trasferimento descrizioni in README

neuron/axon.md

@@ -23,116 +23,6 @@ container: AXON
 
 ## PRESYNAPSE: Container
 
-**Discursive description**:
-
-The presynapse is the sending terminal of a neuron — a small bulb at the tip of an axon whose job is to release chemical signals, called neurotransmitters (NT), into the synaptic cleft, the narrow gap that separates it from the receiving neuron's postsynapse.
-
-To do this, the presynapse maintains a stockpile of NT packed inside small membrane bubbles called vesicles. These vesicles are organised in two pools: a reserve pool (RP), which is the deep storage, and a readily-releasable pool (RRP), which is the small set of vesicles docked at the membrane and ready to fire immediately. When a spike arrives — an electrical pulse called an action potential — it briefly opens specialised calcium channels (VGCCs) in the membrane. Calcium (Ca²⁺) rushes in, and the sudden local surge of calcium triggers the docked vesicles to fuse with the membrane and pour their NT into the cleft.
-
-But the presynapse does not just release blindly. It runs several interlocking feedback loops that continuously regulate how much it releases, how quickly it recovers, and when it should stop entirely to protect itself.
-
-The amount of Ca²⁺ that enters is itself regulated. Three brakes — CDI, eCB, and mGluR — each reduce the effective number of open channels in their own way and on their own timescale. CDI (calcium-dependent inactivation) is a channel-level self-brake: Ca²⁺ that enters during a spike physically blocks the same channels from reopening, accumulating gradually across repeated spikes. eCB (endocannabinoids) is a retrograde signal synthesised by the receiving neuron when it is over-stimulated; it travels backward across the cleft to suppress the presynaptic channels. mGluR is a presynaptic autoreceptor that senses accumulated NT in the cleft and reduces channel conductance through a slower chemical signalling cascade.
-
-The release of vesicles itself is regulated by two separate NT-sensing mechanisms. One acts locally at the release site in the same millisecond: high NT already in the cleft reduces how many docked vesicles fuse, trimming the current release event. The other is the mGluR pathway described above, which acts more slowly and suppresses the next spike's Ca²⁺ influx rather than the current one.
-
-After release the vesicle stockpile must be replenished. The RRP is refilled from the RP on a timescale of seconds, at a speed that depends on recent calcium history — the synapse replenishes faster when it has been active recently. The RP itself is replenished over minutes via a chemical shuttle from the neighbouring astrocyte, a support cell that recycles the released NT back into a precursor form and ships it back to the presynapse.
-
-The astrocyte is also the gateway to the energy supply. All of the active processes — pumping Ca²⁺ back out, docking vesicles, running the membrane pumps that restore the electrical gradient after each spike — consume ATP, the cell's energy currency. The astrocyte delivers glucose, which sets the rate of ATP replenishment. Under sustained high-frequency firing, this energy demand can outpace supply: ATP falls, the Ca²⁺ pumps slow, residual Ca²⁺ accumulates between spikes, CDI cannot recover, and the VGCCs lock shut. The synapse goes silent — not because it is broken, but because it is protecting itself from the toxic consequence of uncontrolled Ca²⁺ overload, a process known as excitotoxicity. This self-imposed silence is the central emergent behaviour we want to comprehend.
-
-The presynapse does not release blindly. Its behaviour is governed by three interlocking closed loops — the NT loop, the Ca²⁺ loop, and the ATP loop — each operating on a different timescale and each feeding back on the others.
-
----
-
-**The NT loop** is the supply chain of the synapse, operating across all three timescales.
-
-- On the millisecond scale, action potentials trigger Ca²⁺-driven release of NT from the RRP into the cleft. NT in the cleft feeds back on itself within the same millisecond — high cleft concentration suppresses further release, acting as a local brake.
-- On the seconds scale, the astrocyte's EAATs actively clear NT from the cleft, and the accumulated clearance load drives the IP3 signal that tells the astrocyte how hard the synapse has been working. EEATs only captures 30% of NT?. The rest is dispersed.
-- On the minutes scale, the astrocyte converts the captured glutamate into glutamine and ships it back to the presynapse, which repackages it into vesicles and restores the RP. The RP then feeds the RRP on the seconds scale via Ca²⁺-trace-gated recruitment.
-- The loop closes when those recycled vesicles are released again at the next burst.
-- The critical asymmetry is timescale: release takes milliseconds, full replenishment takes minutes. Sustained firing depletes faster than the loop can replenish.
-
-**The Ca²⁺ loop** is the timing and intensity controller of the synapse, operating entirely within the millisecond scale with a slow integration tail that reaches into seconds.
-
-- Ca²⁺ enters through VGCCs at every spike and immediately drives two things in parallel:
-  - vesicle release (the higher the Ca²⁺, the more vesicles fuse)
-  - the Tr_Ca trace integrator (which accumulates the recent Ca²⁺ history).
-- Ca²⁺ is then cleared by a single slow decay term, returning toward baseline between spikes.
-- The loop closes through Tr_Ca: a high trace — reflecting a recent burst — accelerates RP→RRP recruitment in the seconds loop, meaning that Ca²⁺ activity directly speeds up the resupply of the very vesicles that Ca²⁺ triggered.
