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organism/neuron/BEH-AXO.md
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BEH-AXO.md

Qui comprendiamo:

  • BEH-AXO: Axon
  • BEH-PRE: Presynapse
  • BEH-VCGG: Voltage-Controlled Gated Channels

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:

  • 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.
container: BEH-AXO

  expansion: BEH-PRE ( fullness: 50x, active: 0x, emptiness: 10x ) 
    # managed_by: BEH-EXH or BEH-INH from winnertakeall
    # developed_by: DEV-AXO-BEH-PRE-TUB from DEV-N

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.

  • Fast Timing -- i VCGG si aprono all'arrivo di un AP dal SOMA. Il numero dei VCGG presenti e' stato modulato (TUN) in una fase di non attivita' della presynapse
    -- I VCGG fanno entrare Ca2+ che ne aumenta la concentrazione
    -- ad un certo livello di concentrazione, viene liberata una vescica, se ci sono ReadyReleasablePool disponibili. La vescica libera xxx Nt nella sinsapsi
  • Medium timing
    -- clearance dei Ca2+ che depolarizza la Presinapsi
    -- riciclo delle vesciche, prendendole dalla Sinapsi e mettenedole dentro a RecyclingPool
  • Slow Timing -- riempimento vesciche di Nt e mettendole dentro Rp
    -- spostamento da ReservePool a ReadyReleasablePool

Actors:

  • CDI (calcium-dependent inactivation of VGCCs) -- CDI rises with Ca_micro each ms: accumulates across inter-spike intervals under pump failure -- CDI recovers when Ca_micro is low: rate -> 0 when Ca_micro is high — the self-locking feedback

  • ATP -- ATP decrease by PMCA / SERCA pumping: (each ms of Ca2+ clearance consumes ATP; modelled implicitly via the demand that sustains Glucose_level depletion) -- ATP decrease by vesicle re-docking (RP -> RRP recruitment): (each refill_amount of vesicles moved to RRP costs ATP for priming/docking machinery) -- ATP decrease by Na/K-ATPase recharge after each AP (largest single ATP cost per spike) -- ATP increase from Astrocyte metabolic support: glucose delivery is the root input — set Glucose_level < 1.0 to engage the full metabolic silencing cascade

Behaviors:

  • Voltage (V_pre / membrane state) -- Voltage increase from AP (external spike drive — V_pre = 1) -- Voltage decrease from Na/K-ATPase recharge after each AP (we might need to include in the model)

  • NT release -- NT_RRP (NT in vesicles in RRP) Piu' vicino alla fullness piu' release -- CaMicro (free calcium) Piu vicino alla fullness, piu' release -- NT_cleft (NT already in the synapse) Piu vicino alla Fullness meno release

  • NT_RRP replenishment -- NT replenishment in RRP from RP: (map_trace_to_speed: rate gated by Tr_Ca trace; fast when Tr_Ca > T_high, slow when Tr_Ca < T_low — the Ca2+ trace is the recruitment memory) -- NT replenishment in RP from Astrocyte: (glutamine shuttle: refill_RP = Glutamine_pool conversion_efficiency, runs once per minute; gated by ATP_level via conversion_efficiency) -- NT degradation / dilution from cleft: (passive: NT_cleft= 1 - dt/tau_NT_decay each ms)

  • Ca2+ evolution -- Ca2+ intake via VGCC on each AP: only the fraction not captured by buffer enters Ca_micro -- Ca2+ buffered into calbindin / calmodulin (fast, on spike): buffer saturates during sustained bursting: B_free -> 0 -- Ca2+ released back from buffer into cytosol (slow recharge)sustains Ca_micro elevation under pump failure -- Ca2+ extruded by PMCA — primary pump, ATP-dependent: first to fail when ATP drops; largest ATP-dependent clearance term -- Ca2+ extruded by NCX — fast exchanger, NOT ATP-dependent: floor mechanism: keeps clearing during metabolic failure; enables auto-reset when high-frequency drive stops -- Ca2+ pumped into ER by SERCA --- Active transport, ATP-dependent, slowest of the three pumps Clears Ca2+ from the cytosol (reduces Ca_micro). Loads the Ca_ER store as a byproduct. -- Ca2+ stored in ER (Ca_ER). Passive reservoir. Fills gradually during normal activity via SERCA. Can be released back into the cytosol via IP3R channels when astrocyte IP3 signalling crosses threshold (not yet implemented — Ca_ER currently only increases). This release pathway would create a slow secondary Ca2+ surge independent of VGCC activity — relevant for plasticity and for amplifying the metabolic silencing cascade if added later.

