--- include_toc: true --- // presynapse.md # PRESYNAPSE Expansions and modulations: - is expanded and developed by: [AXON](axon.md) - is tuned by: [ORGANISM](../../organism.md), organs, modules - expands and tunes: [PRE_VGG](pre_vgcc.md) - develops _Ca2, _Rrp ```Gen include: pre_vgcc.md PRESYNAPSE type: comprehension // Instantion and Expansion PRE_VGCC, il tub _@pre_vgcc serve al tuning _@pre_vgcc: INSTANTIATE [ tub: EXPAND [ comprehension: PRE_VGCC ], full: 10x, active: 5x, empty: 2x ] // Intrication // Scope !DAY: INTRICATE [ scope: &ORGANISM.!DAY ] !NIGHT: INTRICATE [ scope: &ORGANISM.!NIGHT ] // Context *AP: INTRICATE [ context: &SOMA.*AP ] *TunPossible: INTRICATE [ context: &NEURON.*TunPossible ] // Tub _NT: INTRICATE [ tub: &ASTROSYNAPSE._NT ] _ATP: INTRICATE [ tub: &ASTROCYTE._ATP ] _eCB: INTRICATE [ tub: &POSTSYNAPSE._eCB ] // Instantiation // Context *VcggIncrease: INSTANTIATE [ context: local ] *VcggDecrease: INSTANTIATE [ context: local ] *Ca2PrePreActiveDecrease: INSTANTIATE [ context: local ] *Ca2PreActiveDecrease: INSTANTIATE [ context: local ] *RrpPreActiveDecrease: INSTANTIATE [ context: local ] *RrpPreActiveDecrease: INSTANTIATE [ context: local ] // Tub _Ca2: INSTANTIATE [ tub: local, full: 60x, act: 30x, empty: 0x ] _Rrp: INSTANTIATE [ tub: local, full: 60x, act: 30x, empty: 0x ] _Rp: INSTANTIATE [ tub: local, full: 60x, act: 30x, empty: 0x ] _CaTracesHigh: INSTANTIATE [ tub: local, full: 60x, act: 30x, empty: 0x ] _CaTracesMedium: INSTANTIATE [ tub: local, full: 60x, act: 30x, empty: 0x ] _CaTracesLow: INSTANTIATE [ tub: local, full: 60x, act: 30x, empty: 0x ] _Ca2FullDev: INSTANTIATE [ tub: local, full: 60x, act: 30x, empty: 0x ] _RrpFullDev: INSTANTIATE [ tub: local, full: 60x, act: 30x, empty: 0x ] // serve al DEV // Container $: INSTANTIATE [ container: MAIN ] $: INSTANTIATE [ container: TRACE ] $: INSTANTIATE [ container: DECAY ] $: INSTANTIATE [ container: RECOVER ] $: INSTANTIATE [ container: ADJUST ] // Tuning $: INSTANTIATE [ container: DEVELOP ] // !NIGHT ``` ## MAIN | !DAY ```Gen MAIN type: container within_scope: !DAY // snippet: *AP @: INCLUDE [ accumulator: NTreleaseLow, event: act 12x, cost: act 3x ] @: INCLUDE [ accumulator: NTreleaseMedium, event: act 9x, cost: act 3x ] @: INCLUDE [ accumulator: NTreleaseHigh, event: act 6x, cost: act 3x ] ``` #### *AP ##### NTreleaseLow ```Gen NTreleaseLow type: accumulator in_context: *AP hypothesis: _Ca2 mediumness AND _Rrp mediumness AND NOT _ATP empty action: [ _Rrp decrease, _NT increase, _ATP decrease ] trace: None ``` ##### NTreleaseMedium ```Gen NTreleaseMedium type: accumulator in_context: *AP hypothesis: ( _Ca2 fullness AND _Rrp mediumness ) OR ( _Ca2 mediumness AND _Rrp fullness ) AND NOT _ATP empty action: [ _Rrp decrease, _NT increase, _ATP decrease ] trace: None ``` ##### NTreleaseHigh ```Gen NTreleaseHigh type: accumulator in_context: *AP hypothesis: _Ca2 fullness AND _Rrp fullness AND NOT _ATP empty action: [ _Rrp decrease, NT increase, _ATP decrease ] trace: None ``` ## TRACE | !DAY ```Gen TRACE type: container within_scope: !DAY // snippet: *AP @: INCLUDE [ accumulator: TracesAccLow, event: act 3x, cost: act 3x ] @: INCLUDE [ accumulator: TracesAccMedium, event: act 6x, cost: act 3x ] @: INCLUDE [ accumulator: TracesAccHigh, event: act 10x, cost: act 3x ] ``` #### *AP ```Gen Ca2TracesAccuLow type: accumulator in_context: *AP hypothesis: _Ca2 emptiness action: [ _CaTraceLow increase ] trace: None ``` ##### Ca2TracesAccMedium ```Gen Ca2TracesAccMedium type: accumulator in_context: *AP hypothesis: _Ca2 mediumness action: [ _CaTraceMed increase ] trace: None ``` ##### Ca2TracesAccHigh ```Gen Ca2TracesAccumulationHigh type: accumulator in_context: *AP hypothesis: _Ca2 fullness action: [ _CaTraceHigh increase ] trace: None ``` ## DECAY | !DAY ```Gen MAIN type: container within_scope: !DAY // snippet: NOT *AP @: INCLUDE [ accumulator: eCBClearenceMedium, event: act 24x, cost: act 3x ] @: INCLUDE [ accumulator: eCBClearenceLow, event: act 48x, cost: act 3x ] @: INCLUDE [ accumulator: TracesClearance, event: act 30x, cost: act 3x ] ``` #### NOT *AP ##### eCBClearance 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 event di questo episodio. ```Gen eCBClearance: ( act: 24x ) # Slow type: accumulator in_context: NOT *AP hypothesis: NOT _eCB empty action: [ _eCB decrease ] trace: None ``` ##### Ca2TracesClearance Qui facciamo un flush di CaTraceX. Deve essere fatto a valle del tuning. ```Gen Ca2TracesClearance type: accumulator in_context: NOT *TunPossible hypothesis: NOT _CaTraceHigh empty action: [ _CaTRaceHigh decrease ] trace: None hypothesis: NOT _CaTraceMedium empty action: [ _CaTRaceMedium decrease ] trace: None hypothesis: NOT _CaTraceLow empty action: [ _CaTRaceLow decrease ] trace: None ``` ## RECOVER | !DAY ```Gen RECOVER type: container within_scope: !DAY // snippet: NOT *AP @: INCLUDE [ accumulator: RPShuttleLow, event: act 24x, cost: act 3x ] @: INCLUDE [ accumulator: RPShuttleMedium, event: act 48x, cost: act 3x ] @: INCLUDE [ accumulator: RefillGlutamine, event: act 24x, cost: act 3x ] ``` #### NOT *AP ##### RPShuttleLow This happens in the seconds loop, once per second. 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 ```Gen RPShuttleLow type: accumulator in_context: NOT *AP hypothesis: _CaTraceLow fullness OR _RP emptiness OR _Rrp fullness action: [ _RP decrease, _Rrp increase ] trace: None ``` ##### RPShuttleMedium 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 ```Gen RPShuttleMedium type: accumulator in_context: *AP hypothesis: ( _CaTraceMedium fullness AND _RP mediumness AND _Rrp mediumness ) OR ( _CaTraceHigh fullness AND _RP mediumness AND _Rrp mediumness ) OR # signal boost ( _CaTraceMedium fullness AND _RP fullness AND _Rrp mediumness ) OR # supply boost ( _CaTraceMedium fullness AND _RP mediumness AND _Rrp emptiness ) # vacancy boost action: [ _RP decrease, _Rrp increase ] trace: None ``` ##### RPShuttleHigh 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 ```Gen RPShuttleHigh type: accumulator in_context: *AP hypothesis: ( _CaTraceHigh fullness AND _RP fullness AND _Rrp mediumness ) OR # signal + supply ( _CaTraceHigh fullness AND _RP mediumness AND _Rrp