Using week-old zebrafish larvae, Weill Cornell Medicine researchers and collaborators have decoded the way neural connections in the brainstem influence the gaze of these fish. As detailed in the November 22 issue of Nature Neuroscience, their findings revealed that a streamlined artificial circuit inspired by this neural architecture can foresee network activity. Not only do these insights illuminate how the brain manages short-term memory, but they may also pave the way for innovative treatments for eye movement disorders.
Organisms constantly process a mixture of sensory inputs as their environment fluctuates moment by moment. To properly evaluate situations, the brain needs to hold onto these bits of information long enough to piece together a fuller picture — such as linking words in a sentence or allowing eyes to remain focused on a specific spot.
“Our main aim is to grasp how these short-term memory behaviors arise from neural mechanisms,” said senior author Dr. Emre Aksay, associate professor at Weill Cornell Medicine. He led the study alongside Dr. Mark Goldman from the University of California Davis and Dr. Sebastian Seung from Princeton University.
To decipher the operations of such neural circuits, neuroscientists apply the principles of dynamic systems. This involves formulating mathematical models that map the evolution of the system’s state, where the current state dictates future outcomes based on certain rules. A short-term memory circuit, for instance, stays in one favored state until it’s influenced by a new stimulus, shifting it to a new state of activity. Within the visual-motor system, each state can encode the memory location an organism is intended to focus on.
But what conditions establish this kind of dynamic system? The circuit’s layout—how neurons connect and the extent of those connections—could be one factor. Another consideration is the physiological vigor of those connections, determined by elements like neurotransmitter levels, types of synaptic receptors, and their concentration.
To investigate the role of circuit configuration, Dr. Aksay and his team studied larval zebrafish. By five days post-hatch, these little fish are swimming and preying, demonstrating visual focus abilities. Their brains, which manage eye movement, exhibit structural parallels with those of mammals but are composed of only 500 neurons. “We can scrutinize the whole circuit, both microscopically and functionally,” Dr. Aksay noted. “That’s a challenge in other vertebrates.”
Leveraging advanced imaging technologies, Dr. Aksay’s group pinpointed neurons influencing the zebrafish’s gaze and discerned their connectivity. They found two significant feedback loops within the system, each formed by closely-knit groups of cells. They constructed a computational model based on this setup and observed that their synthetic network could reliably predict the zebrafish circuit’s activity, verified against physiological data.
“As primarily a physiologist, I was amazed by how much circuit behavior we could infer purely from its anatomy,” Dr. Aksay added.
Future efforts will probe how individual cell groups affect the circuit’s behavior and if neuron clusters display unique genetic traits. This knowledge might enable targeted therapeutic interventions for malfunctioning cells involved in eye movement disorders. The findings also offer a framework for understanding more intricate brain systems dependent on short-term memory, such as those for interpreting visual scenes or processing language.
This research received funding from the National Institutes of Health (NIH) grants via the National Institute of Neurological Disorders and Stroke R01 NS104926 and the Brain initiative award 5U19NS104648; the National Eye Institute R01 EY027036, R01 EY021581, and K99 EY027017; and the National Cancer Institute UH2 CA203710.