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@@ -23,7 +23,45 @@ container: BEH-AXO
## BEH-PRE: Container ## 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. **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.
**Behaviors** Related to:
- 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 (neurotransmitter / vesicle pools)
-- NT released from RRP (instead of modeling this as stochastic_release: p = p_release_base *Ca_micro, I'd like to model this as a function of Ca-micro, number of vescicles in RRP, modulated down by NT already released)
-- 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)
-- NT clearance from cleft by Astrocyte EAATs: (cleared_NT = NT_cleft * 0.3, once per second)
- VGCC (voltage-gated calcium channels)
-- VGCC increase in number by slow activity-dependent upregulation
-- VGCC conductance suppressed by eCB (retrograde brake)
-- VGCC conductance suppressed by mGluR autoreceptor tracks NT_cleft directly via Michaelis-Menten occupancy, fastest of the three brakes — no postsynaptic relay needed
-- VGCC conductance suppressed by CDI (calcium-dependent inactivation) CDI rises with Ca_micro via k_CDI_rise, recovers only when Ca_micro falls — the metabolic silence lock
- Ca2+
-- 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 — slowest pump, ATP-dependent: also loads Ca_ER store; fails alongside PMCA under low ATP
-- Ca2+ stored in ER (Ca_ER) (Ca_ER += cleared_SERCA; ER store is a future IP3-release target)
- 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 of CASCADE 5
- ATP
-- ATP decrease by PMCA / SERCA pumping: (each ms of Ca2+ clearance consumes ATP; modelled implicitly via the demand that sustains Glucose_level depletion in Loop 3)
-- ATP decrease by vesicle re-docking (RP -> RRP recruitment): (each refill_amount of vesicles moved to RRP costs ATP for priming/docking machinery; modelled implicitly in CASCADE 2 demand)
-- ATP decrease by Na/K-ATPase recharge after each AP (largest single ATP cost per spike; drives CASCADE 2 during high firing)
-- ATP increase from Astrocyte metabolic support: glucose delivery is the root input — set Glucose_level < 1.0 to engage the full metabolic silencing cascade
**Tubs:** **Tubs:**
@@ -83,261 +121,3 @@ container: BEH-PRE
tub_intricated: tub_intricated:
``` ```
### Ca2+Concentration: 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: Ca2+Concentration
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:
```
### Slow-ReservePooltoReadilyReleasable: 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
```
### Medium-ReservePooltoReadilyReleasable: 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
```
### Fast-ReservePooltoReadilyReleasable: 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
```
## 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
```