Movement, the fundamental component of behavior and the principal extrinsic action of the brain, is produced when skeletal muscles contract and relax in response to patterns of action potentials generated by motoneurons. The processes that determine the firing behavior of motoneurons are therefore important in understanding the transformation of neural activity to motor behavior. Here, we review recent studies on the control of motoneuronal excitability, focusing on synaptic and cellular properties. We first present a background description of motoneurons: their development, anatomical organization, and membrane properties, both passive and active. We then describe the general anatomical organization of synaptic input to motoneurons, followed by a description of the major transmitter systems that affect motoneuronal excitability, including ligands, receptor distribution, pre-and postsynaptic actions, signal transduction, and functional role. Glutamate is the main excitatory, and GABA and glycine are the main inhibitory transmitters acting through ionotropic receptors. These amino acids signal the principal motor commands from peripheral, spinal, and supraspinal structures. Amines, such as serotonin and norepinephrine, and neuropeptides, as well as the glutamate and GABA acting at metabotropic receptors, modulate motoneuronal excitability through pre-and postsynaptic actions. Acting principally via second messenger systems, their actions converge on common effectors, e.g., leak K + current, cationic inward current, hyperpolarization-activated inward current, Ca 2+ channels, or presynaptic release processes. Together, these numerous inputs mediate and modify incoming motor commands, ultimately generating the coordinated firing patterns that underlie muscle contractions during motor behavior.

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Liquid–liquid phase separation (LLPS) is involved in both physiological and pathological processes. The intrinsically disordered protein Tau and its K18 construct can undergo LLPS in a distinct temperature-dependent manner, and the LLPS of Tau protein can initiate Tau aggregation. However, the underlying mechanism driving Tau LLPS remains largely elusive. To understand the temperature-dependent LLPS behavior of Tau at the monomeric level, we explored the conformational ensemble of Tau at different temperatures by performing all-atom replica-exchange molecular dynamic simulation on K18 monomer with an accumulated simulation time of 26.4 μs. Our simulation demonstrates that the compactness, β-structure propensity, and intramolecular interaction of K18 monomer exhibit nonlinear temperature-dependent behavior. 295DNI­KHV300/326GNI­HHK331/337VEV­KSE342 make significant contributions to the temperature dependence of the β propensity of K18 monomer, while the two fibril-nucleating cores display relatively high β propensity at all temperatures. At a specific temperature, K18 monomer adopts the most collapsed state with exposed sites for both persistent and transient interactions. Given that more collapsed polypeptide chains were reported to be more prone to phase separate, our results suggest that K18 monomer inherently possesses conformational characteristics favoring LLPS. Our simulation predicts the importance of 295DNI­KHV300/326GNI­HHK331/337VEV­KSE342 to the temperature-dependent conformational properties of K18, which is corroborated by CD spectra, turbidity assays, and DIC microscopy. Taken together, we offer a computational and experimental approach to comprehend the structural basis for LLPS by amyloidal building blocks.