Acetylcholine

Summary

Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Parts in the body that use or are affected by acetylcholine are referred to as cholinergic. Substances that increase or decrease the overall activity of the cholinergic system are called cholinergics and anticholinergics, respectively. Acetylcholine is the neurotransmitter used at the neuromuscular junction—in other words, it is the chemical that motor neurons of the nervous system release in order to activate muscles. This property means that drugs that affect cholinergic systems can have very dangerous effects ranging from paralysis to convulsions. Acetylcholine is also a neurotransmitter in the autonomic nervous system, both as an internal transmitter for the sympathetic nervous system and as the final product released by the parasympathetic nervo

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In this work, the specific and nonspecific binding of proteins to planar surfaces was investigated. The surfaces were first modified by the spontaneous adsorption of a number of synthesized 1,2-diacyl-sn-glycero-3-phosphatidylcholine lipids with different ω-mercapto fatty acids. The influence of packing density, order, fluidity, and mobility of the head groups of these supported thiolipid monolayers on the nonspecific adsorption of proteins was systematically investigated. Nonspecific binding of fibrinogen, IgG, BSA, and rabbit serum to such surfaces was monitored on-line by surface plasmon resonance spectroscopy (SPR) and was found to be exceptionally low. Characterization of the supported thiolipid monolayers by grazing incidence infrared spectroscopy, wetting, impedance spectroscopy, calorimetry, and SPR indicates that protein adsorption is influenced by the nature of the fatty acids and suggests that besides the molecular structure of the layer-forming molecules, other supramolecular aspects such as flexibility of the immobilized lipid layer or protrusion of the lipid head groups play a role. These investigations point the way for the construction of even more highly protein repellent surfaces with potential technical applications in the medical (implants) and diagnostic fields (biosensors). To investigate specific protein-surface interactions, acetylcholine containing ligand molecules of the general molecular structure HS(CH2)15(CO)O(CH2CH2O)nCH2(CO)OCH2CH2N+(CH3)3 X- (n = 4, 6, 13) were synthesized. They allow acetylcholine, the natural agonist of the acetylcholine receptor, to be covalently immobilized on a surface. Mixed layers of thiolipids and ligand molecules were formed by self-assembly on planar gold substrates and specific interactions between the immobilized acetylcholine and the nicotinic acetylcholine receptor (nAchR) from Torpedo Californica have were investigated on-line by SPR. Though it seems that the receptor binds specifically, bound receptor could be only partially displaced from the surface by excess free ligand. However, further improvement of the sensor surfaces will surely provide in the future a powerful tool for the investigation of membrane proteins and transmembrane communication.

EPFL1997

Neuromodulation of neocortical microcircuitry: a multi-scale framework to model the effects of cholinergic release

Cristina Colangelo

Neuromodulation of neocortical microcircuits is one of the most fascinatingand mysterious aspects of brain physiology. Despite over a century of research,the neuroscientific community has yet to uncover the fundamentalbiological organizing principles underlying neuromodulatory release. Phylogenetically,Acetylcholine (ACh) is perhaps the oldest neuromodulator,and one of the most well-studied. ACh regulates the physiology of neuronsand synapses, and modulates neural microcircuits to bring about areconfiguration of global network states. ACh is known to support cognitiveprocesses such as learning and memory, and is involved in the regulationof arousal, attention and sensory processing. While the effects of ACh inthe neocortex have been characterized extensively, integrated knowledge ofits mechanisms of action is lacking. Furthermore, the ways in which AChis released from en-passant axons originating in subcortical nuclei are stilldebatable. Simulation-based paradigms play an important role in testingscientific hypotheses, and provide a useful framework to integrate what isalready known and systematically explore previously uncharted territory.Importantly, data-driven computational approaches highlight gaps in currentknowledge and guide experimental research. To this end, I developed amulti-scale model of cholinergic innervation of rodent somatosensory cortexcomprising two distinct sets of ascending projections implementing eithersynaptic (ST) or volumetric transmission (VT). The model enables the projectiontypes to be combined in arbitrary proportions, thus permitting investigationsof the relative contributions of these two transmission modalities.Using our ACh model, we find that the two modes of cholinergic release actin concert and have powerful desynchronizing effects on microcircuit activity.Furthermore we show that this modeling framework can be extendedto other neuromodulators, such as dopamine and serotonin, with minimalconstraining data. In summary, our results suggest a more nuanced view ofneuromodulation in which multiple modes of transmitter release - ST vs VT- are required to produce synergistic functional effects.

EPFL2022

Cellular, Synaptic and Network Effects of Acetylcholine in the Neocortex

Cristina Colangelo, Daniel Keller, Henry Markram, Srikanth Ramaswamy, Polina Shichkova

The neocortex is densely innervated by basal forebrain (BF) cholinergic neurons. Long-range axons of cholinergic neurons regulate higher-order cognitive function and dysfunction in the neocortex by releasing acetylcholine (ACh). ACh release dynamically reconfigures neocortical microcircuitry through differential spatiotemporal actions on cell-types and their synaptic connections. At the cellular level, ACh release controls neuronal excitability and firing rate, by hyperpolarizing or depolarizing target neurons. At the synaptic level, ACh impacts transmission dynamics not only by altering the presynaptic probability of release, but also the magnitude of the postsynaptic response. Despite the crucial role of ACh release in physiology and pathophysiology, a comprehensive understanding of the way it regulates the activity of diverse neocortical cell-types and synaptic connections has remained elusive. This review aims to summarize the state-of-the-art anatomical and physiological data to develop a functional map of the cellular, synaptic and microcircuit effects of ACh in the neocortex of rodents and non-human primates, and to serve as a quantitative reference for those intending to build data-driven computational models on the role of ACh in governing brain states.

FRONTIERS MEDIA SA2019

EPFL1997

Neuromodulation of neocortical microcircuitry: a multi-scale framework to model the effects of cholinergic release

Cristina Colangelo

EPFL2022