organism/neuron/axon.md

axon.md

Qui comprendiamo:

• AXON: Axon
• PRESYNAPSE: Presynapse
• VGCC-PRE: Voltage-Controlled Gated Channels

AXON: Container

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 PRESYNAPSE which:

• can be developed by DEV-PRE
• the associations between PRESYNAPSE, 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.

container: AXON

  expansion: PRESYNAPSE ( full: 50x, active: 0x, empty: 10x ) 
    # managed_by: EXCITATION or INHIBITION from winnertakeall
    # developed_by: AXO-PRE-TUB-DEV from NIGHT-N

PRESYNAPSE: Container

Simplified Behaviors:

— ms:

• AP fires → VGCCs open, Ca²⁺ enters, based on eCB e mGluR
• 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
• NT released accumulates (feeds sec behavior)
• NT passively diffuses out of cleft
• 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 clear 30% of remaining NT in the cleft (Atrocyte behavior)
• eCB retrograde signal updates from postsynapsis (postsynaptic input)
• eCB suppresses NT release (feeds back into ms behavior release rate)
• RP → RRP recruitment runs (rate gated by Tr_Ca)
• NT released in sec resets to zero

— mins:

• Glucose level sets base conversion_efficiency (Atrocyte behavior)
• If astrocyte wave was triggered → conversion_efficiency boosted temporarily
• Glutamine shuttle refills NT reserve from astrocyte store (faster if wave active, baseline if not)
• Wave boost decays back to baseline over subsequent cycles

---

G expression:

PRESYNAPSE
  - AP_ctx
    -- NT Release
    NTreleaseHigh: interacting 
    NTreleaseMedium: interacting
    NTreleaseLow: interacting
    -- Ca Clearence
    AP-CaClearanceHigh: interacting
    AP-CaClearanceMedium: interacting

  - NOT AP_ctx:
    -- Ca Clearence
    NotAP-CaClearance: interacting
    -- Ca Traces
    CaTracesAccumulationFast: interacting
    CaTracesAccumulationSlow: interacting
    CaTracesClearance: interacting
    -- eCB Clearence
    eCBClearance: interacting
    -- RP Shuttle
    RPShuttleLow: interacting
    RPShuttleMedium: interacting
    RPShuttleHigh: interacting

VGCC-PRE
  - AP_ctx
    -- Ca Influx
    Ca2+enterLow: interacting
    Ca2+enterMedium: interacting
    Ca2+enterSuppressed: interacting

Tubs:

• Ca2+: Calcium Ion entering the Presynapse when VCGG open that influence NT release. Normally returns to ~0 between spikes; stays elevated when pumps fail. They are key to check the concentration, release NT and modulation
• Rrp: Readily Releasable Pool: The Readily Releasable Pool consists of the vesicles that are "docked" and "primed" at the active zone of the synapse. This pool is very small (usually only about 0.5% to 5% of total vesicles) and can be exhausted quickly during high-frequency firing, leading to "short-term depression" of the signal. Here we consider them as NT ready to be released.
• Rp: Reserve Pool: The bulk of the vesicles held further back in the terminal, often tethered by a protein called synapsin. These are only mobilized during intense, prolonged stimulation. This makes up the vast majority of the vesicles (up to 80% or 90%). Here we consider them NT in reserve that can be transfered to RRP and created using Glutamine from Astorcyte.
• NT: Neuro Transmitter, released in the synapse by the vescicles. The release increses NT and decreases RRP
• CaTraces: sono le tracce di permanenza della concentrazione di Ca2+. Servono alla modulazione (TUN)
• eCB: retrograde signal updates from postsynapsis (postsynaptic input)

---

container: PRESYNAPSE

  expansion: VGCC-PRE ( full: 10x, active: 5x, empty: 2x )

  tub_local:
    - Ca2+ ( full: 60x, active: 30x, empty: 0x )
       # developed_by: DEV-PRE-CA2+FULL from DEV.N

