Studying the Role of Inhibition and Neuro-estrogens in Bird Song

zebra finch singing

Neurobiologist Luke Remage-Healey, associate professor of psychological and brain sciences, recently received a five-year, $1.7 million grant, the renewal of a prior period of funding from the National Institutes of Health. He and colleagues plan to investigate fundamental mechanisms of how the brain learns and processes complex stimuli like birdsong.

As anyone learning a new foreign language can report, sensory stimuli like speech and song are near-continuous streams of complex sound and can be difficult to understand. But “with practice, listeners can learn to parse the meaning in streams of Mandarin or Stravinsky, just like birds learn to process high-velocity songs,” he explains. The new grant will allow Remage-Healey and colleagues to investigate in detail the timing and precision of neurons that encode streams of complex vocal signals.

He says of earlier work in his lab and elsewhere, “We already knew that estrogens are really important for brain function. If we experimentally slow estrogen synthesis in the brain of songbirds, they are unable to respond normally to sounds, just like people who take estrogen synthesis inhibitors can experience deficits in verbal memory.” Further, “We know that sensory neurons are sensitive to estrogens produced in the brain, and that they play a role in learning songs. We have a hunch that this depends on specific actions on one class of inhibitory neurons in the cortex.”

Better understanding these mechanisms and neural circuits could eventually lead to highly-targeted estrogen-based therapies to treat cognitive and neurological disorders such as Parkinson’s and Alzheimer’s diseases, Remage-Healey says.

For this work, he will collaborate with Yoko Yazaki-Sugiyamaat the University of Tokyo, an expert in genetic techniques that can target specific classes of neurons. The technique will allow them to identify how the neurons regulate so-called “fast-spiking inhibitory inter-neurons” in the auditory cortex. They also plan to take advantage of newly available advanced molecular tools, Remage-Healey says.

The researchers seek to identify what type of cells are involved and whether and how neuro-estrogens directly modulate certain inter-neurons in the cortex to regulate timing precision and behavioral discrimination learning such as used for songs. “We can’t figure this out until we know what type of cells are involved,” in particular the roles of inhibitory vs. excitatory neurons he notes.

“It’s counter-intuitive,” he adds, “but to get things done faster and more precisely, the brain will use ‘stop’ neurons instead of ‘go’ neurons. We see time and time again that a hormone like oxytocin or serotonin will target inhibitory neurons rather than excitatory neurons to regulate behavior. Inhibitory neurons can be super-fast firing, faster than excitatory neurons, and they can sharpen a response to stimulus like sound.”

In complex streams like listening to a symphony, the brain needs to be able to process each sound quickly, “which we think is accomplished with a combination of excitation that is tuned by inhibition. This allows high precision in unpacking the bits coming at you. It means the sounds are not perceived as a continuous stream, but as a series of discrete, interpretable elements,” Remage-Healey explains.

He and colleagues hypothesize that estrogens may be helping to encode certain stimuli, and ignoring others, as a way to modulate a circuit, to tune it up or down. Targeting inhibition may offer “the perfect knob to do that, if you want to process something like music or speech really fast. We’re beginning to see that this is something more widespread and that maybe it’s not just a songbird thing. We hope what we’re learning in the auditory cortex of songbirds is helping us to understand other instances of this behavior, too.”