Among the myriad chemicals that neurons release as signals, acetylcholine was the very first to be identified at the interface between nerve and muscle. In the 90 years that have elapsed since that Nobel-winning discovery, neuroscientists have learned a lot about the many ways that acetylcholine exerts its effects. Within the two broad classes of molecular receptors for acetylcholine—nicotinic and muscarinic—there are multiple subtypes found throughout the nervous system.
Nicotine, the active ingredient in tobacco, acts through nicotinic acetylcholine receptors (nAChRs) to stimulate the nervous system; nAChRs have been much studied in the context of nicotine addiction. But Jerrel Yakel, Ph.D., is much more interested in how these receptors respond to intrinsic brain signals. For a man who has devoted much of his career to studying the properties of these tiny molecular machines, Yakel has a broad perspective. “The brain is the big kahuna,” said Yakel. “My overarching focus now is understanding the functional role of nAChRs in brain circuits.”
Recently, he and his post-doctoral fellow, Zhenglin Gu, Ph.D., have begun to study acetylcholine signals to the hippocampus, a brain structure considered critical for the formation of new memories. Circuits in the hippocampus are capable of changing the strengths of their internal connections on the basis of prior activity patterns. This “long-term potentiation” (LTP) could be part of the mechanism used by the brain to lay down new memories.
In order to activate only the microscopic fibers in the hippocampus that release acetylcholine, Gu and Yakel turned to the recently developed technique of optogenetics. Acetylcholine-containing fibers originate in a region of the brain called the septum; Gu and Yakel introduced a genetic modification of neurons in the mouse septum to render them electrically active in response to a flash of light. They were then able to record electrical signals from hippocampal neurons in a slice of brain tissue while optically activating the septum to release acetylcholine.
“We found that by pairing activation of acetylcholine with stimulation of other inputs to hippocampal neurons, we were able to induce three different forms of plasticity that were dependent on precise timing,” said Yakel. “We’re excited because we’re showing endogenous acetylcholine induces plasticity through a couple of different mechanisms.”
Moreover, Gu and Yakel have shown that these circuit changes are vulnerable to the kind of amyloids found in Alzheimer’s disease. Application of very low doses of Aß disrupted all three forms of the plasticity that they had observed. “It seems possible that Aß is interfering with the acetylcholine signaling,” said Yakel cautiously. Clearly, more work is necessary, which Yakel views with anticipation.
“I love what I do, I get a kick out of what I do,” said Yakel. While focusing on his research, Yakel, who is part Native American, has worked to provide mentorship opportunities for trainees, including minorities. “I do a lot of mentoring. It’s a way of giving back. I want people to be happy that they picked me for their career development,” said Yakel. He is also serious about doing work that contributes to public health, but is seeking no particular holy grail in his research. “Ultimately, I just want to keep doing more and better work.”
Jerrel Yakel, Ph.D., is a Principal Investigator in the Ion Channel Physiology Group of the National Institute of Environmental Health Sciences (NIEHS).