Although species like mice and zebrafish diverged on the evolutionary tree millions of years ago, they still have biological features in common. Those shared characteristics can indicate that something has a fundamental nature, and also enables the study of similar mechanisms in different species. One example is the brain circuitry that is essential for vigilance or alertness. Investigators utilized a method that could have many research applications; it can reveal wiring in the brain that is likely very important to survival for that humans share it as well.
"Vigilance gone awry marks states such as mania and those seen in post-traumatic stress disorder and depression," said Joshua Gordon, M.D., Ph.D., the Director of the NIH's National Institute of Mental Health (NIMH), which funded the work along with the National Institute on Drug Abuse. "Gaining familiarity with the molecular players in a behavior - as this new tool promises - may someday lead to clinical interventions targeting dysfunctional brain states."
The method the investigators used, Multi-MAP (Multiplexed-alignment of Molecular and Activity Phenotypes), enabled them to observe activity in many different brain cells at once, without needing a genetically altered animal model for each one. They have reported their work in Cell.
“We looked at every neuron in the fish’s brain during life, when those cells were actively firing, and learned which cells were most active at moments when we knew that the fish was most alert,” said study author Karl Deisseroth. “Then, after the fish’s brain tissue was preserved with a fixative without altering relative positions of cells within the fish’s head, we could target those neurons with molecular probes and determine their cell types,” explained Deisseroth. He is a Howard Hughes Medical Institute Investigator and holds Professorships in Bioengineering, Psychiatry and Behavioral Sciences at Stanford.
With Multi-MAP, researchers can see the neurons that are activated in an animal during some specific brain state while also analyzing only those active neurons; the subtypes and circuits that are involved can thus be identified.
The technique was used to check neuronal activity in genetically engineered zebrafish. They make a great research model in part because they are transparent. The scientists assessed vigilance by noting how long it took for the fish to move their tails after being threatened by a stimulus.
The research revealed six potential circuits, each with its own set of neurons, and only one has been previously linked to vigilance. In follow up experiments that used mouse brains, virtually the same circuits were implicated. With another tool Deisseroth and colleagues created, optogenetics, the candidates for alertness were reduced to three in mice. One was confirmed as the one previously known, and the others may have a reporting instead of regulating role.
The investigators believe this work could have far-reaching implications. “The more we understand the landscape of neurons that underlie a brain state like alertness, the more we understand the brain state concept itself — and we may even be able to help design brain-state targeted clinical interventions,” Deisseroth said.
In the video above from Bozeman Science, hear more about how similarities in genetic sequences help scientists learn about evolution.