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The organization and composition of body fluids
© 2015 Published by Elsevier Ltd. The water contained in the body is divided amongst compartments of differing sizes and compositions. The dynamic balance across these compartments is an essential component of normal physiology. Here, the calculation of these volumes by measuring the dilution of markers able to permeate specific compartments is considered. Furthermore, the potential disadvantages to the approach are discussed. The differences in ionic concentration between intracellular and extracellular fluid are quantified and the effects of greater relative protein concentration within cells are also considered. To illustrate daily fluid balance in a healthy individual, a typical intake and output over 24 hours is quantified before consideration of iatrogenic contributions to this equilibrium. The way in which clinically administered fluids of varying compositions affect the fluid compartments is subsequently discussed. The endogenous processes contributing to volume homeostasis are then deliberated including the detection of fluid imbalance through intracellular and extracellular systems as well as the hypothalamic and renal effector mechanisms. Finally, the regulation of sodium is discussed with examination of the mechanisms controlling natriuresis and the reciprocity with potassium balance.
Tsc1-mTORC1 signaling controls striatal dopamine release and cognitive flexibility.
Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder caused by mutations in TSC1 or TSC2, which encode proteins that negatively regulate mTOR complex 1 (mTORC1). TSC is associated with significant cognitive, psychiatric, and behavioral problems, collectively termed TSC-Associated Neuropsychiatric Disorders (TAND), and the cell types responsible for these manifestations are largely unknown. Here we use cell type-specific Tsc1 deletion to test whether dopamine neurons, which modulate cognitive, motivational, and affective behaviors, are involved in TAND. We show that loss of Tsc1 and constitutive activation of mTORC1 in dopamine neurons causes somatodendritic hypertrophy, reduces intrinsic excitability, alters axon terminal structure, and impairs striatal dopamine release. These perturbations lead to a selective deficit in cognitive flexibility, preventable by genetic reduction of the mTOR-binding protein Raptor. Our results establish a critical role for Tsc1-mTORC1 signaling in setting the functional properties of dopamine neurons, and indicate that dopaminergic dysfunction may contribute to cognitive inflexibility in TSC.