Johnson, B. P. | bioRxiv Science

bioRxiv2023

Spatially and Blood Flow-Dependent Tissue Distribution of Thyroid Hormones by Plasma Thyroid Hormone Binding Proteins

Plasma thyroid hormone (TH) binding proteins (THBPs), including thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB), carry THs to extrathyroidal sites, where THs are unloaded locally and then taken up via membrane transporters into the tissue proper. The respective roles of THBPs in supplying THs for tissue uptake are not completely understood. To investigate this, we developed a spatial human physiologically based kinetic (PBK) model of THs, which produces several novel findings. (1) Contrary to postulations that TTR and/or ALB are the major local T4 contributors, the three THBPs may unload comparable amounts of T4 in Liver, a rapidly perfused organ; however, their contributions in slowly perfused tissues follow the order of abundances of T4TBG, T4TTR, and T4ALB. The T3 amounts unloaded from or loaded onto THBPs in a tissue acting as a T3 sink or source respectively follow the order of abundance of T3TBG, T3ALB, and T3TTR regardless of perfusion rate. (2) Any THBP alone is sufficient to maintain spatially uniform TH tissue distributions. (3) The TH amounts unloaded by each THBP species are spatially dependent and nonlinear in a tissue, with ALB being the dominant contributor near the arterial end but conceding to TBG near the venous end. (4) Spatial gradients of TH transporters and metabolic enzymes may modulate these contributions, producing spatially invariant or heterogeneous TH tissue concentrations depending on whether the blood-tissue TH exchange operates in near-equilibrium mode. In summary, our modeling provides novel insights into the differential roles of THBPs in local TH tissue distribution. Key PointsO_LIThyroxine-binding globulin (TBG), transthyretin (TTR), and albumin (ALB) are plasma thyroid hormone (TH) binding proteins (THBPs) that carry THs from the thyroid gland to extrathyroidal tissues. C_LIO_LIThe respective roles of the 3 THBP species in unloading THs once arriving at a tissue are not completely understood. C_LIO_LIHere we developed a spatial human kinetic model of THs and showed that the three THBPs may unload comparable amounts of thyroxine (T4) in the liver but TBG is dominant in contributing T4 in tissues slowly perfused by blood as well as in contributing triiodothyronine (T3) regardless of the tissues perfusion rate. C_LIO_LIThe TH amounts unloaded by each THBP species are spatially dependent and nonlinear, with ALB being the dominant contributor near the arterial end but conceding to TBG near the venous end in a tissue. C_LIO_LIOur model provides novel insights into the differential roles of THBPs in local TH tissue distribution. C_LI

physiology↗

bioRxiv2023

Generalization of procedural motor sequence learning after a single practice trial

When humans begin learning new motor skills, they typically display early rapid performance improvements. It is not well understood how knowledge acquired during this early skill learning period generalizes to new, related skills. Here, we addressed this question by investigating factors influencing generalization of early learning from a skill A to a different, but related skill B. Early skill generalization was tested over four experiments (N = 2,095). Subjects successively learned two related motor sequence skills (skills A and B) over different practice schedules. Skill A and B sequences shared ordinal (i.e. - matching keypress locations), transitional (i.e. - ordered keypress pairs), parsing rule (i.e., distinct sequence events like repeated keypresses that can be used as a breakpoint for segmenting the sequence into smaller units) structures, or possessed no structure similarities. Results showed generalization for shared parsing rule structure between skills A and B after only a single 10-second practice trial of skill A. Manipulating the initial practice exposure to skill A (1 to 12 trials) and inter-practice rest interval (0 to 30s) between skills A and B had no impact on parsing rule structure generalization. Furthermore, this generalization was not explained by stronger sensorimotor mapping between individual keypress actions and their symbolic representations. In contrast, learning from skill A did not generalize to skill B during early learning when the sequences shared only ordinal or transitional structure features. These results document sequence structure that can be very rapidly generalized during initial learning to facilitate generalization of skill.

neuroscience↗