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Acetylcholine's role in cognitive flexibility

The neurotransmitter acetylcholine plays a key role in cognitive flexibility, a finding that has implications for treatments to restore brain function, according to research from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) recently published in the Journal of Neuroscience.

Early in the progression of Alzheimer’s disease a bundle of axons in the brain called the fornix degenerates, which contributes to memory loss, but the researchers found that if a patient had a relatively intact system to produce acetylcholine then it led brain areas involved in memory to engage alternative connections and so compensate for the memory loss effect of fornix degeneration. Drugs like donepezil that boost the level of acetylcholine in the brain are commonly used as a treatment for Alzheimer’s and this research points to an additional possible mechanism for how these drugs act, so could lead to cholinergic drugs like donepezil being used to help restore brain function in other situations, such as after head injuries.

“Drugs that mimic or boost acetylcholine may work not only by ameliorating individual symptoms but also by promoting flexibility of function,” said Dr Mike O’Sullivan, of the Department of Basic and Clinical Neurosciences, IoPPN, and senior author of the research. “One possible mechanism is that these drugs promote forms of plasticity that lead to long-term beneficial changes in brain structure. This view could lead to wider use of cholinergic drugs to improve restoration of function after many types of brain injury.”

To test the role of acetylcholine in cognitive flexibility, 25 participants with mild cognitive impairment (MCI) were recruited alongside 20 healthy volunteers and each participant underwent MRI scans, behavioural assessment and also had the size of their basal forebrain measured. The basal forebrain is where brain cells that produce acetylcholine originate, and from where they send projections into the brain’s grey matter that release acetylcholine. The presumption was that a large and healthy basal forebrain will release more acetylcholine in the target regions, and the research found that participants with larger basal forebrains made better use of alternative pathways that bypassed the fornix, which in turn reduced memory loss resulting from fornix degeneration. The researchers deduced that cognitive flexibility, and potentially neuroplasticity, work better in the presence of high levels of acetylcholine.

“We showed that patients with a relatively intact cholinergic basal forebrain were better able to engage alternative connections to compensate for degeneration of the fornix, a key tract for memory that is damaged early in Alzheimer’s disease,” said Dr O’Sullivan.

“It has been known for some time that acetylcholine has a wide variety of functions in the brain, including the promotion of plasticity, whereas clinical use of drugs like donepezil has focussed only on the neurotransmitter’s direct effects on memory and cognition. These results could lead to a renewal of interest in the wider roles of acetylcholine and the potential to harness them for patient benefit.”

The study was funded by Medical Research Council Grants G0701912 and MR/K022113/1 and was also supported by the National Institute for Health Research (NIHR) (Mental Health Biomedical Research Centre) at South London, Maudsley National Health Service Foundation Trust, King’s College London, the Wellcome Trust, and by the NIHR Biomedical Research Unit for Dementia. 

Paper reference: Ray, N. J. et al. ‘Cholinergic Basal Forebrain Structure Influences the Reconfiguration of White Matter Connections to Support Residual Memory in Mild Cognitive Impairment’ published in Journal of Neuroscience DOI: 10.1523/JNEUROSCI.3617-14.2015 

For further information contact Tom Bragg, Press Officer at IoPPN, King’s College London, on +44(0)2078485377 or email