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@@ -23,6 +23,8 @@ container: BEH-AXO
## BEH-PRE: Container ## BEH-PRE: Container
**Discursive description**:
The presynapse is the sending terminal of a neuron — a small bulb at the tip of an axon whose job is to release chemical signals, called neurotransmitters (NT), into the synaptic cleft, the narrow gap that separates it from the receiving neuron's postsynapse. The presynapse is the sending terminal of a neuron — a small bulb at the tip of an axon whose job is to release chemical signals, called neurotransmitters (NT), into the synaptic cleft, the narrow gap that separates it from the receiving neuron's postsynapse.
To do this, the presynapse maintains a stockpile of NT packed inside small membrane bubbles called vesicles. These vesicles are organised in two pools: a reserve pool (RP), which is the deep storage, and a readily-releasable pool (RRP), which is the small set of vesicles docked at the membrane and ready to fire immediately. When a spike arrives — an electrical pulse called an action potential — it briefly opens specialised calcium channels (VGCCs) in the membrane. Calcium (Ca²⁺) rushes in, and the sudden local surge of calcium triggers the docked vesicles to fuse with the membrane and pour their NT into the cleft. To do this, the presynapse maintains a stockpile of NT packed inside small membrane bubbles called vesicles. These vesicles are organised in two pools: a reserve pool (RP), which is the deep storage, and a readily-releasable pool (RRP), which is the small set of vesicles docked at the membrane and ready to fire immediately. When a spike arrives — an electrical pulse called an action potential — it briefly opens specialised calcium channels (VGCCs) in the membrane. Calcium (Ca²⁺) rushes in, and the sudden local surge of calcium triggers the docked vesicles to fuse with the membrane and pour their NT into the cleft.
@@ -74,24 +76,22 @@ The astrocyte is also the gateway to the energy supply. All of the active proces
- conversion_efficiency gates glutamine shuttle throughput - conversion_efficiency gates glutamine shuttle throughput
- Glutamine shuttle refills N_RP from astrocyte store - Glutamine shuttle refills N_RP from astrocyte store
**Semplified comprehension**: **Semplified behaviors**:
In this first comprehension, we decide to simplify: In this comprehension, we decide to simplify:
- The VCGG are active while the AP is active, we do not comprehend the decay - The VCGG are active while the AP is active, we do not comprehend the decay
- We do not comprehend the ATP - We do not comprehend the ATP
- We do not comprehend CDI, we check just for Ca2+ concentration - We do not comprehend CDI, we check just for Ca2+ concentration
- We do not comprehend mGlur, we check for the concentration of NT in the cleft - We do not comprehend mGlur, we check for the concentration of NT in the cleft
- We do not comprehend Ca2+ buffering - We do not comprehend Ca2+ buffering
- We do not comprehend SERCA, we comprehend Ca2+ clearing as a slow process - We do not comprehend PMCA, NCX, and SERCA, we comprehend Ca2+ clearing as a slow process
- We do not comprehend vesicles, we comprehend them as processes releasing NT, fast, medium and slow based on conditions - We do not comprehend vesicles, we comprehend them as processes releasing NT, fast, medium and slow based on conditions
The simplification impies that: The simplification impies that:
- Removing CDI and mGluR means Ca²⁺ concentration and NT in the cleft are now the only two conditions controlling release rate. - Removing CDI and mGluR means Ca²⁺ concentration and NT in the cleft are now the only two conditions controlling release rate.
- Removing ATP removes the metabolic silencing cascade entirely. The mins behavior now only does one thing: replenish the NT reserve. If we want the synapse to still be able to fail under sustained firing, the mechanism would have to come from NT depletion alone (RP exhausted, nothing to replenish) rather than from pump failure and Ca²⁺ accumulation.
- Removing ATP removes the metabolic silencing cascade entirely. The mins loop now only does one thing: replenish the NT reserve. If we want the synapse to still be able to fail under sustained firing, the mechanism would have to come from NT depletion alone (RP exhausted, nothing to replenish) rather than from pump failure and Ca²⁺ accumulation.
