Researchers explore brain estrogens to mitigate learning and memory problems

New studies being launched by neurobiologist Luke Remage-Healey at the University of Massachusetts Amherst will investigate how estrogens produced in the brains of young birds enhance their ability to learn songs during a critical window during development. This period has a parallel to universal language development in human children.

In a separate study, the UMass Amherst neuroscientist and colleagues will explore the idea that estrogens produced in the brain's auditory cortex enhances the representation of sounds in adults, and how these changes are transmitted to other, sensorimotor parts of the brain. This work in zebra finches is supported by two grants, one from the National Science Foundation (NSF) for $640,000 over four years, another from the NIH's National Institute of Neurological Disorders and Stroke for $1.7 million over five years.

Remage-Healey's recent findings are among the first to support the idea that estrogens are not exclusively reproductive hormones, but are in fact also made in the brain like neurotransmitters, where they play a powerful role in cognition, learning and memory.

He says, "There are parts of the human brain important to speech and language, and the songbird brain has analogous regions in the auditory cortex and sensorimotor cortex. We now have a great map to figure out how neural signals propagate from one area to another. Experimentally, we can record how estrogens shape these signals and their propagation. By directly manipulating these pathways we hope to identify key molecular mechanisms and behavioral consequences."

Results of this work could be helpful in understanding human neurobiology, he adds, because a number of neurological disorders such as Alzheimer's and Parkinson's disease and epilepsy, for example, are linked to steroid synthesis in the brain. Researchers are beginning to explore whether brain estrogens might represent a new, far more targeted treatment for cognitive and memory problems related to disease and aging.

The NSF-funded work in young birds will look at how estrogen levels in the brains of juvenile birds affect their song-learning ability, which because of the parallel window of development in humans could shed light on how the hormone affects how children learn speech and language.

"What we sometimes take for granted, our ability to speak and to learn a new language is really an impressive feat," says Remage-Healey. He points out that a rat learning to navigate a maze performs better after an estrogen injection. "In a similar way," he adds, "we are finding that juvenile birds have elevated brain estrogen levels immediately and for about 60 minutes after they hear a new song." This has prompted the hypothesis that brain estrogen production enhances learning of recent experiences during development.

Remage-Healey and colleagues will set up a series of experiments using drugs to up- and down-regulate estrogen in the auditory cortex to determine whether certain treatments have an effect on the birds' ability to learn song. They will also use electrophysiology to record from neurons to assess whether memory consolidation is enhanced by estrogens. "For birds, maintaining your own song is an active, ongoing process. We'll explore whether early tutoring plus estrogen manipulations have consequences for song learning," the neuroscientist notes.

In the NIH-funded studies, the researchers will explore the idea that estradiol in the auditory cortex enhances the representation of sounds in adults, which is transmitted to sensorimotor parts of the brain. "We can modulate the auditory cortex and see downstream effects in the sensorimotor system in adults," Remage-Healey says.

"What this means is that the effects are not all local, and instead we will test how changes in estradiol in one part of the brain are connected to changes in other areas. In this case, we want to uncover the molecular mechanisms for how the changes propagate, along which pathways, and we'll identify how this shapes behavior."

The researchers hope that eventually such studies will lead to new treatment approaches for learning and memory problems that can be targeted to specific brain locations and for particular time windows. This would be an advance for patients taking oral estrogenic drugs, for example, which expose them to potentially adverse whole-body effects.


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