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@@ -10,183 +10,18 @@ Qui comprendiamo:
- VGCC-PRE-TUN: la modulazione della quantita' di VGCC-PRE
- VGCC-PRE: Voltage-Controlled Gated Channels
## PRESYNAPSE: Container
**Traditional 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**:
Qui riportiamo la struttura della espressione G e una descrizione di come leggerla (uno dei possibili modi):
- i possibili behavior della presynapsi sono espressi in due contesti. AP_ctx and NOT AP_ctx. I possibili behavior sono anche raggrupati in ms, sec e min, per facilitarne la verifica. Quello che conta sono gli RF specifici di ciascuno snipplet.
- AP-ctx: all'arrivo di un AP dal SOMA:
- si aprono i canali ionici VGCC. Il numero di VGCC e' soggetto a tuning a medi termine.
- i VGCC fanno entrare ioni Ca2+ nella Presynapse, in base a:
- quanto Ca2+ e' gia' presente (proxy per CDI)
- alla concentrazione di eCB (che arriva dalla Postsynapse e tende a limitare l'ingresso di Ca2+ per limitare indirettamente il rilascio di NT)
- alla concentrazione di NT (proxy per mGlur)
- il rilascio di NT avviene in base:
- alla concetrazione di Ca2+
- alla concentrazione di Rrp (readily release pool)
- l'accumulo di CaTraces avviene durante AP_ctx. Qui cerchiamo di catturare il livello medio che raggiunge Ca2+ durante varie spike. Non lo possiamo catturare in NOT AP_ctx perche' li facciamo clearance.
- NOT AP_ctx: quando la presynapsi e' in fase di "riposo" fra AP facciamo pulizia. Questo riposo e' inter AP non quello alla fine di uno spike train:
- eCB clearance
- Ca2+Traces clearance
- RPShuttle
- RefillRPGlutamine (sec)
## PRESYNAPSE: Comprehension
```Gen
AP_ctx
PRESYNAPSE (ms):
-- NT released into cleft
NTreleaseLow: ( active: 12x ) accumulator
NTreleaseMedium: ( active: 9x ) accumulator
NTreleaseHigh: ( active: 3x ) accumulator
-- CA2+ trace accumulation
Ca2+TracesAccumulationLow: ( active: 10x ) accumulator
Ca2+TracesAccumulationMedium: ( active: 6x ) accumulator
Ca2+TracesAccumulationHigh: ( active: 10x ) accumulator
VGCC-PRE (ms):
Ca2+enterLow: ( active: 12x ) accumulator
Ca2+enterMedium: ( active: 6x ) accumulator
Ca2+enterHigh: ( active: 3x ) accumulator
PRESYNAPSE
type: comprehension
NOT AP_ctx
PRESYNAPSE (sec):
-- eCB
eCBClearance: ( active: 24x ) accumulator
-- RP → RRP recruitment
RPShuttleLow: ( active: 48x ) accumulator
RPShuttleMedium: ( active: 24x ) accumulator
RPShuttleHigh: ( active: 12x ) accumulator
-- CA2+ trace clearance
Ca2+TracesClearance: ( active: 30x ) accumulator
VGCC-PRE (ms):
Ca2+ClearanceLow: ( active: 24x ) accumulator
Ca2+ClearanceHigh: ( active: 4x ) accumulator
TunPossible_ctx
VGCC-PRE-TUN (sec):
CheckVgccPreTun: ( active: 60x ) contexting
TryTunUpPreVcgg_ctx
PossibleUpPreVgccTun: ( active: 10x ) accumulator
TryTunDownPreVcgg_ctx
PossibleDownPreVgccTun: ( active: 10x ) accumulator
expansion:
@VGCC-PRE: VGCC-PRE [ full: 10x, active: 5x, empty: 2x ]
@: VGCC-PRE-TUN [@VGCC-PRE]
```
## Presinapse
I comportamenti sono episodi di integrazione di ipotesi, contestualizzati da condizioni. I comportamenti cambiano le condizioni e le condizioni influiscono sui comportamenti. Ma non in maniera causale, ma su contesti di tempi, spazi e quantita diversi. Gli sniplet di interacting sono quelli che determinano i comportamenti, quelli di contexting mettono constraints sulle condizioni. Le ipotesi fanno parte dei comportamenti, e sono concettualmente diverse dalle condizioni, perche si tratta di un accumulo di evidenza a seguito di ipotesi, evidenza che cambia le condizioni.
E proprio laccumulo che fa vedere come si passi da un tempo/spazio/quantita ad un altro.