- "Ca²⁺ cleared slowly" replaces PMCA, NCX, and SERCA with a single exponential decay. This means Ca²⁺ will still accumulate under high firing if the decay is slow relative to the spike rate, which preserves some of the residual-Ca²⁺ dynamic even without the full pump machinery. - "Ca²⁺ cleared slowly" replaces PMCA, NCX, and SERCA with a single exponential decay. This means Ca²⁺ will still accumulate under high firing if the decay is slow relative to the spike rate, which preserves some of the residual-Ca²⁺ dynamic even without the full pump machinery.
**Simplified Behaviors**: **Simplified Behaviors**:
@@ -102,22 +102,16 @@ The simplification impies that:
- Ca²⁺ cleared slowly (single decay term, no pump detail) - Ca²⁺ cleared slowly (single decay term, no pump detail)
- Ca²⁺ trace (Tr_Ca) integrates every ms - Ca²⁺ trace (Tr_Ca) integrates every ms
- NT released into cleft — rate determined by Ca²⁺ level and NT already in cleft - NT released into cleft — rate determined by Ca²⁺ level and NT already in cleft
- fast release when Ca²⁺ high, NT_cleft low - NT released accumulates (feeds sec behavior)
- medium release when Ca²⁺ medium, or NT_cleft medium
- slow release when Ca²⁺ low, or NT_cleft high
- NT added to cleft
- NT_released_this_window accumulates (feeds seconds loop)
- NT passively diffuses out of cleft - NT passively diffuses out of cleft
**— seconds:** **— seconds:**
- Astrocyte EAATs clear 30% of remaining NT_cleft - Astrocyte EAATs clear 30% of remaining NT in the cleft
- IP3 integrates NT_released_this_window (cumulative burst load) - eCB retrograde signal updates from postsynapsis (postsynaptic input)
- If IP3 exceeds threshold → astrocyte Ca²⁺ wave triggered - eCB suppresses NT release (feeds back into ms behavior release rate)
- eCB retrograde signal updates from V_post history (postsynaptic input)
- eCB suppresses NT release (feeds back into ms loop release rate)
- RP → RRP recruitment runs (rate gated by Tr_Ca) - RP → RRP recruitment runs (rate gated by Tr_Ca)
- NT_released_this_window resets to zero - NT released in sec resets to zero
**— mins:** **— mins:**
@@ -129,17 +123,12 @@ The simplification impies that:
**Tubs:** **Tubs:**
- **Ca2+**: Calcium Ion entering the Presynapse when VCGG open that influence NT release. Normally returns to ~0 between spikes; stays elevated when pumps fail. They are key to check the concentration, release vescicles and modulation - **Ca2+**: Calcium Ion entering the Presynapse when VCGG open that influence NT release. Normally returns to ~0 between spikes; stays elevated when pumps fail. They are key to check the concentration, release NT 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. - **Rrp**: Readily Releasable Pool: The Readily Releasable Pool consists of the vesicles that are "docked" and "primed" at the active zone of the synapse. 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. Here we consider them as NT ready to be released.
-- Location: Directly touching the presynaptic membrane. - **Rp**: Reserve Pool: The bulk of the vesicles held further back in the terminal, often tethered by a protein called synapsin. These are only mobilized during intense, prolonged stimulation. This makes up the vast majority of the vesicles (up to 80% or 90%). Here we consider them NT in reserve that can be transfered to RRP and created using Glutamine from Astorcyte.
-- Function: These are the first to be released when an action potential arrives. - **NT**: Neuro Transmitter, released in the synapse by the vescicles. The release increses NT and decreases RRP
-- 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.
- **Rp**: 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.
