New Research Progresses on Multifaceted Cholinergic Signaling

Dear Colleagues,

The cholinergic signaling system is widespread throughout the body. Cholinergic cells are defined by intracellular expression of the acetylcholine-biosynthesizing enzyme, ChAT, i.e., the explicit marker of cholinergic cells and neurons.

There are two main types of cholinergic cells: neuronal and non-neuronal cells. The neuronal cholinergic system consists of three subnetworks. (1) the central cholinergic system originating from basal forebrain projecting extensively and directly throughout the brain. (2) the parasympathetic system that originates from 12 cranial nerves (CN I-XII), projecting to various organs, tissues, and glands in the body and thereby controlling the function of diverse organs, muscles, and glands. (3) the cholinergic circuitry in the enteric nervous system, where about 64% of neurons are cholinergic, involving sensory and vascular reflexes and controlling motility (muscular) and secretory (mucosal) reflexes within the gastrointestinal tracts. The non-neuronal cholinergic system consists of numerous non-excitable ChAT-positive cells. An example is lymphocytes/spleenocytes forming a so-called cholinergic anti-inflammatory system. Another is the spermic cholinergic system that is involved in sperm motility and capacitation.

Thus, it is hardly surprising that malfunctioning or degeneration of the cholinergic systems can be involved in many disorders. For instance, early degeneration of the central cholinergic neurons is one of the hallmarks of Alzheimer's disease, dementia with Lewy body (including Parkinson’s dementia), and Down’s syndrome. Cholinergic interneurons in the striatum, which target the nigrostriatal system, are affected in Parkinson’s disease, in corticobasal degeneration syndrome, and in progressive supranuclear palsy. Early and progressive cholinergic neurodegeneration occurs also in motor neuron disorders, which are characterized by progressive muscle weakness. A particularly devastating example is amyotrophic lateral sclerosis (ALS), which selectively affects the cholinergic motor neurons in the cortex and spinal cord, as well as various cranial nerves. An age-dependent decline in the efficiency of the cholinergic anti-inflammatory system in the elderly might explain why COVID-19 infection induced a more severe cytokine storm, which was associated with poor prognosis in the elderly population.

Despite all these, basic research on cholinergic systems is currently scarce, perhaps due to the illusion that we already know all about this system! Yet now and then come new insights that put this illusion into question.

In this Special Issue we are calling for new insights and advances about the function of the crucial and multifaceted cholinergic signaling. This Special Issue will consider both original articles, reviews as well as new hypotheses. We are calling for articles in the whole spectrum of the cholinergic signaling system! We, particularly, encourage submission of research papers investigating the intracellular cholinergic signaling and its association with mitochondrial function and the role of cholinergic signaling in resistance, survival, and recolonization of tumor cells following diverse cancer therapy. In addition, we look forward to research papers describing new robust and reliable methodological approaches in, for instance, measuring the function of ChAT, the key cholinergic enzyme, or levels of acetylcholine in biological fluids, which are crucial for developing novel research approaches and for monitoring changes in the cholinergic signaling upon therapeutic strategies that directly or indirectly may be able to restore the neuronal and non-neuronal cholinergic function or prevent further deterioration of the cholinergic system.

Dr. Taher Darreh-Shori
Guest Editor

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