    - Rrp ( full: 30x, active: 15x, empty: 0x )
       # developed_by: DEV-PRE-RRP-FULL from DEV.N

    - Rp ( full: 30x, active: 15x, empty: 0x )
       # developed_by: DEV-PRE-RRP-FULL from DEV.N

    - CaTraces ( full: 50x, active: 0x, empty: 0x )

  tub_intricated:
    - NT ( contained_by: SYN ) 
    - ATP ( contained_by: ? ) 
    - eCB ( contained_by: POST ) 

  context_intricated:
  - AP ( contained_by: SOMA ) 

ms: behaviors

PRE_Status_ms: check_tpc

Il rilascio di NT lo facciamo nel contesto di AP. Biologicamente dovrebbe avvenire solo in base alle concentrazioni, quindi anche al difuori degli AP.

RF di interacting deve essere MOLTO piu' basso di un RF di AP. In maniera da essere attivo varie volte nel contesto di un episodio di AP. Il che ha senso perche' un AP e' SOMA ad un tempo piu' alto che i comportamenti di PRE. Questo poi per permettere la diversa contestualizzazione degli episodi di NTrelease, a piu' o meno alta velocita'.

check_tpc: PRE_Status_ms
  contained_by: PRESYNAPSE

  in_context: AP_ctx
  rf: ( active: 60x )

  condition: ( Ca2+ full ) AND ( Rrp fullness ) 
    out_context: NTreleaseMax_ctx

  condition: ( Ca2+ fullness ) AND ( Rrp fullness ) 
    out_context: NTreleaseHigh_ctx

  condition: (( Ca2+ fullness ) AND ( Rrp mediumness )) OR (( Ca2+ mediumness ) AND ( Rrp fullness ))
    out_context: NTreleaseMed_ctx

  condition: ( Ca2+ mediumness ) AND ( Rrp mediumness )
    out_context: NTreleaseLow_ctx

NTrelease

Non consideriamo le vesicles come liberate, ma direttamente gli NT. Questo permette di gestire la quantita' rilasciata di NT, invece di gestire un numero di vescicles. Nella realta' ciascuna vesicle contiene migliaia di NT. Qui mettiamo un floor a questo tipo di comprensione.

Ci sono 4 casi che dipendono da RRP, Ca2+ e indirettamente da concentrazione di NT nella SYN che diventa mGLur che limita in VGCC l'entrata di Ca2+. L'idea e' che la quantita' di RRP sia il driver principale. Gli NT liberati sono di piu' al crescere di RRP e Ca2+ e di meno (indirettamente) al crescere della concentrazione di NT gia' liberati nella SYN. Gli NT nella sinapsi fanno da moderazione alla ulteriore liberazione di NT, ma non bloccano mai totalmente. NT suppression only matters when everything else is already at maximum, which is exactly the biological purpose: it prevents runaway release during peak activity, not during moderate activity.

NTreleaseMaximum: interacting

NT empty. Qui siamo contestualizzati se Ca2+ full, il che dovrebbe significare indirettamente che non ci sono NT nella SYN.

interacting: NTreleaseMaximum
  contained_by: PRESYNAPSE

  in_context: NTreleaseMax_ctx
  rf: ( active: 3x ) # Maximum

  hypothesis: NOT (NT empty)
    action: [Rrp decrease, Nt increase, ATP decrease]
    trace: None

NTreleaseHigh: interacting

Solo in questo caso NT modera! NT NOT empty, perche' Ca2+ fullness non full.

interacting: NTreleaseHigh
  contained_by: PRESYNAPSE

  in_context: NTreleaseHigh_ctx
  rf: ( active: 6x ) # High

  hypothesis: NOT (NT empty) 
    action: [Rrp decrease, Nt increase, ATP decrease]
    trace: None