-- 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) - **CaTraces**: sono le tracce di permanenza della concentrazione di Ca2+. Servono alla modulazione (TUN)
- **eCB**: retrograde signal updates from postsynapsis (postsynaptic input)
```Gen ```Gen
container: BEH-PRE container: BEH-PRE
@@ -159,11 +148,9 @@ container: BEH-PRE
- CaTraces ( fullness: 50x, active: 0x, emptiness: 0x ) - CaTraces ( fullness: 50x, active: 0x, emptiness: 0x )
- mGluR ( fullness: 50x, active: 0x, emptiness: 0x )
tub_intricated: tub_intricated:
- NT # SYN - NT # SYN
- ATP # AXO? - ATP? #
- eCB # from POST - eCB # from POST
context_intricated: context_intricated:
@@ -211,8 +198,6 @@ context: Ca2+Concentration
Ci sono 4 casi che dipendono da RRP, Ca2+ 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 Ca2+ 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. Ci sono 4 casi che dipendono da RRP, Ca2+ 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 Ca2+ 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.
ATP cost of Na/K-ATPase recharge on each AP. The cost is per action potential. Here we charge it at every release of NT. This is the dominant ATP drain at high firing rates.
![nt-release.png](.attachments/nt-release.png) ![nt-release.png](.attachments/nt-release.png)
##### NTreleaseMaximum: Episode ##### NTreleaseMaximum: Episode
@@ -222,7 +207,7 @@ episode: NTreleaseMaximum
contained_by: BEH-PRE contained_by: BEH-PRE
in_context: (Ca2+Full AND RRPFull) in_context: (Ca2+Full AND RRPFull)
rf: ( active: 6x ) # Maximum rf: ( active: 3x ) # Maximum
hypothesis: (NT empty) hypothesis: (NT empty)
action: [Rrp decrease, Nt increase, ATP decrease] action: [Rrp decrease, Nt increase, ATP decrease]
@@ -250,7 +235,7 @@ episode: NTreleaseMedium
contained_by: BEH-PRE contained_by: BEH-PRE
in_context: (Ca2+Full AND RRPMedium) OR (Ca2+Medium AND RRPFull) in_context: (Ca2+Full AND RRPMedium) OR (Ca2+Medium AND RRPFull)
rf: ( active: 6x ) # Medium rf: ( active: 9x ) # Medium
hypothesis: (NT empty) OR NOT (NT empty) # In tutti i casi hypothesis: (NT empty) OR NOT (NT empty) # In tutti i casi
action: [Rrp decrease, Nt increase, ATP decrease] action: [Rrp decrease, Nt increase, ATP decrease]
@@ -264,7 +249,7 @@ episode: NTreleaseLow
contained_by: BEH-PRE contained_by: BEH-PRE
in_context: (Ca2+Medium AND RRPMedium) in_context: (Ca2+Medium AND RRPMedium)
rf: ( active: 6x ) # Low rf: ( active: 12x ) # Low
hypothesis: (NT empty) OR NOT (NT empty) # In tutti i casi hypothesis: (NT empty) OR NOT (NT empty) # In tutti i casi
action: [Rrp decrease, Nt increase, ATP decrease] action: [Rrp decrease, Nt increase, ATP decrease]
@@ -285,10 +270,6 @@ Quindi non comprendiamo anche il ristabilimento del Voltage, con altri Ioni entr
... ...
#### mGlur concentration
Limita rilascio NT: Dipende da quanti NT sono stati gia' rilasciati nella Syn
#### eCB concentration #### eCB concentration
Limita rilascio NT: Dipende da POST che tende a bloccare rialascio di NT se non servono Limita rilascio NT: Dipende da POST che tende a bloccare rialascio di NT se non servono
@@ -309,8 +290,7 @@ Dipende da Glutamine messa a disposizione dall'Astrocyte
## BEH-PRE-VGCC: Container ## BEH-PRE-VGCC: Container
**Voltage-Controlled Gated Channels**: Voltage-Controlled Gated Channels: Qui per ora non gestiamo l'evoluzione della depolarizzazione. Alla scomparsa dell'AP, i VGCC smettono di funzionare.
Qui per ora non gestiamo l'evoluzione della depolarizzazione. Alla scomparsa dell'AP, i VGCC smettono di funzionare.