Posso provare ad associare comportamenti e condizioni. Perche i comportamenti dipendono dalle condizioni e le condizioni dai comportamenti. E inoltre non avvengono su scala temporale unica e come nel caso dei VGCC anche con molteplicita tunabile.
Ci sono le condizioni come concentrazione di Ca2+ e concentrazione di Rrp. Anche nel caso di Rrp eliminiamo e aggiungiamo, ma sembra che Ca2+ sia piu importante.
## Comportamenti
uscita NT (Rrp)
ingresso Ca2+
uscita Ca2+
ingresso tracceCa2+
uscita tracceCa2+
uscita eCb
ingresso Rrp / uscita Rp
ingresso Rp
tuning VGCC
## Condizioni
### Rilascio NT - comportamento
Il comportamento principale che assegniamo al container Presinspse e quello del rilascio di NT allarrivo di AP_ctx dal SOMA. Il rilascio di NT allarrivo di AP_ctx dal SOMA dipende da:
- Concentrazione di Ca2+
- Quantita di Rrp disponibile
- ATP disponibile?
### Concentrazione di Ca2+ - condizione
La concentrazione di Ca2+ dipende da:
#### Ingresso Ca2+ - comportamento
Lingresso di Ca2+ avviene tramite i VGCC e dipende da:
- quantita di VGCC
- CDI
- eCb
- ATP?
##### CDI - Condizione
Ha un proprio refractory e dipende dalla concentrazione di Ca2+. Normalmente si attiva allapertura dei VGCC, perche deve limitare lingresso di Ca2+, che altrimenti entrerebbero come in una cascata. Invece qui si gestisce anche la coincidenza temporale, ovvero AP deve arrivare quando non ce CDI, altrimenti il sistema non funziona efficientemente.
#### Ristagno Ca2+
Il ristagno di Ca2+ e dovuto:
- Alla mancanza di ATP che non permette leliminazione tramite le pompe
- La alta frequenza di spike che non permette anche in presenza di ATP di eliminare CA2+
#### Eliminazione Ca2+
ATP is consumed continuously by three processes:
- the Na/K-ATPase pump that restores the membrane gradient after each spike (the largest cost, proportional to firing rate)
- the PMCA and SERCA pumps that clear Ca²⁺ from the cytosol
- the molecular machinery that docks and primes vesicles for release.
These costs accumulate in an ATP demand register that grows with every spike and every Ca²⁺ clearance event in the millisecond loop.
#### Permanenza di Ca2+ - Trace - medium/long period
Questo serve per il medio/lungo periodo
### Quantita di Rrp disponibile
### ATP disponibile
---
### PRESYNAPSE-BEH: Container
**Tubs:**
@@ -197,14 +32,11 @@ Questo serve per il medio/lungo periodo
- **CaTraces**: sono le tracce di permanenza della concentrazione di Ca2+. Servono alla modulazione (TUN)
- **eCB**: retrograde signal updates from postsynapsis (postsynaptic input)
---
```Gen
PRESYNAPSE
type: container
PRESYNAPSE-BEH
expansion:
- VGCC-PRE ( full: 10x, active: 5x, empty: 2x )
type: container
activity_scope: !DAY
tub_local:
- Ca2+ ( full: 60x, active: 30x, empty: 0x )
@@ -224,7 +56,7 @@ PRESYNAPSE
- AP_ctx ( contained_by: SOMA )
```
### AP_ctx: PRESYNAPSE
#### AP_ctx: PRESYNAPSE-BEH
Il rilascio di NT lo facciamo nel contesto di AP. Biologicamente dovrebbe avvenire solo in base alle concentrazioni, quindi anche al difuori degli AP.