NTreleaseMediumness: interacting

In tutti i casi di NT

interacting: NTreleaseMedium
  contained_by: PRESYNAPSE

  in_context: NTreleaseMed_ctx
  rf: ( active: 9x ) # Mediumness

  hypothesis: (NT empty) OR NOT (NT empty) 
    action: [Rrp decrease, Nt increase, ATP decrease]
    trace: None

NTreleaseLow: interacting

In tutti i casi di NT

interacting: NTreleaseLow
  contained_by: PRESYNAPSE

  in_context: NTreleaseLow_ctx

  hypothesis: (NT empty) OR NOT (NT empty)
    action: [Rrp decrease, Nt increase, ATP decrease]
    trace: None

CaClearance

Qui eliminiamo Ca2+. Non comprendiamo per ora:

• PMCA: primary, ATP-dependent
• NCX: fast, NOT ATP-dependent
• SERCA: slowest, ATP-dependent

Quindi non comprendiamo anche il ristabilimento del Voltage, con altri Ioni entranti e uscenti, per ora tutto dipende da AP del SOMA.

Abbiamo il caso di clearance nel contesto di un AP e non nel contesto di AP, per eliminare il Ca2+ fra le spike.

AP-CaClearanceHigh: interacting

interacting: AP-CaClearanceHigh
  contained_by: PRESYNAPSE

  in_context: AP
  rf: ( active: 3x ) # High

  hypothesis: (Ca2+ fullness)
    action: [Ca2+ decrease]
    trace: None

AP-CaClearanceMediumness: interacting

interacting: AP-CaClearanceMediumness
  contained_by: PRESYNAPSE

  in_context: AP
  rf: ( active: 6x ) # mediumness

  hypothesis: (Ca2+ mediumness)
    action: [Ca2+ decrease]
    trace: None

NotAP-CaClearance: interacting

interacting: NotAP-CaClearance
  contained_by: PRESYNAPSE

  in_context: NOT AP_ctx
  rf: ( active: 24x ) # Low

  hypothesis: NOT (Ca2+ empty)
    action: [Ca2+ decrease]
    trace: None

CaTraces accumulation

Serve a dare la velocita' al trasporto di vesicles da RP a RRP. The biological meaning is that a synapse that has just been through a burst is primed for fast recovery — the molecular machinery for vesicle docking is already engaged, calcium-dependent priming factors are still elevated, and the system is in a ready state. A synapse that has been silent for several seconds has cooled down and replenishes slowly.

So after one second of silence CaTrace has fallen to ~37% of its peak value, after two seconds to ~14%, after three seconds to ~5%. It asymptotes toward zero but never exactly reaches it. Between spikes, Ca2+ falls toward zero as the pumps clear it.

The result is that Tr_Ca encodes not the instantaneous calcium level but the recent history of calcium activity — a smoothed, time-averaged measure of how active the synapse has been over the past one to two seconds.

CaTracesAccumulationFast: interacting

Qui le tracce CaTrace si accumulano di piu' perche' RF e' minore, se c'e' la condizione, perche' va a fare il controllo piu' spesso.

interacting: CaTracesAccumulationFast
  contained_by: PRESYNAPSE

  in_context: NOT AP_ctx
  rf: ( active: 12x ) # fast

  hypothesis: (Ca2+ fullness)
    action: [CaTrace increase]
    trace: None

CaTracesAccumulationSlow: interacting

interacting: CaTracesAccumulationSlow
  contained_by: PRESYNAPSE

  in_context: NOT AP_ctx
  rf: ( active: 24x ) # Slow

  hypothesis: (Ca2+ mediumness)
    action: [CaTrace increase]
    trace: None

sec: behaviors

PRE_Status_sec: check_tpc

Contestualizziamo in maniera Fixed ogni mezzo secondo?

check_tpc: PRE_Status_sec
  contained_by: PRESYNAPSE

  in_context: NOT AP_ctx
  rf: ( active: 600x )

  condition: NOT (RP empty) AND NOT (RRP full)
    out_context: RPShuttle_ctx

  condition: NOT (CaTrace empty) 
    out_context: CaTracesNotEmpty_ctx

  condition: NOT (eCB empy) 
    out_context: eCBNotEmpty_ctx

eCB clearance: interacting

eCB dipende da POST. Tende a modulare l'entrata di Ca2+ degli VGCC.

