Impaired Phasic Discharge of Locus Coeruleus Neurons Based on Persistent High Tonic Discharge—A New Hypothesis With Potential Implications for Neurodegenerative Diseases

The locus coeruleus (LC) is a small brainstem nucleus with widely distributed noradrenergic projections to the whole brain, and loss of LC neurons is a prominent feature of age-related neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). This article discusses the hypothesis that in early stages of neurodegenerative diseases, the discharge mode of LC neurons could be changed to a persistent high tonic discharge, which in turn might impair phasic discharge. Since phasic discharge of LC neurons is required for the release of high amounts of norepinephrine (NE) in the brain to promote anti-inflammatory and neuroprotective effects, persistent high tonic discharge of LC neurons could be a key factor in the progression of neurodegenerative diseases. Transcutaneous vagal stimulation (t-VNS), a non-invasive technique that potentially increases phasic discharge of LC neurons, could therefore provide a non-pharmacological treatment approach in specific disease stages. This article focuses on LC vulnerability in neurodegenerative diseases, discusses the hypothesis that a persistent high tonic discharge of LC neurons might affect neurodegenerative processes, and finally reflects on t-VNS as a potentially useful clinical tool in specific stages of AD and PD.