Summary: Acetylcholine acting at muscarinic M1 receptors in the prefrontal cortex supports the neuronal activity that holds information in working memory. Because M1 receptor signaling is diminished in conditions that impair working memory, such as schizophrenia and Alzheimer’s disease, the M1 receptor represents an attractive therapeutic target to restore cognitive function.
Source: Yale
Working memory—the brain’s capacity to hold and manipulate information briefly in mind despite distraction—is central to complex thought, decision making, and reasoning. It enables everyday tasks such as keeping in mind a phone number while searching for a pen or remembering an instruction while beginning a new task. Deficits in working memory are a hallmark of several neuropsychiatric and neurodegenerative disorders, including schizophrenia and Alzheimer’s disease, and improving this cognitive faculty is a major goal of current research.
Researchers at Yale report new evidence identifying a specific molecular mechanism that helps sustain the neural activity underlying working memory. Published March 19 in the journal Neuron, the study demonstrates that acetylcholine signaling at muscarinic M1 receptors located on neurons in the prefrontal cortex is essential for maintaining the persistent firing patterns those neurons use to keep information “online.”
“Working memory depends on specialized circuits in the prefrontal cortex,” said senior author Min Wang, senior research scientist in neuroscience. “Our findings indicate these circuits have particular molecular needs to preserve the activity that supports short-term memory.”
The prefrontal cortex contains networks of excitatory neurons that reinforce one another’s activity to hold a representation in mind. These recurrent circuits act like a temporary sketch pad, allowing us to retain a thought or sensory detail while attending to other tasks. The new study shows that acetylcholine, a neurotransmitter long implicated in attention and cognition, exerts a critical modulatory effect on these circuits through muscarinic M1 receptors positioned on neuronal surfaces.
In their experiments, the researchers found that blocking muscarinic M1 receptors reduced the persistent firing of prefrontal neurons that normally supports working memory. Conversely, stimulating M1 receptors helped restore neuronal firing patterns that had been suppressed. These results indicate that M1-mediated acetylcholine signaling stabilizes the recurrent activity required to maintain information in the prefrontal circuits responsible for working memory.
Importantly, prior studies have observed reduced cholinergic signaling and altered muscarinic receptor function in disorders characterized by working memory impairment, such as schizophrenia and Alzheimer’s disease. The new findings therefore provide a mechanistic link between diminished M1 receptor activity and failures in working memory, and they suggest the M1 receptor as a promising target for therapeutic intervention aimed at restoring cognitive function.
Wang noted that a drug currently in development for schizophrenia works by stimulating the M1 receptor and has shown encouraging results in early clinical studies. While additional research and clinical validation are required, targeting M1 receptor signaling could potentially improve working memory and related cognitive abilities in patients with neurocognitive disorders.
Funding and authorship: Veronica Galvin of Yale is the paper’s first author. The work was primarily supported by the National Institutes of Health (NIH). Min Wang is listed as senior author. The full study appears in Neuron and provides experimental evidence linking acetylcholine–M1 receptor signaling to the maintenance of working memory-related neuronal activity.
Source:
Yale
Media Contacts:
Bess Connolly – Yale
Image Source:
The image is in the public domain.
Original Research: The study will appear in Neuron.