# 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, here we comprehend it as a “cable” transporting the AP from SOMA to Presynapse. It expands BEH-PRE which can be Modulated (TUN).

```Gen
container: BEH-AXO

  expansion: 
  - BEH-PRE ( fullness: 50x, active: 0x, emptiness: 10x ) 
    modulated_by: TUN-SYN-AXO-PRE from TUN-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. This ensures both independent computation and cooperative metabolic support within the axonal branch.

**Tubs:**

- Ca2+: Calcium Ion entering the Presynapse when VCGG open. They are key to check the concentration, release vescicles 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.  
  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.
- RecP: 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).
- Rp: 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
- TagRelease: forse non serve, ma indica il rilascio di NT da parte di una syn.

**Behaviors**:
L'idea e' che:

- Fast  
  -- i VCGG si aprano 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 Rrp disponibili. La vescica libera xxx Nt nella sinsapsi
- Medium  
  -- clearance dei Ca2+ che depolarizza la Presinapsi  
  -- riciclo delle vesciche, prendendole dalla Sinapsi e mettenedole dentro a RecP
- Slow  
  -- riempimento vesciche di Nt e mettendole dentro Rp  
  -- spostamento da Rp a RecP

```Gen
container: BEH-PRE

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

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

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

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

    - TagRelease ( fullness: 1x, active: 0x, emptiness: 0x ) 

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

  tub_intricated:
    - Nt ( contained_by: BEH-SYN ) # intricated name (from BEH-SYN)
   
```

### IntegrateCa2+: Context

Qui verifichiamo il livello di CA2+ nella presynapse. I comportamenti nella presinapsi dipendo tutti da questa concentrazione, sia quelli immediati di rilascio NT da vescicles che quelli di modulazione.

***Tens Milliseconds Time Scale***

```Gen
context: IntegrateCa2+
  contained_by: BEH-PRE

  in_context: Fixed
  rf: ( active: 60x )

  condition: (Ca2+ empty) 
    out_context: CaEmpty

  condition: NOT (Ca2+ empty) AND NOT (Ca2+ full) 
    out_context: CaMedium

  condition: (Ca2+ full) 
    out_context: CaFull
```

### VescicleRelease: Episode

Il rilascio di NT avviene solo se Ca+ FULLNESS? Ovviamente se ci sono Vesciche. O dipende da altro? Cioe’ cosi’ rilascerebbe tutte le vesciche se c’e’ fullness. Dovremmo mettere un tag, o una discesa improvvisa di Ca+ al release di una vescica. Perche’ potremmo avere il caso che i VGGC sia talmente tanti da far entrare tanto calcio da far si che la prima vescica consumi CA ma non abbastanza da andare sotto FULLNESS

Rilascio di NT: Geneosoficamente dovremmo aprire un nuovo contesto che rilascia ad un RF veloce un NT alla volta quando sei nel contesto di rilascio vescica, perche’ Geneosoficamente possiamo solo creare/distruggere blocco. Ma forse possiamo mettere un floor per efficienza: rilascio di una vescica == rilascio 1000 NT? Anche se poi l’Astrocita deve fare un uptake NT per NT?

***Time: t = 0.4-1.5 ms after AP arrival***

- Ca²⁺microdomain > 10-25 µM
- Vesicle in RRP (docked & primed)
- Release latency: 0.1-1.0 ms after Ca²⁺ threshold reached
- Release synchrony: Multiple vesicles can release simultaneously

```Gen
episode: VescicleRelease
  contained_by: BEH-PRE

  in_context: CaFull
  rf: ( active: 6x )

  hypothesis: (Ca2+ full) AND NOT (Rrp empty)
  action: [Rrp decrease, Nt increase, Ca2+ decrease, TagRelease increase]
  trace: None
```

### Ca+ClearenceSlow: Episode

Svuotiamo a due velocita’. Il context (Check Ca+ concentration) e’ determinato a epoca piu’ lunga, tanto ci vuole qualche giro per fare entrare i primi Ca+  
Le tracce lasciate servono alla modulazione

***Time: t = 1-50 ms after influx***

```Gen
episode: Ca+ClearenceSlow
  contained_by: BEH-PRE

  in_context: CaMedium
  rf: ( active: 6x )

  hypothesis: NOT (Ca+ empty) AND NOT (Ca+ full)
   action: [Ca+ decrease, CaTraces Increase]
    trace: None
```

### Ca+ClearenceFast: Episode

Qui l'idea oltre che a fare clearance e' anche quella di lasciare tracce su che livello di Ca2+ c'e' stato durante gli episodi. Un livello medio lascia meno tracce di un livello alto, e questo serve a ragionare sulla modulazione.

Clearance mechanisms (in order of speed):

- Fast buffers (calbindin, parvalbumin): <1 ms
- Plasma membrane Ca²⁺ ATPase (PMCA): 10-100 ms
- Na⁺/Ca²⁺ exchanger (NCX): 10-100 ms
- Mitochondrial uptake: 10-1000 ms
- Endoplasmic reticulum uptake: 100-1000 ms
- Residual Ca²⁺: 0.1-0.5 µM persists for 10-1000 ms*

```Gen

episode: Ca+ClearenceFast
  contained_by: BEH-PRE

  in_context: CaFull
  rf: ( active: 1x )

  condition: (Ca2+ full)
  action: [Ca2+ decrease, CaTraces Increase]
  trace: None
```