-- The Ca²⁺ loop is also where the eCB retrograde signal from the postsynapse intersects: sustained postsynaptic depolarisation generates eCB on the seconds scale, which travels back and suppresses VGCC opening at the next spike, reducing Ca²⁺ influx. This makes the Ca²⁺ loop the primary interface between the presynapse and the postsynapse — it is the channel through which the receiving neuron tells the sending terminal to ease off.
-
-**The ATP loop** (not included in the coprehension yet) is the metabolic backbone of the synapse, operating on the minutes scale but with consequences that reach back into every millisecond.
-
-- ATP is consumed continuously by three processes:
-  - the Na/K-ATPase pump that restores the membrane gradient after each spike (the largest cost, proportional to firing rate)
-  - the PMCA and SERCA pumps that clear Ca²⁺ from the cytosol
-  - the molecular machinery that docks and primes vesicles for release.
-- These costs accumulate in an ATP demand register that grows with every spike and every Ca²⁺ clearance event in the millisecond loop.
-- The creation side of the loop runs on the minutes scale and is entirely astrocyte-dependent. The astrocyte delivers glucose from the bloodstream to both itself and the presynapse. Glucose enters glycolysis and the mitochondrial oxidative phosphorylation chain, producing ATP. The astrocyte also produces lactate as an intermediate, which it shuttles directly to the presynaptic terminal as an additional fuel source. The rate of ATP production is therefore set by glucose availability — the root input of the loop.
-- The loop closes through Ca²⁺ clearance. If firing is sustained long enough that ATP demand outpaces glucose-driven production, ATP falls, the PMCA and SERCA pumps slow, and residual Ca²⁺ builds between spikes. This elevated residual Ca²⁺ suppresses CDI recovery, causing VGCCs to gradually lock shut and silencing the synapse. Silence stops consuming ATP, allowing the production side to catch up and ATP to recover. The ATP loop therefore has a natural self-resetting property: the same mechanism that causes silence also triggers recovery.
-- The ATP loop intersects both other loops. It shares Ca²⁺ clearance with the Ca²⁺ loop — pump failure is what connects ATP depletion to VGCC inactivation. It shares the glutamine shuttle with the NT loop — when the astrocyte is energy-starved, conversion efficiency falls and RP replenishment slows, making vesicle depletion more severe and prolonged. ATP depletion is therefore the single point of failure that can cascade across all three loops simultaneously, which is why it is the mechanistic basis of excitotoxic protection.
-
----
-
-**Behaviors**:
-
-— ms:
-
-- AP fires → membrane jumps to peak, decays toward rest (Na/K-ATPase)
-- ATP cost charged per AP (Na/K-ATPase recharge)
-- Ca²⁺ enters via VGCCs, gated by CDI, eCB, and mGluR suppression
-- Ca²⁺ buffered by calbindin / calmodulin (fast capture, slow release)
-- Ca²⁺ cleared by NCX (always), PMCA and SERCA (ATP-dependent)
-- ATP cost charged per unit Ca²⁺ extruded by PMCA and SERCA
-- SERCA loads Ca_ER store as a side-effect of clearance
-- CDI rises with Ca²⁺ — only during spike (channels open and Ca²⁺ entering)
-- CDI recovers every ms — rate suppressed when Ca²⁺ is high (self-locking)
-- Ca²⁺ trace (Tr_Ca) integrates every ms, including between spikes
-- Vesicles release from RRP — driven by Ca²⁺ Hill sensor, suppressed by NT_cleft
-- NT added to cleft
-- NT_released_this_window accumulates (feeds mGluR and IP3 in seconds loop)
-- NT passively diffuses out of cleft (physical, not astrocyte)
-- Observed behaviors:
--- STD: exhaustion of NT momentarly stops presynapse from releasing NT
--- STP: Ca2+ left in the presynapse beteween spikes primes next NT release.
-
-— seconds:
-
-- Astrocyte EAATs actively clear 30% of remaining NT_cleft
-- IP3 integrates NT_released_this_window (cumulative burst load)
-- If IP3 exceeds threshold → astrocyte Ca²⁺ wave triggered
-- mGluR autoreceptor activation updates from NT_released_this_window
-- eCB retrograde signal updates from V_post history (postsynaptic input)
-- RP → RRP recruitment runs (rate gated by Tr_Ca, costs ATP)
-- NT_released_this_window resets to zero
-
-— mins:
-
-- ATP_demand (accumulated from ms loop) reduces ATP_level
-- ATP_demand resets to zero
-- Glucose level sets metabolic health and conversion_efficiency
-- conversion_efficiency gates glutamine shuttle throughput
-- Glutamine shuttle refills N_RP from astrocyte store
-
----
-
-**Semplified comprehension**:
-
-In this comprehension, we decide to simplify:
-
-- The VCGG are active while the AP is active, we do not comprehend the Voltage increase and decay
-- We do not comprehend the ATP
-- We do not comprehend CDI, we check just for Ca2+ concentration
-- We do not comprehend mGlur, we check for the concentration of NT in the cleft
-- We do not comprehend Ca2+ buffering
-- We do not comprehend PMCA, NCX, and SERCA, we comprehend Ca2+ clearing as a slow process
-- We do not comprehend vesicles, we comprehend them as processes releasing NT, fast, mediumness and slow based on conditions
-
-The simplification impies that:
-
-- Removing CDI and mGluR means Ca²⁺ concentration and NT in the cleft are now the only two conditions controlling release rate.
-- Removing ATP removes the metabolic silencing cascade entirely. The mins behavior now only does one thing: replenish the NT reserve. If we want the synapse to still be able to fail under sustained firing, the mechanism would have to come from NT depletion alone (RP exhausted, nothing to replenish) rather than from pump failure and Ca²⁺ accumulation.
-- "Ca²⁺ cleared slowly" replaces PMCA, NCX, and SERCA with a single exponential decay. This means Ca²⁺ will still accumulate under high firing if the decay is slow relative to the spike rate, which preserves some of the residual-Ca²⁺ dynamic even without the full pump machinery.
-
 **Simplified Behaviors**:
 
 **— ms:**