An ancient brain circuit, crucial for stabilizing the gaze of vertebrates—including humans—has been found to develop in a surprising way during early life, a study led by researchers from NYU Grossman School of Medicine reveals. This circuit, called the vestibulo-ocular reflex (VOR), is essential for allowing vertebrates to keep their eyes fixed on a target even as they tilt or move their bodies. In adult vertebrates, including humans, this reflex system stabilizes the gaze by responding to any changes in orientation detected by the balance (vestibular) organs in the inner ear and reflexively coordinating eye movement in opposition.
The study, published in the journal Science, offers fresh insights into how this vital circuit develops, potentially paving the way for understanding disorders that disrupt eye movements and balance. While the reflex is essential to functioning for vertebrates, ranging from primitive fish to mammals, how it matures has previously been unclear. The traditional assumption held that the development of the VOR depends on sensory feedback from both visual input and the balance system. However, the new research challenges this belief, revealing that, contrary to what was long assumed, sensory input—such as sight or gravity-sensing organs—is not necessary for the early stages of circuit development.
The study focused on zebrafish larvae, which were chosen because their gaze-stabilizing reflex shares similarities with the human VOR. Zebrafish also present the added advantage of being transparent, a unique characteristic that allowed the researchers to observe the development of brain cells known as neurons in real-time. With this transparency, the team was able to track the precise changes in neuronal development that allowed the larvae to successfully rotate their eyes upwards when their bodies tilted downward, or downwards when their bodies tilted upward. These observations provided novel insights into how early development processes give rise to the reflexes that stabilize an organism’s gaze during body movements.
The central discovery of the study revolved around the maturation process of the vestibulo-ocular reflex. In the past, it was believed that feedback from sensory organs such as the eyes and inner ear were crucial for tuning this circuit during the development of the reflex. To test this long-held hypothesis, the researchers created a specialized apparatus to study the reflex by tilting zebrafish in a way that simulated these changes in orientation. In one experiment, they specifically studied fish that had been made blind since birth, eliminating the possibility of visual feedback. The findings were surprising—these blind zebrafish larvae were still able to counter-rotate their eyes with the same precision as larvae that could see, demonstrating that the eye movement response to body tilt was not contingent upon sensory feedback from visual input.
Moreover, the study provided further evidence that feedback from the vestibular system—the organs responsible for sensing gravity and motion—was also not necessary in early stages of reflex maturation. This points to the idea that the VOR circuit matures largely independent of these sensory inputs, and it is only in the later developmental stages that these sensory components start to refine the reflex. The significance of this finding is that it suggests the presence of intrinsic mechanisms in the neural circuits governing eye movements, shaping the response to tilts before external sensory feedback comes into play.
While sensory input is not required to trigger the reflex initially, the research led the team to hypothesize that the slowest-maturing part of the vestibulo-ocular reflex circuit would determine the timing of its maturation. To explore this possibility, the researchers closely observed the response of neurons across different stages of zebrafish development as they subjected the fish to split-second body tilts. They found that the central neurons in the brain, which are responsible for processing motion and guiding motor responses, matured quickly in comparison to other parts of the reflex system. However, a more significant delay was observed at the neuromuscular junction—the interface between the motor neurons and the muscles responsible for moving the eyes. The researchers’ work demonstrated that the maturation of this neuromuscular junction was the rate-limiting step in the overall development of the reflex. This was a key finding, as it had long been assumed that the primary bottleneck in the maturation of the reflex circuit occurred within the brain.
Understanding the development of the VOR and its reliance on the maturation of the neuromuscular junction sheds new light on how the human and animal vestibulo-ocular reflex circuits form. The research suggests that while the circuits in the central nervous system mature relatively quickly, the final stages of proper motor coordination involve complex interactions between motor neurons and the muscles that must work together to enable effective eye movements.
The implications of this discovery are vast and may help inform research into a variety of neurological and developmental disorders. For instance, when the proper function of the vestibulo-ocular reflex is impaired in humans, individuals can experience severe disorientation or dizziness due to the inability to stabilize their gaze during movement. In extreme cases, it can feel as if the world is constantly bouncing or spinning whenever the individual moves, resulting in difficulty maintaining balance or engaging in daily activities. Conditions such as these can arise from neurological damage, stroke, trauma, or certain genetic conditions.
As Dr. David Schoppik, the senior author of the study, emphasized, understanding how reflex circuits mature could have significant implications for counteracting pathologies that affect balance and eye movements, providing valuable therapeutic insights for conditions like strabismus, also known as crossed eyes or lazy eye. Strabismus occurs when the eyes are not properly aligned and can cause issues with vision and depth perception. The developmental trajectory uncovered in this study could help address the underlying causes of such motor coordination issues, offering hope for new interventions for affected patients.
In addition to examining the neuromuscular junction’s role in the maturation of the VOR, the researchers intend to explore other neural circuits involved in regulating balance and gaze-stabilization. One key area of interest is understanding how interneurons, located just upstream of motor neurons within the vestibulo-ocular circuit, process and integrate the sensory information coming from the eyes and balance organs. Disruptions to these complex processes, particularly during early development, may explain some of the balance and coordination problems that affect children. Around 5% of children in the U.S. struggle with balance disorders, and this research provides an avenue for potentially better understanding the roots of these developmental issues.
The work of Dr. Schoppik’s lab highlights how discoveries related to basic biological principles can ultimately be used to address significant real-world health challenges. As Dr. Paige Leary, the first author of the study, explained, further research into the maturation of vestibular circuits and the mechanisms underlying balance disorders could make important strides toward improving therapies and treatments for a variety of neurodevelopmental and neurological conditions.
Reference: Paige Leary et al, Sensation is dispensable for the maturation of the vestibulo-ocular reflex, Science (2025). DOI: 10.1126/science.adr9982