Bioimaging, optical stimulation enable real-time observation of brain circuits

In a study using multiphoton microscopy and stimulation via light flashes along optical fibers, a team of researchers at McGill University (Montreal, QC, Canada) has shown—in real time—how the brain re-wires and fine-tunes its connections differently depending on the relative timing of sensory stimuli. The ability to observe this activity is promising for treatment of nervous system injuries and human brain disorders.

Related: High-resolution serial two-photon tomography images whole brains fast

By using multiphoton microscopy to observe cells in the brains of intact animals, the researchers discovered that asynchronous firing, or “firing out of sync,” not only caused brain cells to lose their ability to make other cells fire, but unexpectedly also caused them to dramatically increase their elaboration of new branches in search of better matched partners.

“The surprising and entirely unexpected finding is that even though nerve circuit remodeling from asynchronous stimulation actively weakens connections, there is a 60-percent increase in axon branches that are exploring the environment, but these exploratory branches are not long-lived,” says Dr. Edward Ruthazer, senior investigator on the study at the Montreal Neurological Institute and Hospital –The Neuro at McGill University and the McGill University Health Centre.

Dr. Ruthazer’s lab charts the formation of brain circuitry during development in the hopes of better understanding the rules that control healthy brain wiring and of advancing treatments for injuries to the nervous system and therapies for neurodevelopmental disorders such as autism and schizophrenia.

In the developing brain, initially imprecise connections between nerve cells are gradually pruned away, leaving connections that are stronger and more specific. This refinement occurs in response to patterned stimulation from the environment. “The way we perceive the world as adults is directly impacted by what we saw when we were younger,” says Dr. Ruthazer.

Dr. Ruthazer’s team studies brain development in Xenopus tadpoles, which have the distinct advantage of being transparent, enabling the team to clearly see the nervous system inside. They have developed a model that allows them to watch nerve cell remodeling in vivo, in real time, and to measure the efficacy of connections between cells. Optical fibers were used to stimulate the eyes of the tadpoles with different light patterns while imaging and recording nerve cell branch formation. Asynchronous stimulation involved light flashes presented to each eye at different times, while synchronous stimulation involved simultaneous stimulation of both eyes.

Importantly, Dr. Ruthazer’s group also has begun to identify the molecular mechanisms underlying these changes in the nervous system. They show that the stabilization of the retinal nerve cell branches caused by synchronous firing involves signaling downstream of the synaptic activation of a neurotransmitter receptor called the N-methyl-D-aspartate receptor. In contrast, the enhanced exploratory growth that occurs with asynchronous activity does not appear to require the activation of this receptor.

Full details of the work appear in the journal Science; for more information, please visit


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