Editorial: Brain cholinergic mechanisms

While historically acetylcholine (ACh) holds a central place in the discovery of chemical transmission in the nervous system, progress in our knowledge of the mechanistic underpinnings of cholinergic transmission in the central nervous system (CNS) has lagged behind its sister transmitters. For example, unlike what we know about glutamatergic transmission, neither the prevalence of fast cholinergic transmission or postsynaptic specializations at cholinergic synapses, is well understood. Every level of inquiry into the cholinergic system reveals a bewildering complexity in signaling and transduction mechanisms. Receptor localizations within and among neurons, along with transmitter source and access to receptors, provide for a system that is capable of neuromodulation at multiple time scales that allow for short-and long-term regulation of circuit output in the brain. The compilation of reviews and primary papers in this research topic provides a sampling of findings at different levels of integration that highlight both the current status of our understanding of CNS cholinergic mechanisms as well as reveals the gaps in our knowledge that need to be filled. How ACh mediates signaling in the brain is still an unresolved issue at the level of synaptic physiology. Cholinergic innervation in the brain arises from two main loci-the basal forebrain and the pendunculo-pontine area of the hindbrain. In both instances a relatively small cluster of neurons send diffuse projections into various target areas. The diffuse nature of the projections, as well as the non-planar relationship between the cholinergic neurons and their targets precludes traditional slice electrophysiology approaches to examining signaling. Recent advances in optogenetic techniques offer a potential solution to this problem and some of the advances made thus far are reviewed in this research topic (Luchicchi et al., 2014). Some of the relevant issues that need to be resolved are the prevalence of synaptic vs. non-synaptic modes of activation, the role of transmitter diffusion, relationship between ACh release sites and the distribution of acetylcholine esterases, and the potential co-release of other transmitters from cholinergic terminals. In addition to the centrifugal cholinergic inputs, areas of the cortex also express their own, resident, cholinergic interneurons. Well studied among these are the cholinergic interneurons of the striatum, relevant to disorders like Parkinson's disease. These are large aspiny neurons that are small in number (about 1% of the total neuronal population) but send dense projections throughout the area. Recent findings that are summarized here (Lim et al., 2014) show that these neurons themselves …