  • NT_cleft evolution -- NT release -- NT degradation / dilution from cleft -- NT clearance from cleft by Astrocyte EAATs

  • VGCC behaviour -- conductance suppressed by eCB (retrograde brake) -- VGCC conductance suppressed by mGluR autoreceptor -- VGCC conductance suppressed by CDI -- VGCC modulation

  • VCGG modulation -- VGCC increase in number by slow activity-dependent upregulation

  • CaTraces

Tubs:

  • Ca2+: Calcium Ion entering the Presynapse when VCGG open. They are key to check the concentration, release vescicles and modulation
  • Ca2Micro: free cytosolic Ca2+ in microdomain that influence NT release. Normally returns to ~0 between spikes; stays elevated when pumps fail
  • Rrp: Readily Releasable Pool: The Readily Releasable Pool consists of the vesicles that are "docked" and "primed" at the active zone of the synapse.
    -- Location: Directly touching the presynaptic membrane.
    -- Function: These are the first to be released when an action potential arrives.
    -- Characteristics: 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.
  • RecyclingPool: Recycling Pool
    --The Recycling Pool is the next line of reinforcement.
    -- Location: Slightly further back from the membrane than the RRP.
    -- Function: These vesicles maintain release during moderate, physiological levels of stimulation.
    -- Characteristics: They are continuously refilled as the neuron "recycles" the membranes of used vesicles through endocytosis. This pool is larger than the RRP (roughly 5% to 20% of the total).
  • ReservePool: The "Reserve Pool" (The true RP)
    -- In many textbooks, RP specifically stands for the Reserve Pool. -- Location: The bulk of the vesicles held further back in the terminal, often tethered by a protein called synapsin.
    -- Function: These are only mobilized during intense, prolonged stimulation once the RRP and Recycling pools are depleted.
    -- Characteristics: This makes up the vast majority of the vesicles (up to 80% or 90%).
  • Nt: Neuro Transmitter, released in the synapse by the vescicles
  • CaTraces: sono le tracce di permanenza della concentrazione di Ca2+. Servono alla modulazione (TUN)
container: BEH-PRE

  expansion: BEH-PRE-VGCC ( fullness: 10x, active: 5x, emptiness: 2x )
              # tuned_by: TUN-PRE-VGCC from TUN.N

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

    - CaMicro ( fullness: 60x, active: 30x, emptiness: 0x )

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

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

    - CaTraces ( fullness: 50x, active: 0x, emptiness: 0x )

  tub_intricated:
    - NT

  context_intricated:
  - AP ( contained_by: BEH-SOMA )

RRPConcentration: Context

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

context: RRPConcentration
  contained_by: BEH-PRE

  in_context: AP
  rf: ( active: 60x )

  condition: NOT (Rrp empty) AND NOT (Rrp full) 
    out_context: RRPMedium

  condition: (Rrp full) 
    out_context: RRPFull

Ca2MicroConcentration: Context

context: Ca2MicroConcentration
  contained_by: BEH-PRE

  in_context: AP
  rf: ( active: 60x )

  condition: NOT (Ca2Micro empty) AND NOT (Ca2Micro full) 
    out_context: Ca2MicroMedium

  condition: (Ca2Micro full) 
    out_context: Ca2MicroFull

NTrelease episodes

Ci sono 4 casi che dipendono da RRP, CaMicro e NT. L'idea e' che la quantita' di RRP sia il driver principale. Gli NT liberati sono di piu' al crescere di RRP e CaMicro e di meno al crescere di NT. 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 episodes

episode: NTreleaseMaximum
  contained_by: BEH-PRE

  in_context: (Ca2MicroFull AND RRPFull)
  rf: ( active: 6x ) # Maximum

  hypothesis: (NT empty)
    action: [Rrp decrease, Nt increase, ATP decrease]
    trace: None

NTreleaseHigh episodes

episode: NTreleaseHigh
  contained_by: BEH-PRE

  in_context: (Ca2MicroFull AND RRPFull)
  rf: ( active: 6x ) # High

  hypothesis: NOT (NT empty) # solo in questo caso NT modera!
    action: [Rrp decrease, Nt increase, ATP decrease]
    trace: None

NTreleaseMedium episodes

episode: NTreleaseMedium
  contained_by: BEH-PRE

  in_context: (Ca2MicroFull AND RRPMedium) OR (Ca2MicroMedium AND RRPFull)
  rf: ( active: 6x ) # Medium

  hypothesis: (NT empty) OR NOT (NT empty) # In tutti i casi
    action: [Rrp decrease, Nt increase, ATP decrease]
    trace: None

NTreleaseLow episodes

episode: NTreleaseLow
  contained_by: BEH-PRE

  in_context: (Ca2MicroMedium AND RRPMedium)
  rf: ( active: 6x ) # Low

  hypothesis: (NT empty) OR NOT (NT empty) # In tutti i casi
    action: [Rrp decrease, Nt increase, ATP decrease]
    trace: None

BEH-PRE-VGCC: Container

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

container: BEH-PRE-VGCC

  tub_intricated:
   - Ca2+ ( contained_by: BEH-PRE )

 context_intricated:
    - AP ( contained_by: BEH-SOMA )
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