@@ -242,11 +74,11 @@ NT empty. Qui siamo contestualizzati se Ca2+ full, il che dovrebbe significare i
In tutti i casi di NT
#### NTreleaseLow: ( active: 12x ) accumulator
##### NTreleaseLow: ( active: 12x ) accumulator
```Gen
NTreleaseLow: ( active: 12x ) # Low
type: accumulator
contained_by: PRESYNAPSE
contained_by: PRESYNAPSE-BEH
in_context: AP_ctx
hypothesis: ( Ca2+ mediumness ) AND ( Rrp mediumness ) AND NOT( ATP empty )
@@ -254,11 +86,11 @@ NTreleaseLow: ( active: 12x ) # Low
trace: None
```
#### NTreleaseMedium: ( active: 9x ) accumulatorv
##### NTreleaseMedium: ( active: 9x ) accumulatorv
```Gen
NTreleaseMedium: ( active: 9x ) # Medium
type: accumulator
contained_by: PRESYNAPSE
contained_by: PRESYNAPSE-BEH
in_context: AP_ctx
hypothesis: (( Ca2+ fullness ) AND ( Rrp mediumness ) OR
@@ -268,11 +100,11 @@ NTreleaseMedium: ( active: 9x ) # Medium
trace: None
```
#### NTreleaseHigh: ( active: 3x ) accumulator
##### NTreleaseHigh: ( active: 3x ) accumulator
```Gen
NTreleaseHigh: ( active: 3x ) # High
type: accumulator
contained_by: PRESYNAPSE
contained_by: PRESYNAPSE-BEH
in_context: AP_ctx
hypothesis: ( Ca2+ fullness ) AND ( Rrp fullness ) AND
@@ -281,7 +113,7 @@ NTreleaseHigh: ( active: 3x ) # High
trace: None
```
#### Ca2+TracesAccumulationLow: accumulator
##### Ca2+TracesAccumulationLow: accumulator
Serve a:
- fare il tuning dei VGCC
@@ -294,11 +126,11 @@ Serve a:
---
#### Ca2+TracesAccumulationLow: ( active: 10x ) accumulator
##### Ca2+TracesAccumulationLow: ( active: 10x ) accumulator
```Gen
Ca2+TracesAccumulationLow: ( active: 10x )
type: accumulator
contained_by: PRESYNAPSE
contained_by: PRESYNAPSE-BEH
in_context: AP_ctx
hypothesis: (Ca2+ emptiness)
@@ -306,11 +138,11 @@ Ca2+TracesAccumulationLow: ( active: 10x )
trace: None
```
#### Ca2+TracesAccumulationMedium: ( active: 6x ) accumulator
##### Ca2+TracesAccumulationMedium: ( active: 6x ) accumulator
```Gen
Ca2+TracesAccumulationMedium: ( active: 6x ) # medium
type: accumulator
contained_by: PRESYNAPSE
contained_by: PRESYNAPSE-BEH
in_context: AP_ctx
hypothesis: (Ca2+ mediumness)
@@ -318,11 +150,11 @@ Ca2+TracesAccumulationMedium: ( active: 6x ) # medium
trace: None
```
#### Ca2+TracesAccumulationHigh: ( active: 10x ) accumulator
##### Ca2+TracesAccumulationHigh: ( active: 10x ) accumulator
```Gen
Ca2+TracesAccumulationHigh: ( active: 10x ) # high
type: accumulator
contained_by: PRESYNAPSE
contained_by: PRESYNAPSE-BEH
in_context: AP_ctx
hypothesis: (Ca2+ fullness)
@@ -330,19 +162,19 @@ Ca2+TracesAccumulationHigh: ( active: 10x ) # high
trace: None
```
### NOT AP_ctx: PRESYNAPSE
#### NOT AP_ctx: PRESYNAPSE-BEH
#### eCB clearance: accumulator
##### eCB clearance: accumulator
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.
#### eCBClearance: ( active: 24x ) accumulator
##### eCBClearance: ( active: 24x ) accumulator
```Gen
eCBClearance: ( active: 24x ) # Slow
type: accumulator
contained_by: PRESYNAPSE
contained_by: PRESYNAPSE-BEH
in_context: NOT AP_ctx
hypothesis: NOT (eCB empty)
@@ -350,7 +182,7 @@ eCBClearance: ( active: 24x ) # Slow
trace: None
```
#### RPShuttleLow: ( active: 48x ) accumulator
##### RPShuttleLow: ( active: 48x ) accumulator
This happens in the seconds loop, once per second.
@@ -361,7 +193,7 @@ Rate: 0.00 0.25
```Gen
RPShuttleLow: ( active: 48x ) # Low
type: accumulator
contained_by: PRESYNAPSE
contained_by: PRESYNAPSE-BEH
in_context: NOT AP_ctx
hypothesis: (CaTraceLow fullness) OR
@@ -371,7 +203,7 @@ RPShuttleLow: ( active: 48x ) # Low
trace: None
```
#### RPShuttleMedium: ( active: 24x ) accumulator
##### RPShuttleMedium: ( active: 24x ) accumulator
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.
@@ -380,7 +212,7 @@ Rate: 0.50 0.97
```Gen
RPShuttleMedium: ( active: 24x ) # Medium
type: accumulator
contained_by: PRESYNAPSE
contained_by: PRESYNAPSE-BEH
in_context: AP_ctx
hypothesis: (CaTraceMedium fullness) AND (RP mediumness) AND (RRP mediumness) OR
@@ -391,7 +223,7 @@ RPShuttleMedium: ( active: 24x ) # Medium
trace: None
```
#### RPShuttleHigh: ( active: 12x ) accumulator
##### RPShuttleHigh: ( active: 12x ) accumulator
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.
