An ancient brain circuit, which enables the eyes to reflexively rotate up as the body tilts down, tunes itself early in life as an animal develops, a new study finds.

Led by researchers at NYU Grossman School of Medicine, the study revolves around how vertebrates, which include humans and animals spanning evolution from primitive fish to mammals, stabilize their gaze as they move. To do so, they use a brain circuit that turns any shifts in orientation sensed by the balance (vestibular) system in their ears into an instant counter-movement by their eyes.

The research is published in the journal Science.

Called the vestibulo-ocular reflex, the circuit enables the stable perception of surroundings. When it is broken—by trauma, stroke, or a genetic condition—a person may feel like the world bounces around every time their head or body moves. In adult vertebrates, it and other brain circuits are tuned by feedback from the senses (vision and balance organs). The current study authors were surprised to find that in contrast, sensory input was not necessary for maturation of the reflex circuit in newborns.

The study featured experiments done in zebrafish larvae, which have a similar gaze-stabilizing reflex to the one in humans. Further, zebrafish are transparent, so researchers literally watched brain cells called neurons mature to understand the changes that let a newborn fish rotate its eyes up appropriately as its body tilts down (or its eyes down as its body tilts up).

“Discovering how vestibular reflexes come to be may help us find new ways to counter pathologies that affect balance or eye movements,” says study senior author David Schoppik, Ph.D., associate professor in the Departments of Otolaryngology—Head & Neck Surgery, Neuroscience & Physiology, and the Neuroscience Institute, at NYU Langone Health.

Split-second tilts

To test the long-held assumption that the reflex is tuned by visual feedback, the research team invented an apparatus to elicit the reflex by tilting and monitoring the eyes of zebrafish that were blind since birth. The team observed that the ability of the fish to counterrotate their eyes after tilt was comparable to larvae that could see.

Although past studies have established that sensory input helps animals learn to move properly in their environment, the new work suggests that such tuning of the vestibulo-ocular reflex comes into play only after the reflex has fully matured. Remarkably, another set of experiments showed that the reflex circuit also reaches maturity during development without input from a gravity-sensing vestibular organ called the utricle.

Because the vestibulo-ocular reflex could mature without sensory feedback, the researchers theorized that the slowest-maturing part of the brain circuit must set the pace for the development of the reflex. To find the rate-limiting part, the research team measured the response of neurons throughout development as they gave zebrafish split-second body tilts.

The researchers found that central and motor neurons in the circuit showed mature responses before the reflex had finished developing. Consequently, the slowest part of the circuit to mature could not be in the brain as long assumed, but was found instead to be at the neuromuscular junction—the signaling space between motor neurons and the muscle cells that move the eye. A series of experiments revealed that only the pace of maturation of the junction matched the rate at which fish improved their ability to counter-rotate their eyes.

Moving forward, Dr. Schoppik’s team will study their newly detailed circuit in the context of human disorders. Ongoing work explores how failures of motor neuron and neuromuscular junction development lead to disorders of the ocular motor system, including a common misalignment of the eyes called strabismus (also known as lazy eye and crossed eyes).

Just upstream of motor neurons in the vestibulo-ocular circuit are interneurons that sculpt incoming sensory information and integrate what the eyes see with balance organs. Another of Dr. Schoppik’s goals is to better understand how the function of such cells is disrupted as balance circuits develop, with the goal of helping the 5% of children in the U.S. wrestling with some form of balance problem.

“Understanding the basic principles of how vestibular circuits emerge is a prerequisite to solving not only balance problems, but also brain disorders of development,” says first study author Paige Leary, Ph.D. She was a graduate student in Dr. Schoppik’s lab who led the study and has since left the institution.

Along with Drs. Schoppik and Leary, study authors from the departments of Otolaryngology–Head & Neck Surgery, Neuroscience & Physiology, and the Neuroscience Institute at NYU Langone Health included Celine Bellegarda, Cheryl Quainoo, Dena Goldblatt, and Basak Rosti.