```Gen

episode: Ca+ClearenceMedium
  contained_by: BEH-PRE

  in_context: CaMedium
  rf: ( active: 1x )

  hypothesis: NOT (Ca2+ full) AND NOT (Ca2+ empty)
  action: [Ca2+ decrease, CaTraces Increase]
  trace: None
```

### STP - Pr Upregulation: Observable

**Observed behavior**
Upregulation (Facilitation): Residual Ca²⁺ from previous spikes increases P_r for next release

***Timing: > 10 ms***

### STD - Pr Downregulation: Observable

**Observed behavior**
Downregulation (Depression): High-frequency firing depletes readily releasable vesicle pool, decreasing P_r

***Timing: > 10 ms***

### VesciclesRecycling: Episode

Dobbiamo capire se lasciare il recicling RecP oppure avere solo un Rp, almeno al primo giro di comprensione, per semplificare.

Sequential steps:

- Endocytosis (clathrin-mediated, kiss-and-run, bulk)
- Vesicle re-acidification (v-ATPase)
- Neurotransmitter reloading (vesicular transporters)
- Priming (SNARE assembly, docking)
- Return to RRP
- Recycling rate: Limited by ATP availability

***Time: t = 10 ms - 10 s (depending on activity)***

```Gen
episode: VesciclesRecycling
  contained_by: BEH-PRE

  in_context:
  rf: ( fullness: 10x, active: 5x, emptiness: 2x ) 
# si parte con active, poi viene modulato
# modulated_by: DEV-PRE-VesciclesRecycling-RF

  hypothesis:  
```

### VescicleFromRPtoRRP-Slow: Episode

Superpriming requires ATP for phosphorylation reactions and for molecular motors that move vesicles. If the reserve pool is depleted or ATP is low, the superpriming "conveyor belt" has nothing to feed into the RRP. (Astrocyte)

Tracce? non ci sono abbastanza RP, lascio tracce per la modulazione UP, devo capire modulazione DOWN

From The Reserve Pool and Recently Endocytosed Vesicles

***Seconds-Minutes Time Scale***

```Gen
episode: VescicleFromRPtoRRP-Slow
  contained_by: BEH-PRE

  in_context: CaEmpty
  rf: ( active: 30x )

  hypothesis: NOT (RP empty)
  action: [RP decrease, RRP increase]
  trace: None 
```

### VescicleFromRPtoRRP-Medium: Episode

***Seconds-Minutes Time Scale***

```Gen
episode: VescicleFromRPtoRRP-Medium
  contained_by: BEH-PRE

  in_context: CaMedium
  rf: ( active: 15x )

  hypothesis: NOT (RP empty) 
  action: [RP decrease, RRP increease]
  trace: None
```

### VescicleFromRPtoRRP-Fast: Episode

***Seconds-Minutes Time Scale***

```Gen
episode: VescicleFromRPtoRRP-Fast
  contained_by: BEH-PRE

  in_context: CaFull
  rf: ( active: 5x )

  hypothesis: NOT (RP empty)
    action: [RP decrease, RRP increase]
    trace: None 
```

### VesiclesFillingRP: Episode

Qui riempiamo le vesciche. Fino ad un numero massimo, che viene modulato in DEV

***Seconds-Minutes Time Scale***

```Gen
episode: VesiclesFillingRP
  contained_by: BEH-PRE

  in_context: AwayFromSpike
  rf: ( fullness: 100x, active: 60x, emptiness: 30x ) 
   modulated_by: DEV-PRE-VesiclesFillingRP-RF from TUN-N

  hypothesis: 
```

## BEH-PRE-VGCC: Container

**Voltage Gated Ion Channels**: When an AP arrives from the SOMA, VCGG are opened and they let in CA2+ initiating the possible release of NT from the vescicles. In theory each RRP has its own VCGG nearby. We do not comprehend this, but consider VCGG shared between all the RPP of the presynapse (we impose a floor)

```Gen
container: BEH-PRE-VGCC

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

 context_intricated:
    - AP ( contained_by: BEH-SOMA )
```

### VgccOpen: Episode

Auto-inhibition? Ca²⁺ binding to calmodulin on VGCC. 5-50 ms

SK Channels: non comprendiamo i K+ CHannels che si aprono quando entra Ca+ e servono a ripolazzare la presinapsi per chiudere i VGCC. Il tutto viene compreso come contestualizzazione AP.

***Time: t = 0 ms***

- AP Arrives
- Trigger: Depolarization from axon hillock
- Mechanism: Na⁺/K⁺ voltage-gated channel cascade
- State: Terminal depolarizes from -70 mV to +30 mV
- Duration: \~1 ms

***Time: t = 0.2-0.5 ms after AP arrival***

- VGCC Open
- Trigger: Membrane depolarization > -40 mV
- Open probability: \~0.3-0.8 during AP peak
- Open duration: \~0.5-2 ms
- Ca2+ Influx

***Time: t = 0.3-1 ms after AP arrival***

- Ca²⁺ source: Extracellular (1.2 mM) → intracellular (50 nM baseline)
- Influx rate: \~3000-10000 Ca²⁺ ions per VGCC per ms
- Microdomain formation:
  - Within 20 nm of VGCC: 10-100 µM
  - At vesicle release site: 10-25 µM threshold for release
  - Rise time: <100 µs
  - Diffusion-limited spread: \~100-200 nm radius

```Gen
episode: VgccOpen
  contained_by: BEH-VGCC

  in_context: AP
  rf: ( active: 1x )

 hypothesis: NOT (Ca2+ full)
  action: [Ca2+ increase]
  trace: None # Se Ca+FULLNESS, lascio tracce di overflow per modulazione DOWN, da capire UP
```