emptiness ) OR # signal + vacancy ( _CaTraceMedium fullness AND _RP fullness AND _Rrp emptiness ) # supply + vacancy action: [ _RP decrease, _Rrp increase ] trace: None ``` ##### RefillRPGlutamine 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. ## ADJUST | !DAY ```Gen ADJUST // qui stiamo attivando e disattivando PRE_VGCC. Fra un massimo full e minimo empty (empty puo' non essere 0) type: container activity_scope: !DAY // snippet: *TunPossible @: INCLUDE [ contextor: VgccCheck, event: act 60x ] // *VcggIncrease @: INCLUDE [ accumulator: VcggIncrease, event:act 10x ] // *VcggDecrease @: INCLUDE [ accumulator: VcggDecrease, event:act 10x ] ``` #### *TunPossible ##### VgccCheck Qui controlliamo che ci siano le condizioni per aumentare o diminuire l'attivazione di VGCC ```Gen VgccCheck type contextor in_context: *TunPossible condition: _CaTraceHigh fullness out_context: *VcggIncrease condition: _CaTraceLow fullness out_context: *VcggDecrease ``` #### *VcggIncrease ##### VcggIncrease ```Gen VcggIncrease type: accumulator in_context: *VcggIncrease hypothesis: action: trace: ``` #### *VcggDecrease ##### VcggDecrease ```Gen VcggDecrease type: accumulator in_context: *VcggDecrease hypothesis: action: trace: ``` ## DEVELOP | !NIGHT ```Gen DEVELOP type: container activity_scope: !NIGHT // snippet: *fixed @: INCLUDE [ contextor: Ca2Check, event: act 60x ] // snippet: *CaFullDecrease @: INCLUDE [ accumulator: CaFullDecrease, event: act 12x, cost: act 3x ] // snippet: *Ca2FullIncrease @: INCLUDE [ accumulator: Ca2FullIncrease, event: act 12x, cost: act 3x ] @: INCLUDE [ contextor: RrpCheck, event: act 60x ] // snippet: *RrpFullDecrease @: INCLUDE [ accumulator: RrpFullDecrease, event: act 12x, cost: act 3x ] // snippet: *IncreaseRrpFull @: INCLUDE [ accumulator: IncreaseRrpFull, event: act 12x, cost: act 3x ] ``` #### *fixed ##### Ca2Check ***Tens Milliseconds Time Scale*** ```Gen Ca2Check type: contextor in_context: *fixed condition: ( empty ) out_context: *CaFullDecrease condition: ( full) out_context: *Ca2FullIncrease ``` ##### *CaFullDecrease ###### CaFullDecrease ```Gen DecreasePreCa2Full type: accumulator in_context: *CaFullDecrease hypothesis: NOT ( full ) AND NOT ( empty ) action: [ increase, decrease] trace: None ``` ##### *Ca2FullIncrease ###### Ca2FullIncrease ```Gen IncreasePreCa2Full type: accumulator in_context: *Ca2FullIncrease hypothesis: NOT ( full ) AND NOT ( empty ) action: [ increase, decrease] trace: None ``` #### *fixed ##### RrpCheck ***Tens Milliseconds Time Scale*** ```Gen RrpCheck type: contextor in_context: *fixed condition: ( empty ) out_context: *RrpFullDecrease condition: ( full) out_context: *IncreaseRrpFull ``` ##### *RrpFullDecrease ###### RrpFullDecrease ```Gen DecreasePreRrpFull type: accumulator in_context: *RrpFullDecrease hypothesis: NOT ( full ) AND NOT ( empty ) action: [ increase, decrease] trace: None ``` ##### *RrpFullIncrease ###### RrpFullIncrease ```Gen RrpFullIncrease type: accumulator in_context: *RrpFullIncrease hypothesis: NOT ( full ) AND NOT ( empty ) action: [ increase, decrease] trace: None ```