Qui non facciamo un flush di eCB, riduciamo ogni mezzo secondo (context) di un RF di questo episodio.

interacting: eCBClearance
  contained_by: PRESYNAPSE

  in_context: eCBNotEmpty_ctx
  rf: ( active: 24x ) # Slow

  hypothesis: NOT (eCB empty)
    action: [eCB decrease]
    trace: None

CaTracesClearance: interacting

Qui non facciamo un flush di Catrace, riduciamo ogni mezzo secondo (context) di un RF di questo episodio.

interacting: CaTracesClearance
  contained_by: PRESYNAPSE

  in_context: CaTracesNotEmpty_ctx
  rf: ( active: 24x ) # Slow

  hypothesis: NOT (CaTrace empty)
    action: [CaTRace decrease]
    trace: None

RPShuttling

This happens in the seconds loop, once per second.

RPShuttleSlow: interacting

The "Hard Bottleneck" State. Recruitment is throttled by a lack of signal, a lack of supply, or a lack of space. If even one of these "Near-Stop" conditions is met, the rate cannot exceed "Slow," regardless of the other two conditions.

Rate: 0.00 – 0.25

interacting: RPShuttleSlow
  contained_by: PRESYNAPSE

  in_context: RPShuttle_ctx
  rf: ( active: 48x ) # Slow

  hypothesis: (CaTrace emptiness) OR (RP emptiness) OR (RRP fullness)  
    action: [RP decrease, RRP increase]
    trace: None

RPShuttleModerate: interacting

The "Sub-Optimal" State. The machinery is working, but it's held back by partial limitations. This covers cases where the signal is steady but the "piston" isn't firing at full speed, or where a high vacancy in the RRP (emptiness) forces a low signal to work a bit harder.

Rate: 0.50 – 0.97

interacting: RPShuttleModerate
  contained_by: PRESYNAPSE

  in_context: RPShuttle_ctx
  rf: ( active: 24x ) # Slow

  hypothesis: ((CaTrace mediumness) AND (RP mediumness) AND (RRP mediumness)) OR 
              ((CaTrace fullness) AND (RP mediumness) AND (RRP mediumness)) OR # signal boost
              ((CaTrace mediumness) AND (RP fullness) AND (RRP mediumness)) OR # supply boost
              ((CaTrace mediumness) AND (RP mediumness) AND (RRP emptiness)) # vacancy boost
    action: [RP decrease, RRP increase]
    trace: None

RPShuttleFast: interacting

The "High Performance" State. Multiple systems are optimized, but one is still at a "mediumness" level. This represents an active synapse that hasn't reached its absolute peak because either the supply is only 50% or the RRP isn't empty enough to create that "maximal vacuum" pull.

Rate: 1.25 – 1.94

interacting: RPShuttleFast
  contained_by: PRESYNAPSE

  in_context: RPShuttle_ctx
  rf: ( active: 12x ) # Fast

  hypothesis: ((CaTrace fullness) AND (RP fullness) AND (RRP mediumness)) OR # signal + supply
              ((CaTrace fullness) AND (RP mediumness) AND (RRP emptiness)) OR # signal + vacancy
              ((CaTrace mediumness) AND (RP fullness) AND (RRP emptiness)) # supply + vacancy
    action: [RP decrease, RRP increase]
    trace: None

RPShuttleMaximal: interacting

The "Total Recovery" State. All systems are at their theoretical peak for speed.

