A healthy brain has just the right ratio of cells that enhance signals (excitatory neurons) and cells that tone down signals (inhibitory neurons). These two sets of neurons start out looking exactly the same, so what determines their roles?
A new study in animal models from The Scripps Research Institute (TSRI) suggests that stimulation from the outside world guides these neurons' early development so that inhibitory neurons split into two different types of neurons, each with a different job in the brain. This adds another level of complexity and regulation to this circuitry.
If these findings hold true in humans, they could provide insight into how brain circuits develop and how future therapeutics might better treat neurological disorders such as autism, schizophrenia and depression.
"The function of inhibitory neurons in developing circuits is defined at earlier stages of development than previously thought -- and it's defined, at least partly, by the responses of the neurons to sensory input," said study senior author Hollis Cline, chair of the Department of Molecular and Cellular Neuroscience and director of the Dorris Neuroscience Center at TSRI.
The study was published May 26, 2016, in the journal Neuron.
A Window into Early Development
In the study, Cline and her colleagues used a technique called in vivo time lapse imaging, which allowed them to track the development of individual neurons over time. They chose tadpoles for the experiment, which, in addition to being translucent enough to see neurons in action, correspond to stages of brain development that occur before a mammal's birth.
Tadpoles in the experiment swam freely under a panel of shifting lights, which mimicked what they would see if they were swimming in a stream. The researchers found that some inhibitory neurons strengthened their connections and proclivity to fire in response to the lights, just like excitatory neurons. A second population of inhibitory neurons decreased their connections and firing activity in response to lights.
The team looked for biochemical signatures and other markers that distinguish excitatory and inhibitory neurons, but found no known markers at this early stage, leading them to conclude that visual stimulation might be triggering the expression of certain genes that make the neuron types different.
In other words, some neurons might not be pre-programmed to have a certain function--their experiences might instead determine how they develop.
"The big surprise was that neurons that look very similar have opposite plasticity responses to experience," said TSRI Senior Research Associate Hai-yan He, first author of the study.
"It was a huge shock that experience would play such a strong role so early in brain development," added Cline.
Clues to Better Drug Design
In the healthy brain, inhibitory neurons work in a circuit with excitatory neurons to ensure that the excitatory neurons don't fire too much or too little. How could these two opposite types of inhibitory neurons work together in a circuit to control excitatory neurons? The researchers suggest that one type of inhibitory neuron inhibits the other inhibitors, adding a second layer of control to this complicated system and keeping the overall circuit in balance.
It will be important to consider both subtypes of inhibitory neurons when developing new therapies for neurological disorders, He said. If scientists develop a treatment to boost the response of all inhibitory neurons, for example, they could inadvertently send the system further out of balance.
"If you target a therapy at the whole population, and disregard the diversity within that population, then you're not actually going to achieve the intended outcome," said He.
The researchers noted further studies are needed to understand exactly how much of a neuron's identity is driven by experience and what determines the two types of inhibitory neurons.
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