Fig 1.
Visualization of glycogen granules in a 3D reconstructed astrocyte.
A) Rendering of one astrocytic process (grey), in semi-transparency to highlight the presence within its cytosol of the glycogen granules. B) Top and bottom panels, rendering of two reconstructed astrocytic processes (green, adult, red, aged), semi-transparent to show the intracellular content of glycogen granules (grey). Whisker plot of the density of glycogen granules per astrocytic process in adult (4 months old 442.3 ± 112.2 granules / μ3, n = 3) and aged (24 months old; 526.3 ±98.6 granules / μ3, n = 3).
Fig 2.
Noradrenergic modulation in glia.
A) Schematic compartmental diagram of the NGV model with noradrenergic locus coeruleus (LC) inputs, astrocyte, extracellular and neuronal compartments. The vasculature blood flow has been clamped for these simulations for simplicity. B) Distance of NE release site from astrocyte was simulated as differences in rise time constant (four NE waveforms with τrise = 1, 10, 100 and 1000 sec). C) Corresponding NE receptor (β2R) activation levels show maximum receptor activation to each NE waveform. Inset: time domain zoom. Astrocytic β2R receptor activation is largely invariant except within initial 50 ms from neurotransmitter release when source of NE release is varied over 4 orders of magnitude. D) Dose-response relationship for NE and β2R activation (Kd = 300 nM). E) cAMP production levels in response to 1 second pulses of NE and τrise = 10 (representing a constant, relatively close proximity of the LC input, see S1 Text) at 4 different adenylate cyclase amplification factors selected in order to empirically produce a wide dynamic range of cAMP. Inset: time domain zoom. NE duration indicated by gray shaded areas.
Fig 3.
Activation of glycolytic enzyme cascade by cAMP in the astrocytic compartment.
A) The sequence of glycolytic enzyme cascade includes: protein kinase A (PKA), glycogen phosphorylase a (GPa), hexokinase/phosphofructokinase combined (HKPFK), phosphoglycerate kinase (PGK), pyruvate kinase (PK) and lactate dehydrogenase (LDH). B) Responses are normalized to emphasize temporal relationship. Insets in A and B: Zoom-in showing later activation of LDH. C) Separated from other enzymes for clarity, reciprocal enzyme relationships shown for protein phosphatase 1 (PP1) and when complexed with glycogen phosphorylase (PP1-GPa), as well as GPa and glycogen synthase (GSa). NE duration indicated by gray shaded areas.
Fig 4.
Production of metabolites by cAMP-dependent, NE-stimulated glycogen mobilization.
A1) Percent increase of sequence of metabolites triggered by cAMP including: glucose-6-phosphate (G6P), glyceraldehyde-3-phosphate (GAP), phosphoenolpyruvate (PEP), pyruvate (PYR) and lactate (LAC). Inset: zoom that better shows relative rises of smaller responses from phoshoenolpyruvate to lactate. A2) same metabolites as in A1 but normalized to emphasize longer response development and duration of lactate (LAC). A3) same metabolites as in A1, shown as concentrations. B) Production of ergogenic byproducts ATP and NADH in response to cAMP. B1) Percent increase showing relative magnitude. B2) Normalized traces showing relative time of activation. NE duration indicated by gray shaded areas. B3) same metabolites as in B1, shown as concentrations.
Fig 5.
Glycogen and cellular energy status.
A) mobilization of glycogen in response to NE-triggered cAMP at each of 4 cyclase amplification coefficients (cyclase coef. in panels). B) Indicators of cellular energy status: astrocytic, cytosolic NAD+/NADH ratio (oxidative state) as well as energy charge ((ATP + 0.5ADP)/(ATP+ADP+AMP)) in response to cAMP. NE duration indicated by gray shaded areas.
Fig 6.
Glycogen derived lactate shuttle.
A) Lactate (LAC) transients from 3 compartments in response to NE-dependent cAMP signaling. Responses from astrocyte, extracellular space and neuron all show same kinetics and are nearly overlapping, but slightly shifted in time, reflecting the transport time between compartments. B) Zoom-in of a region of almost overlapping LAC traces from 3 compartments that demonstrates the flow of LAC from astrocyte to extracellular space to neighboring neuron. Arrows indicate direction of LAC wave flow. C) ANLS with a characteristic lactate oxidative dip (upper panel, arrow) produced by synaptic excitation instead of NE stimulation (lower panel, V from neuron). The lactate dip is absent from the ANLS produced by glycogenolysis (panel A). NE duration indicated by gray shaded areas.