@@ -400,7 +232,7 @@ Rate: 1.25 1.94
```Gen
RPShuttleHigh: ( active: 12x ) # Fast
type: accumulator
contained_by: PRESYNAPSE
contained_by: PRESYNAPSE-BEH
in_context: AP_ctx
hypothesis: (CaTraceHigh fullness) AND (RP fullness) AND (RRP mediumness) OR # signal + supply
@@ -410,7 +242,7 @@ RPShuttleHigh: ( active: 12x ) # Fast
trace: None
```
#### RefillRPGlutamine: accumulator
##### RefillRPGlutamine: accumulator
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.
@@ -440,9 +272,7 @@ Gln — depletes over bursts, refilled by glucose (slowest, astrocyte-depend
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.
### TunPossible_ctx: PRESYNAPSE
#### Ca2+TracesClearance: ( active: 30x ) accumulator
##### Ca2+TracesClearance: ( active: 30x ) accumulator
Qui facciamo un flush di CaTraceX. Deve essere fatto a valle del tuning.
@@ -465,13 +295,92 @@ Ca2+TracesClearance: ( active: 30x ) # Slow
trace: None
```
## VGCC-PRE: Container
### VGCC-PRE-TUN: Container
```Gen
VGCC-PRE-TUN
# qui stiamo aggiungendo o eliminando VGCC-PRE. Fra un massimo full e minimo empty (empty puo' non essere 0)
# contained_by: PRESYNAPSE non e' contenuto, si attacca.
type: container
activity_scope: !DAY
tunes: PRESYNAPSE/expansion/VCGG-PRE
tub_modulation:
- VCGG-PRE
context_intricated:
- TunPossible_ctx ( contained_by: DAY-N )
tub_local:
tub_intricated:
```
#### TunPossible_ctx: VGCC-PRE-TUN
##### CheckVgccPreTun: ( active: 60x ) contexting
Qui controlliamo che ci siano le condizioni per aumentare o diminuire la quantita' di VGCC
```Gen
CheckVgccPreTun: ( active: 60x )
type: contexting
contained_by: VGCC-PRE-TUN
in_context: TunPossible_ctx
condition: ( CaTraceHigh fullness )
out_context: TryTunUpPreVcgg_ctx
condition: ( CaTraceLow fullness )
out_context: TryTunDownPreVcgg_ctx
```
##### PossibleUpPreVgccTun: ( active: 10x ) accumulator
```Gen
PossibleUpPreVgccTun: ( active: 10x )
type: accumulator
contained_by: VGCC-PRE-TUN
in_context: TryTunUpPreVcgg_ctx
hypothesis:
action:
trace:
```
##### PossibleDownPreVgccTun: ( active: 10x ) accumulator
```Gen
PossibleDownPreVgccTun: ( active: 10x )
type: accumulator
contained_by: VGCC-PRE-TUN
in_context: TryTunDownPreVcgg_ctx
hypothesis:
action:
trace:
```
## VGCC-PRE: Comprehension
Voltage-Controlled Gated Channels: Qui per ora non gestiamo l'evoluzione della depolarizzazione. Alla scomparsa dell'AP, i VGCC smettono di funzionare.
```Gen
VGCC-PRE
type: comprehension
expansion:
@: VGCC-PRE-BEH []
```
### VGCC-PRE-BEH: Container
Voltage-Controlled Gated Channels: Qui per ora non gestiamo l'evoluzione della depolarizzazione. Alla scomparsa dell'AP, i VGCC smettono di funzionare.
```Gen
VGCC-PRE-PRE
type: container
activity_scope: !DAY
tub_intricated:
- Ca2+ ( contained_by: PRESYNAPSE )
@@ -481,7 +390,7 @@ VGCC-PRE
- AP ( contained_by: SOMA )
```
### AP_ctx: VGCC-PRE
#### AP_ctx: VGCC-PRE-BEH
Da rivedere le condizioni per aggiungere mGluR che ha come proxy NT concentration!!!!!
@@ -503,11 +412,11 @@ Qui semplifichiamo:
Devo controllare che le condizioni sotto siano esaustive. Qui ho confuso high con low, e inoltre ho messo NT per mGluR che devo controllare che abbia senso.
