It’s long been known that the seat of executive function resides in the brain’s frontal lobe. Cognitive capabilities like attention, mental representations, and inhibition are linked specifically to the dorsolateral prefrontal cortex. The puzzle was how, exactly, the neurons in this area mediate such complex reasoning, but a new study out of Yale University suggests one protein, the α7 nicotinic acetylcholine receptor (or α7-nAChR), plays a vital role. Therapies targeting this receptor might ease a range of neuropsychiatric disorders that impair higher level cognition, such as schizophrenia.
Pyramidal cells and cognition
Pyramidal cells are cortical neurons that feature a triangular-shaped soma, or cell body, as well as highly branched axons and dendrites. Patricia Goldman-Rakic, a pioneering neuroscientist at Yale and a member of the Dana Alliance for Brain Initiatives (DABI) until her untimely death in 2003, was the first to demonstrate the relationship between pyramidal cell circuits in prefrontal cortex and working memory.
“These pyramidal cell circuits are in deep in the dorsolateral prefrontal cortex,” says Amy Arnsten at Yale’s Kavli Institute of Neuroscience. “Patricia Goldman-Rakic’s work showed us that these are the circuits that generate higher-order thought. These circuits, she thought, and consequent work has certainly supported her ideas, are the foundation of abstraction. They allow us to represent things that aren’t currently stimulating our senses.”
Goldman-Rakic’s groundbreaking studies found that in order to keep information in working memory, these pyramidal cells need to excite one another through NMDA receptors, a type of glutamate receptor. Arnsten and her colleagues wondered which neuromodulator was stimulating the receptor to make that happen.
“We had to ask ourselves, ‘what is exciting the membrane and allowing these NMDA receptors to open, thus allowing prefrontal circuits to talk to each other?”’ says Arnsten. “And we found that α7-nAChRs are playing a very large role in this fundamental operation behind working memory.”
A new role for acetylcholine
A good bit of Goldman-Rakic’s work focused on the role of dopamine receptors in exciting the pyramidal cell circuits. Neurobiologists since then have been interested in glutamate and catecholamine receptors, but recently there’s been increased curiosity about how the neuromodulator acetylcholine may be influencing these cells. Acetylcholine has been linked to sleep-wake states—as well as arousal—but new evidence suggests that it also enhances cognitive function.
“Certainly, in subjects that have diminished acetylcholine levels, you see that cognitive functions are also reduced,” says Alexander Thiele, a neuroscientist at Newcastle University. “And then if you give someone with diminished acetylcholine function something that enhances the acetylcholine function, you see improvement in cognitive function.” Three out of the four FDA approved drugs for Alzheimer’s disease also target acetylcholine.
In the November 6, 2011, issue of Nature Neuroscience, Mark Baxter, a scientist at Mount Sinai School of Medicine, and colleagues showed that depleting acetylcholine in the brains of primates resulted in a striking impairment to working memory function.
“It’s a very specific effect. And, honestly, it’s remarkable what primates can do without acetylcholine in their prefrontal cortex,” says Baxter. “Their inhibitory control is normal. Their episodic memory is normal. Their ability to apply behavioral strategies is normal. Their ability to adjust their behavioral response to changes is normal. There are lots of things they can do without acetylcholine, but what they can’t do is this very rapid, high interference spatial working memory task.”
In addition to this result, the receptor α7-nAChR is a “gene of interest” in schizophrenia. “We’ve known it plays an important role in schizophrenia for a very long time,” says Arnsten. “But we didn’t know why it was so important.”
Arnsten and her colleagues decided to take a closer look at this particular receptor in primate brains. They found that acetylcholine activates the α7-nAChR, providing the necessary stimulation to excite the NMDA receptors on the pyramidal neural circuits. The results were published in the July 1 issue of the Proceedings of the National Academy of Sciences.
“It is remarkable how this result brings so many things together. It explains so much of our everyday behavior,” says Arnsten. “When you are asleep and you don’t have acetylcholine, α7-nAChR is not stimulated. That means the NMDA receptors can’t open, prefrontal circuits can’t talk to each other and we’re unconscious. Then we wake up, acetylcholine is released, and the NMDA receptors are engaged and we have conscious thought as well as the ability to organize, focus and plan.”
Potential Drug Targets
Arnsten’s goal is to understand the molecular needs of circuits linked to mental illnesses like schizophrenia to identify new, effective treatments. She thinks α7-nAChR may be a target for potential treatments.
“Schizophrenia is a disease with a lot of thought disorder and cognitive symptoms,” says Arnsten. “These results may explain why almost all schizophrenics smoke. The nicotine in cigarettes is probably cognitively useful—strengthening these cognitive circuits and helping them with their cognitive abilities.”
She does not, of course, recommend taking up smoking—but does believe that a drug that promotes α7-nAChR might help treat schizophrenia and other neuropsychiatric disorders with cognitive symptoms.
Baxter agrees, and says this sort of result may help change the way we think about neuropsychiatric treatments. “Certainly, there’s been a bit of frustration overall with psychiatry and treatments. We’ve had trouble finding genes. We’ve had trouble finding new targets. The things that seemed the most promising just aren’t panning out,” he says. “But a result like this makes you wonder if we should be taking a different approach. Instead of trying to treat a disease, with a whole host of symptoms, you look at the mechanisms that are common to all these different disorders and conditions and focus on that. Some schizophrenics may have problems with working memory. Others may not. Some patients with Alzheimer’s disease might have similar problems with working memory. Treating ‘working memory’ instead of some categorical diagnosis may give you a better biological hold and better results.”