activity across hemispheres or circuits. 

Until recently, traditional setups have limited researchers to observation separate from manipulation. The size and complexity of conventional optogenetic and fiber photometry headstages made integration of the two technologies impractical.

Tethered vs Wireless: Separate and Integrated Approaches

Combined optogenetics and fiber photometry usher in a new era in neuroscience

With wireless optogenetic stimulation and fiber photometric recording integrated into a single compact headstage, researchers can design closed-loop experiments that investigate cause and effect within the brain with high precision. By activating or silencing the input end of a circuit while recording the output end in real time, they can reveal how one brain region influences another as the animal behaves, learns, or remembers. This simultaneous approach provides a more holistic understanding of brain function. 

TeleFiOpto, one of the first commercially available systems that combines wireless optogenetics and fiber photometry, has been instrumental in advancing studies of learning and memory. In one example, scientists using TeleFiOpto have shown that dopaminergic inputs from the ventral tegmental area (VTA) to the hippocampus are essential for maintaining and adapting spatial memory in mice. In another instance, TeleFiOpto has helped clarify the interactions among various types of neurons in hippocampal disinhibitory circuits while  subjects explore novelty in their environment, revealing the mechanisms underlying the formation of recognition memory. 

These findings, made possible only through wireless simultaneous stimulation and recording, underscore how the integration of these technologies is transforming our understanding of complex neural processes.

Wireless fiber photometry and optogenetics untether technological advances in translational science

Wireless systems that combine optogenetics and fiber photometry, such as TeleFiOpto, help scientists explore the brain in novel ways that can directly link activity of specific cell populations to corresponding behavior, particularly in pathological conditions. These systems offer real-time manipulation and recording of cellular activity within freely moving and behaving subjects, minimizing invasiveness and stress on subjects while maximizing control and data quality. 

With the continued evolution of these systems, our understanding of how brain circuits drive behavior, emotion, and learning continue to expand.

Considering Closed-Loop Experiments?

If you’re planning to combine wireless optogenetics and fiber photometry in a
closed-loop workflow, our team can help you think through configuration,
channels, and experimental design.

Talk with an Amuza neuroscience specialist

References

Tamatsu Y, Azechi H, Takahashi R, et al. Optogenetic activation of the ventral tegmental area-hippocampal pathway facilitates rapid adaptation to changes in spatial goals. iScience. 2023;26(12):108536. Published 2023 Nov 23. doi:10.1016/j.isci.2023.108536

Tamboli S, Singh S, Topolnik D, et al. Mouse hippocampal CA1 VIP interneurons detect novelty in the environment and support recognition memory. Cell Rep. 2024;43(4):114115. doi:10.1016/j.celrep.2024.114115