Rate: 2.50 – 5.00

interacting: RPShuttleMaximal
  contained_by: PRESYNAPSE

  in_context: RPShuttle_ctx
  rf: ( active: 6x ) # Maximal

  hypothesis: (CaTrace fullness) AND (RP fullness) AND RRP (emptiness)
    action: [RP decrease, RRP increase]
    trace: None

min: behaviors

Refill RP from Glutamine

This happens in the minutes loop, once per minute, via the glutamine shuttle from the astrocyte. It is a two-step process across two cells.

Step 1 — astrocyte side The astrocyte has been accumulating cleared glutamate from the cleft since the last minutes-loop execution. Its glutamine synthetase enzyme converts that glutamate into glutamine, filling the Glutamine_pool. The fraction successfully converted per cycle is conversion_efficiency, which is set by glucose availability and boosted temporarily if the astrocyte calcium wave fired during the preceding seconds:

refill_RP = Glutamine_pool * conversion_efficiency Glutamine_pool = max(0.0, Glutamine_pool - refill_RP)

Step 2 — presynapse side

The glutamine crosses into the presynapse, where glutaminase converts it back into glutamate. That glutamate is immediately repackaged into vesicles and added to N_RP:

The asymmetry that makes depletion possible:

The chain reveals why sustained high-frequency firing eventually depletes the synapse even with all replenishment mechanisms running.

The RRP holds at most Max_RRP = 20 vesicles. At 20 Hz with strong Ca²⁺, release can draw 2-4 vesicles per spike — potentially exhausting the RRP in under a second. The seconds loop can move vesicles from RP to RRP at a maximum rate of k_rec_fast = 5 /s, meaning at most 5 vesicles per second under ideal conditions. Release outpaces recruitment by roughly an order of magnitude during a burst.

The RP holds up to Max_RP = 200 vesicles — ten times the RRP. At sustained 20 Hz the RP can sustain firing for tens of seconds even after the RRP is repeatedly emptied, as long as recruitment keeps pace. But the minutes loop only refills N_RP once per minute at a rate limited by Glutamine_pool * conversion_efficiency. If glucose is low or the astrocyte wave has not fired, this replenishment may add only a fraction of what was consumed.

The result is a three-tier buffer with mismatched timescales:

RRP — depletes in seconds, refilled in seconds (fast but shallow) RP — depletes in minutes, refilled in minutes (deep but slow) Gln — depletes over bursts, refilled by glucose (slowest, astrocyte-dependent)

Each tier buys time for the one below it to respond. When all three are depleted simultaneously — which only happens under prolonged high-frequency firing with insufficient glucose — the synapse has no remaining buffer and goes silent until the minutes loop restores the Glutamine_pool.

VGCC-PRE-TUN: Tuner

tuner: VGCC-PRE-TUN

 contained_by: PRESYNAPSE

 tunes: PRESYNAPSE/expansion/PRESYNAPSE-VCGG
  
 tub_modulation: # in TUN agiamo su POS/ACT
   - posMod ( fullness: None, active: PRESYNAPSE-VCGG/fullness, empty: 0x)  # riferimento a possible di PRESYNAPSE-VCGG
   - actMod ( fullness: None, active: PRESYNAPSE-VCGG/active, empty: PRESYNAPSE-VCGG/emptiness)  # riferimento a active di PRESYNAPSE-VCGG
# qui stiamo modulando possible e actual di PRESYNAPSE-VCGG associandoli
# a posMod e actMod. Non serve associare una fullness perche' 
# la modulazione e' una pompa fra posMod e actMod e controlliamo
# solo empty

 check_tpc_intricated:
  - TunPossible ( contained_by: DAY-N )

 tub_local:

 tub_intricated:

check_tpc

context: Check
  contained_by: VGCC-PRE-TUN

  in_context: TunPossible
  rf: ( active: 60x )

  condition:  
  out_context: TunPreVcgg

interacting

interacting: Tun
  contained_by: VGCC-PRE-TUN

  in_context: TunPreVcgg
  rf: ( active: x )

 hypothesis:  
  action: 
  trace: 

