ristrutturato i commenti alla comprensione. Simplified behavior.

2026-03-26 12:19:57 +01:00
parent b3b7e53840
commit 5475f8df48
1 changed files with 88 additions and 29 deletions
@@ -8,7 +8,7 @@ Qui comprendiamo:
 ## BEH-AXO: Container
-**Axon**: Axon does not contain specific behavior. We might add balancing of ATP within PRE later. Here we comprehend it as a “cable” transporting the AP from SOMA to Presynapse. It expands BEH-PRE which:
+The axon does not contain specific behavior. We might add balancing of ATP within PRE later. Here we comprehend it as a “cable” transporting the AP from SOMA to Presynapse. It expands BEH-PRE which:
 - can be developed by DEV-PRE
 - the associations between BEH-PRE, BEH-POST e BEH-SYN is performed by the module that instantiate the Neurons and the Atrocytes, for example BEH-EXH or BEH-INH from winnertakeall.
@@ -23,49 +23,108 @@ container: BEH-AXO
 ## BEH-PRE: Container
-**Presynapse:** We treat each presynapse as standalone. The vesicle reserve pool is a strictly private, local resource of each individual presynaptic bouton. What is shared between synapses on the same axon are signals (neuromodulators) and metabolic resources (energy), but not the synaptic vesicles themselves.
+**High level 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.
 **Behaviors**:
---
+— ms:
-**Fast — ms**:
+- AP fires → membrane jumps to peak, decays toward rest (Na/K-ATPase)
-
+- ATP cost charged per AP (Na/K-ATPase recharge)
 - AP fires → membrane jumps to peak, decays toward rest (Na/K-ATPase recharge). Here we do not comprehend the decay.
 - ATP cost charged per AP (Here we can comprehend it with an integrator)
 - Ca²⁺ enters via VGCCs, gated by CDI, eCB, and mGluR suppression
- ATP cost charged per unit Ca²⁺ cleared. Here we charge per Ca2+ entered
+- Ca²⁺ buffered by calbindin / calmodulin (fast capture, slow release)
- CDI (calcium-dependent inactivation of VGCCs)
+- Ca²⁺ cleared by NCX (always), PMCA and SERCA (ATP-dependent)
-- CDI rises with Ca2+ each ms: accumulates across inter-spike intervals under pump failure
+- ATP cost charged per unit Ca²⁺ extruded by PMCA and SERCA
-- CDI recovers when Ca2+ is low: rate -> 0 when Ca2+ is high — the self-locking feedback
+- SERCA loads Ca_ER store as a side-effect of clearance
- Ca²⁺ trace integrates toward CaTraces
+- CDI rises with Ca²⁺ — only during spike (channels open and Ca²⁺ entering)
- Vesicles release from RRP, based on Ca2+ and RRP, suppressed by NT_cleft
+- 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 Medium)
+- NT_released_this_window accumulates (feeds mGluR and IP3 in seconds loop)
- NT passively diffuses out of cleft (Astrocyte behavior)
+- NT passively diffuses out of cleft (physical, not astrocyte)
 - Postsynaptic receptor activation and desensitization (Postsynaptic behavior)
---
+— seconds:
-**Medium — seconds**:
+- Astrocyte EAATs actively clear 30% of remaining NT_cleft
 - Astrocyte EAATs clear 30% of remaining NT_cleft (Astrocyte behavior)
 - 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 (from postsynapse)
+- eCB retrograde signal updates from V_post history (postsynaptic input)
- RP → RRP recruitment runs (rate gated by CaTraces, costs ATP)
+- RP → RRP recruitment runs (rate gated by Tr_Ca, costs ATP)
 - NT_released_this_window resets to zero
---
+— mins:
-**Slow — mins**: Metabolic
+- ATP_demand (accumulated from ms loop) reduces ATP_level
-
+- ATP_demand resets to zero
- Glucose level sets metabolic health
+- Glucose level sets metabolic health and conversion_efficiency
- ATP_demand (accumulated from Loop 1) reduces ATP_level
+- conversion_efficiency gates glutamine shuttle throughput
 - conversion_efficiency written → gates glutamine shuttle
 - Glutamine shuttle refills N_RP from astrocyte store
---
+**Semplified comprehension**:
 In this first comprehension, we decide to simplify:
 - The VCGG are active while the AP is active, we do not comprehend the 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 SERCA, we comprehend Ca2+ clearing as a slow process
 - We do not comprehend vesicles, we comprehend them as processes releasing NT, fast, medium and slow based on conditions
 The simplification impies that:
 - Removing CDI and mGluR means Ca²⁺ concentration and NT_cleft are now the only two variables controlling release rate. This is cleaner and matches your fast/medium/slow framing directly — the release rate table from earlier becomes the core logic of the ms loop.
 - Removing ATP removes the metabolic silencing cascade entirely. The mins loop now only does one thing: replenish the NT reserve. If you 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:**
 - AP fires → VGCCs open, Ca²⁺ enters
 - Ca²⁺ cleared slowly (single decay term, no pump detail)
 - Ca²⁺ trace (Tr_Ca) integrates every ms
 - NT released into cleft — rate determined by Ca²⁺ level and NT already in cleft
  - fast release when Ca²⁺ high, NT_cleft low
  - medium release when Ca²⁺ medium, or NT_cleft medium
  - slow release when Ca²⁺ low, or NT_cleft high
 - NT added to cleft
 - NT_released_this_window accumulates (feeds seconds loop)
 - NT passively diffuses out of cleft
 **— seconds:**
 - Astrocyte EAATs clear 30% of remaining NT_cleft
 - IP3 integrates NT_released_this_window (cumulative burst load)
 - If IP3 exceeds threshold → astrocyte Ca²⁺ wave triggered
 - eCB retrograde signal updates from V_post history (postsynaptic input)
 - eCB suppresses NT release (feeds back into ms loop release rate)
 - RP → RRP recruitment runs (rate gated by Tr_Ca)
 - NT_released_this_window resets to zero
 **— mins:**
 - Glucose level sets conversion_efficiency
 - Glutamine shuttle refills NT reserve from astrocyte store
 **Tubs:**