diff --git a/elements/astrocyte/appunti/2026-06-04-modulation-of-future-behavior.md b/elements/astrocyte/appunti/2026-06-04-modulation-of-future-behavior.md index ca4eaad..278da2f 100644 --- a/elements/astrocyte/appunti/2026-06-04-modulation-of-future-behavior.md +++ b/elements/astrocyte/appunti/2026-06-04-modulation-of-future-behavior.md @@ -10,8 +10,6 @@ Description of the pseudocode. The three compartments maintain distinct but coupled state variables across three time horizons. At the fast scale, the presynapse tracks residual calcium and its readily-releasable vesicle pool — both of which encode the very recent history of firing. The postsynapse tracks membrane voltage and the amplitude and speed of its calcium rise, which together encode the instruction for future change. The astrocyte tracks glutamate concentration both inside and outside the cleft, its own local and global calcium state, and its fuel output. At the intermediate scale, the shared signal layer tracks whether the mGluR overflow sensors have fired, and whether the neuromodulatory context gate has been set — specifically whether PKA has primed the AMPA insertion machinery, silenced the forgetting phosphatase, and enabled gene expression in the nucleus. At the slow scale, all three compartments track their own physical architecture: the postsynapse its receptor count and spine size, the presynapse its docking slot count and vesicle channel clustering, and the astrocyte its wall distance from the synapse, its matrix density, and its baseline co-agonist supply. ---- - ## Fast scale: what happens spike by spike Every action potential sets off a precise sequence across all three compartments simultaneously. The presynapse converts the electrical event into a chemical wavefront: calcium floods in, drives probabilistic vesicle release from the readily-releasable pool, and leaves a residual trace that biases the next release upward if spikes keep arriving and downward if they stop. The amount of glutamate released fills the cleft and begins diffusing outward. @@ -22,8 +20,6 @@ The postsynapse responds to the glutamate wavefront through its AMPA receptors, Once the spike is complete, the astrocyte vacuums up residual glutamate via its transporter proteins, and the harder it works at this clearance the faster it runs its glycolysis engine, converting blood glucose into lactate and pumping it into the extracellular space. Both the presynapse and postsynapse absorb this lactate to power their reset pumps — refilling the vesicle pool and restoring the resting membrane potential respectively. The energy supply is therefore coupled to activity: busier synapses generate more demand on the astrocyte, which in turn fuels faster recovery. ---- - ## Intermediate scale: temporary tuning between spikes If firing is sustained rather than isolated, the system begins temporary adjustments that do not yet commit to structural change. In the presynapse, sustained high-frequency firing keeps residual calcium elevated, progressively increasing release probability and mobilizing vesicles from deep reserve storage into the readily-releasable pool — a priming of the launchpad without permanently expanding it. If frequency is low and sparse, the reverse happens: the pool depletes faster than it refills and release probability falls. @@ -34,8 +30,6 @@ In the astrocyte, sustained activity keeps mGluR5 activated and D-serine release The neuromodulatory broadcast then sets the critical context gate. If dopamine or norepinephrine levels cross their respective thresholds — signaling that the current activity pattern is behaviorally significant — PKA activity rises and phosphorylates three targets in sequence. It lowers the threshold for AMPA receptor insertion by priming the GluA1 subunit at Ser845. It silences the LTD phosphatase PP1 by phosphorylating DARPP-32, effectively blocking the forgetting machinery from running while the save signal is present. And it translocates to the nucleus to phosphorylate CREB, enabling the gene expression needed to build new structural proteins. Acetylcholine from the basal forebrain acts in parallel, lowering the global LTP threshold — making the entire system more sensitive to incoming patterns during periods of high attention. ---- - ## Slow scale: the commit decision and structural rewriting Once the fast and intermediate dynamics have run, the system evaluates a three-layer filter to decide whether to permanently rewrite its architecture. The first layer asks whether a genuine event occurred — specifically whether postsynaptic calcium rose above the high threshold at sufficient speed to activate the LTP kinase pathway. The second layer asks whether that event was excessive enough to saturate the cleft and trigger mGluR5 on the astrocyte. The third layer asks whether the neuromodulatory context validated the event as worth saving — whether PKA has primed the insertion machinery and silenced the forgetting machinery. @@ -48,8 +42,6 @@ In the depression branch, the phosphatase PP1 wins instead of CaMKII, and all th If the calcium event occurred but the neuromodulatory save signal did not arrive, only transient changes happen — early receptor insertion and brief facilitation — both of which reverse within minutes without trace. If no threshold was crossed at all, nothing changes and the current structural state is simply held. ---- - ## The critical asymmetry The astrocyte's perisynaptic wall distance is the variable that makes both outcomes self-reinforcing rather than merely additive. When it moves inward during potentiation, it concentrates glutamate at the cleft, maintains D-serine near the postsynapse, and tightens the presynaptic feedback loop — making future high-frequency events even more likely to cross the threshold. When it moves outward during depression, it dilutes the signal, starves the NMDA gate, and loosens the presynaptic feedback — making future events even less likely to reach threshold. The astrocyte therefore does not simply mirror what the neurons decide: it actively deepens the valley the synapse has already rolled into, in whichever direction that happens to be. @@ -58,7 +50,6 @@ The astrocyte's perisynaptic wall distance is the variable that makes both outco [pseudocode](tripartite_synapse_full_pseudocode.html) - ## global state variables ### ── Fast (ms–s): wave propagation ───────────────────────────── #### Presynapse