VGCC-PRE: Container

Voltage-Controlled Gated Channels: Qui per ora non gestiamo l'evoluzione della depolarizzazione. Alla scomparsa dell'AP, i VGCC smettono di funzionare.

container: VGCC-PRE

  tub_intricated:
    - Ca2+ ( contained_by: PRESYNAPSE )
    - NT ( contained_by: SYN )

  context_intricated:
    - AP ( contained_by: SOMA )

ms: behavior

Ca2+enter

Here we comprehend the breaking activity on VGCC by: CDI, eCB and mGluR:

Qui sostituiamo:

• Approssimiamo CDI con concentrazione di Ca2+. -- CDI is calcium-dependent inactivation of VGCCs. The inactivation happens because Ca²⁺ enters through the channel and binds to a calmodulin tethered to the channel's intracellular face, physically blocking it from reopening. This is a local, channel-specific event — it requires Ca²⁺ to be flowing through that channel right now, not residual Ca²⁺ drifting in the cytosol between spikes. -- The recovery, by contrast, should run every millisecond unconditionally — CDI de-inactivation is a continuous process that proceeds whenever Ca²⁺ dissociates from calmodulin, which depends on the ambient Ca_micro level at all times.

• Approssimiamo mGluR con concentrazione NT

• Open — zero active brakes. mGluR alone never escapes this group because its ceiling is alpha_mGluR = 0.4, meaning even at full it only removes 40% of conductance, leaving 60% — still above the 85% threshold. So mGluR is irrelevant to the open/not-open boundary. Only CDI and eCB decide.

• Reduced/partial — exactly one meaningful brake active. Either CDI has started building (mediumness), or eCB has risen from sustained postsynaptic activity, but not both simultaneously. The system is aware something is happening but has not compounded yet. This is the normal operating range during moderate sustained firing.

• Suppressed — two brakes multiplying. The compounding is what defines this zone — no single variable alone produces it (except CDI approaching full). 0.5 × 0.5 = 0.25 remaining is where the synapse starts losing significant transmission efficacy. Biologically this is the pre-silence warning zone: CDI is building from residual Ca²⁺ while eCB is already engaged from postsynaptic activity.

• Closed — CDI = full is the only reliable hard rule. Because CDI can reach 1.0 and appears as (1 - CDI_factor) in the formula, it alone drives conductance to zero regardless of eCB and mGluR state. The three-brake overlap corner case (eCB=full + CDI=mediumness + mGluR=full) also reaches here, but in practice CDI reaching full is the primary biological mechanism.

Devo controllare che le condizioni sotto siano esaustive.

Ca2+enterOpen: interacting

interacting: Ca2+enterOpen
  contained_by: VGCC-PRE

  in_context: AP_ctx
  rf: ( active: 6x )

  hypothesis: (Ca2+ empty) and (eCB empty)
    action: [Ca2+ increase, ATP decrease]
    trace: None

Ca2+enterReduced-partial: interacting

interacting: Ca2+enterReduced-partial
  contained_by: VGCC-PRE

  in_context: AP_ctx
  rf: ( active: 6x )

  hypothesis: (Ca2+ mediumness) OR ((eCB mediumness) AND (Ca2+ empty)) OR ((eCB full) AND (Ca2+ empty) AND (NT empty))
    action: [Ca2+ increase, ATP decrease]
    trace: None

Ca2+enterSuppressed: interacting

interacting: Ca2+enterSupressed
  contained_by: VGCC-PRE

  in_context: AP_ctx
  rf: ( active: 6x )

  hypothesis: ((Ca2+ mediumness) AND (eCB full) OR (eCB mediumness))
    action: [Ca2+ increase, ATP decrease]
    trace: None