```Gen ```Gen
container: BEH-PRE-VGCC container: BEH-PRE-VGCC
@@ -330,16 +310,18 @@ Here we comprehend the breaking activity on VGCC by: CDI,eCB and mGluR:
![breaking-cases.png](.attachments/breaking-cases.png) ![breaking-cases.png](.attachments/breaking-cases.png)
Qui sostituiamo:
- CDI con concentrazione Ca2+
-- CDI is calcium-dependent inactivation of VGCCs. The inactivation happens because Ca²⁺ enters through the channel and binds to a calmodulin tethered to the channel's intracellular face, physically blocking it from reopening. This is a local, channel-specific event — it requires Ca²⁺ to be flowing through that channel right now, not residual Ca²⁺ drifting in the cytosol between spikes.
-- The recovery, by contrast, should run every millisecond unconditionally — CDI de-inactivation is a continuous process that proceeds whenever Ca²⁺ dissociates from calmodulin, which depends on the ambient Ca_micro level at all times.
- mGluR con concentrazione NT (forse su tempi di sec e quindi avremmo bisono di un altro Tub)
- **Open** — zero active brakes. mGluR alone never escapes this group because its ceiling is alpha_mGluR = 0.4, meaning even at full it only removes 40% of conductance, leaving 60% — still above the 85% threshold. So mGluR is irrelevant to the open/not-open boundary. Only CDI and eCB decide. - **Open** — zero active brakes. mGluR alone never escapes this group because its ceiling is alpha_mGluR = 0.4, meaning even at full it only removes 40% of conductance, leaving 60% — still above the 85% threshold. So mGluR is irrelevant to the open/not-open boundary. Only CDI and eCB decide.
- **Reduced/partial** — exactly one meaningful brake active. Either CDI has started building (medium), or eCB has risen from sustained postsynaptic activity, but not both simultaneously. The system is aware something is happening but has not compounded yet. This is the normal operating range during moderate sustained firing. - **Reduced/partial** — exactly one meaningful brake active. Either CDI has started building (medium), or eCB has risen from sustained postsynaptic activity, but not both simultaneously. The system is aware something is happening but has not compounded yet. This is the normal operating range during moderate sustained firing.
- **Suppressed** — two brakes multiplying. The compounding is what defines this zone — no single variable alone produces it (except CDI approaching full). 0.5 × 0.5 = 0.25 remaining is where the synapse starts losing significant transmission efficacy. Biologically this is the pre-silence warning zone: CDI is building from residual Ca²⁺ while eCB is already engaged from postsynaptic activity. - **Suppressed** — two brakes multiplying. The compounding is what defines this zone — no single variable alone produces it (except CDI approaching full). 0.5 × 0.5 = 0.25 remaining is where the synapse starts losing significant transmission efficacy. Biologically this is the pre-silence warning zone: CDI is building from residual Ca²⁺ while eCB is already engaged from postsynaptic activity.
- **Closed — CDI** = full is the only reliable hard rule. Because CDI can reach 1.0 and appears as (1 - CDI_factor) in the formula, it alone drives conductance to zero regardless of eCB and mGluR state. The three-brake overlap corner case (eCB=full + CDI=medium + mGluR=full) also reaches here, but in practice CDI reaching full is the primary biological mechanism. - **Closed — CDI** = full is the only reliable hard rule. Because CDI can reach 1.0 and appears as (1 - CDI_factor) in the formula, it alone drives conductance to zero regardless of eCB and mGluR state. The three-brake overlap corner case (eCB=full + CDI=medium + mGluR=full) also reaches here, but in practice CDI reaching full is the primary biological mechanism.
Qui sostituiamo il CDI con Ca2+:
- CDI is calcium-dependent inactivation of VGCCs. The inactivation happens because Ca²⁺ enters through the channel and binds to a calmodulin tethered to the channel's intracellular face, physically blocking it from reopening. This is a local, channel-specific event — it requires Ca²⁺ to be flowing through that channel right now, not residual Ca²⁺ drifting in the cytosol between spikes.
- The recovery, by contrast, should run every millisecond unconditionally — CDI de-inactivation is a continuous process that proceeds whenever Ca²⁺ dissociates from calmodulin, which depends on the ambient Ca_micro level at all times.
Devo controllare che le condizioni sotto siano esaustive. Devo controllare che le condizioni sotto siano esaustive.
##### Open: Episode ##### Open: Episode