“How Newborn Brain Connections Fine-Tune Focused Vision”

Directed by scholars at NYU Grossman School of Medicine, the research focuses on how vertebrates, including humans and species that have evolved from basic fish to mammals, stabilize their vision as they navigate their surroundings. To achieve this, they employ a neural circuit that translates any orientation changes detected by the equilibrium (vestibular) apparatus in their ears into an immediate counter-movement of their eyes.

Known as the vestibulo-ocular reflex, this circuit facilitates a consistent awareness of one’s environment. When it is impaired — due to injury, stroke, or a hereditary condition — an individual may perceive the world as jostling whenever their head or body shifts. In mature vertebrates, it and other neural pathways are refined by sensory feedback (from vision and balance mechanisms). The authors of the current study were astonished to discover that, conversely, sensory input was not essential for the development of the reflex circuit in infants.

Published online on January 2 in the journal Science, the research included experiments conducted on zebrafish larvae, which possess a gaze-stabilizing reflex akin to that in humans. Additionally, zebrafish are transparent, permitting researchers to directly observe the maturation of brain cells known as neurons to comprehend the alterations enabling a newborn fish to appropriately rotate its eyes upward as its body tilts downward (or downward as its body tilts upward).

“Understanding how vestibular reflexes are established may assist us in discovering innovative methods to combat disorders affecting balance or eye movements,” states the senior author of the study, David Schoppik, PhD, associate professor in the Departments of Otolaryngology — Head & Neck Surgery, Neuroscience & Physiology, and the Neuroscience Institute, at NYU Langone Health.

Split-Second Tilts

To assess the long-standing assumption that visual feedback fine-tunes the reflex, the research team devised a device to evoke the reflex by tilting and observing the eyes of zebrafish that had been blind from birth. The team noted that the ability of the fish to counter-rotate their eyes following a tilt was similar to that of larvae capable of seeing.

While previous research indicated that sensory input aids animals in learning to navigate their environment correctly, the new findings imply that such fine-tuning of the vestibulo-ocular reflex emerges only after the reflex has fully matured. Remarkably, additional experiments demonstrated that the reflex circuit also achieves maturity during development without reliance on input from a gravity-detecting vestibular organ known as the utricle.

Given that the vestibulo-ocular reflex could mature in the absence of sensory feedback, the researchers hypothesized that the slowest-developing aspect of the neural circuit must govern the pace of the reflex’s maturation. To identify the rate-limiting component, the research team evaluated the responsiveness of neurons throughout development while administering rapid body tilts to zebrafish.

The investigators discovered that central and motor neurons within the circuit exhibited mature responses prior to the reflex’s complete development. As a result, the slowest segment of the circuit to mature was not located in the brain as previously thought; it was instead found at the neuromuscular junction — the signaling region between motor neurons and the muscle cells responsible for eye movements. A series of experiments revealed that only the maturation pace of this junction corresponded to the rate at which fish enhanced their ability to counter-rotate their eyes.

Looking ahead, Dr. Schoppik’s team is funded to investigate their newly outlined circuit within the context of human disorders. Ongoing efforts explore how deficiencies in motor neuron and neuromuscular junction development lead to ocular motor system disorders, including a common misalignment of the eyes termed strabismus (also known as lazy eye or crossed eyes).

Positioned just upstream of motor neurons in the vestibulo-ocular circuit are interneurons that refine incoming sensory signals and integrate visual input with balance organs. Another of Dr. Schoppik’s funding endeavors aims to deepen understanding of how the functionality of such cells is disrupted as balance circuits evolve, with the objective of assisting the five percent of children in the U.S. contending with some form of balance issue.

“Comprehending the fundamental principles governing the emergence of vestibular circuits is essential for addressing not only balance issues but also developmental brain disorders,” asserts the primary author of the study, Paige Leary, PhD. She was a graduate student in Dr. Schoppik’s lab who spearheaded the research but has since moved on from the institution.

Alongside Drs. Schoppik and Leary, study contributors 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. This work was supported by the National Institutes of Health through grants from the National Institute on Deafness and Communication Disorders R01DC017489 and F31DC020910, and by the National Institute for Neurological Disorders and Stroke grant F99NS129179. The National Science Foundation also contributed to the study through graduate research fellowship DGE2041775.