#### Ca2+enterLow: ( active: 12x ) accumulator
##### Ca2+enterLow: ( active: 12x ) accumulator
```Gen
Ca2+enterLow: ( active: 12x ) # Low
type: accumulator
contained_by: VGCC-PRE
contained_by: VGCC-PRE-BEH
in_context: AP_ctx
hypothesis: (Ca2+ empty) AND (eCB empty)
@@ -515,11 +424,11 @@ Ca2+enterLow: ( active: 12x ) # Low
trace: None
```
#### Ca2+enterMedium: ( active: 6x ) accumulator
##### Ca2+enterMedium: ( active: 6x ) accumulator
```Gen
Ca2+enterMedium: ( active: 6x ) # Medium
type: accumulator
contained_by: VGCC-PRE
contained_by: VGCC-PRE-BEH
in_context: AP_ctx
hypothesis: (Ca2+ mediumness) OR
@@ -529,11 +438,11 @@ Ca2+enterMedium: ( active: 6x ) # Medium
trace: None
```
#### Ca2+enterHigh: ( active: 3x ) accumulator
##### Ca2+enterHigh: ( active: 3x ) accumulator
```Gen
Ca2+enterHigh: ( active: 3x ) # High
type: accumulator
contained_by: VGCC-PRE
contained_by: VGCC-PRE-BEH
in_context: AP_ctx
hypothesis: (Ca2+ mediumness) AND (eCB full) OR
@@ -542,7 +451,7 @@ Ca2+enterHigh: ( active: 3x ) # High
trace: None
```
### NOT AP_ctx: VGCC-PRE
#### NOT AP_ctx: VGCC-PRE-BEH
Qui eliminiamo Ca2+. Il tempo che ci mette ad eliminare il Ca2+ dovrebbe essere minoe dell'inervallo fra un AP_ctx e un'altra. Siccome non comprendiamo per ora ATP, non c'e' accumulo di Ca2+ per mancanza di ATP (stanchezza).
@@ -556,11 +465,11 @@ Qui disinguiamo:
- NOT ca2+ fullness che svuota piu' lentamente
- da capire se serve veramente questa distinzione per il tempo di svuotamento.
#### Ca2+ClearanceLow: ( active: 24x ) accumulator
##### Ca2+ClearanceLow: ( active: 24x ) accumulator
```Gen
Ca2+ClearanceLow: ( active: 24x ) # Low
type: accumulator
contained_by: PRESYNAPSE
contained_by: VGCC-PRE-BEH
in_context: NOT AP_ctx
hypothesis: (NOT Ca2+ fullness) AND (NOT Ca2+ empty)
@@ -568,11 +477,11 @@ Ca2+ClearanceLow: ( active: 24x ) # Low
trace: None
```
#### Ca2+ClearanceHigh: ( active: 4x ) accumulator
##### Ca2+ClearanceHigh: ( active: 4x ) accumulator
```Gen
Ca2+ClearanceHigh: ( active: 4x ) # High
type: accumulator
contained_by: PRESYNAPSE
contained_by: VGCC-PRE-BEH
in_context: NOT AP_ctx
hypothesis: NOT (Ca2+ empty)
@@ -580,65 +489,3 @@ Ca2+ClearanceHigh: ( active: 4x ) # High
trace: None
```
## VGCC-PRE-TUN: Tuner
```Gen
VGCC-PRE-TUN
type: tuner
# qui stiamo aggiungendo o eliminando VGCC-PRE. Fra un massimo full e minimo empty (empty puo' non essere 0)
# contained_by: PRESYNAPSE non e' contenuto, si attacca.
tunes: PRESYNAPSE/expansion/VCGG-PRE
tub_modulation:
- VCGG-PRE
context_intricated:
- TunPossible_ctx ( contained_by: DAY-N )
tub_local:
tub_intricated:
```
### TunPossible_ctx: ( active: 60x ) VGCC-PRE-TUN
#### CheckVgccPreTun: contexting
Qui controlliamo che ci siano le condizioni per aumentare o diminuire la quantita' di VGCC
```Gen
CheckVgccPreTun: ( active: 60x )
type: contexting
contained_by: VGCC-PRE-TUN
in_context: TunPossible_ctx
condition: ( CaTraceHigh fullness )
out_context: TryTunUpPreVcgg_ctx
condition: ( CaTraceLow fullness )
out_context: TryTunDownPreVcgg_ctx
```
#### PossibleUpPreVgccTun: ( active: 10x ) accumulator
```Gen
PossibleUpPreVgccTun: ( active: 10x )
type: accumulator
contained_by: VGCC-PRE-TUN
in_context: TryTunUpPreVcgg_ctx
hypothesis:
action:
trace:
```
#### PossibleDownPreVgccTun: ( active: 10x ) accumulator
```Gen
PossibleDownPreVgccTun: ( active: 10x )
type: accumulator
contained_by: VGCC-PRE-TUN
in_context: TryTunDownPreVcgg_ctx
hypothesis:
action:
trace:
```