From b729ce524bcba3160c77d93933852e857ae74ff7 Mon Sep 17 00:00:00 2001 From: ocrampal Date: Sun, 31 May 2026 16:58:11 +0200 Subject: [PATCH] Update README.md --- elements/neuron/README.md | 268 ++++++++++++++------------------------ 1 file changed, 97 insertions(+), 171 deletions(-) diff --git a/elements/neuron/README.md b/elements/neuron/README.md index 521a70c..a19506c 100644 --- a/elements/neuron/README.md +++ b/elements/neuron/README.md @@ -4,9 +4,93 @@ include_toc: true # README.md -Qui mettiamo la descrizione del neurone. Infatti l'espressione G. non e' come un programma tradizionale che puo' essere letto e capito, essendo i comportamenti omomorfi rispetto al codice. In un'espressione G. i comportamenti sono locali in tempo e spazio (contestualizzazione). Non essendoci un flusso programmatico, il commento ai comportamenti locali, non e' sufficienti a spiegare i comportamenti che sara' possibile verificare in diversi ambiti. C'e' quindi bisogno di esprimere i flussi e le chiusure che in diversi ambiti abbiamo voluto esprimere, tramite espressioni locali. +## The neuron loops -## Containers +### The NT loop +is the supply chain of the synapse, operating across all three timescales. + +- On the millisecond scale, action potentials trigger Ca²⁺-driven release of NT from the RRP into the cleft. NT in the cleft feeds back on itself within the same millisecond — high cleft concentration suppresses further release, acting as a local brake. +- On the seconds scale, the astrocyte's EAATs actively clear NT from the cleft, and the accumulated clearance load drives the IP3 signal that tells the astrocyte how hard the synapse has been working. EEATs only captures 30% of NT?. The rest is dispersed. +- On the minutes scale, the astrocyte converts the captured glutamate into glutamine and ships it back to the presynapse, which repackages it into vesicles and restores the RP. The RP then feeds the RRP on the seconds scale via Ca²⁺-trace-gated recruitment. +- The loop closes when those recycled vesicles are released again at the next burst. +- The critical asymmetry is timescale: release takes milliseconds, full replenishment takes minutes. Sustained firing depletes faster than the loop can replenish. + +### The Ca²⁺ loop +is the timing and intensity controller of the synapse, operating entirely within the millisecond scale with a slow integration tail that reaches into seconds. + +- Ca²⁺ enters through VGCCs at every spike and immediately drives two things in parallel: + - vesicle release (the higher the Ca²⁺, the more vesicles fuse) + - the Tr_Ca trace integrator (which accumulates the recent Ca²⁺ history). +- Ca²⁺ is then cleared by a single slow decay term, returning toward baseline between spikes. +- The loop closes through Tr_Ca: a high trace — reflecting a recent burst — accelerates RP→RRP recruitment in the seconds loop, meaning that Ca²⁺ activity directly speeds up the resupply of the very vesicles that Ca²⁺ triggered. +- The Ca²⁺ loop is also where the eCB retrograde signal from the postsynapse intersects: sustained postsynaptic depolarisation generates eCB on the seconds scale, which travels back and suppresses VGCC opening at the next spike, reducing Ca²⁺ influx. This makes the Ca²⁺ loop the primary interface between the presynapse and the postsynapse — it is the channel through which the receiving neuron tells the sending terminal to ease off. + +### The ATP loop +(not included in the coprehension yet) is the metabolic backbone of the synapse, operating on the minutes scale but with consequences that reach back into every millisecond. + +- 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. +- The creation side of the loop runs on the minutes scale and is entirely astrocyte-dependent. The astrocyte delivers glucose from the bloodstream to both itself and the presynapse. Glucose enters glycolysis and the mitochondrial oxidative phosphorylation chain, producing ATP. The astrocyte also produces lactate as an intermediate, which it shuttles directly to the presynaptic terminal as an additional fuel source. The rate of ATP production is therefore set by glucose availability — the root input of the loop. +- The loop closes through Ca²⁺ clearance. If firing is sustained long enough that ATP demand outpaces glucose-driven production, ATP falls, the PMCA and SERCA pumps slow, and residual Ca²⁺ builds between spikes. This elevated residual Ca²⁺ suppresses CDI recovery, causing VGCCs to gradually lock shut and silencing the synapse. Silence stops consuming ATP, allowing the production side to catch up and ATP to recover. The ATP loop therefore has a natural self-resetting property: the same mechanism that causes silence also triggers recovery. +- The ATP loop intersects both other loops. It shares Ca²⁺ clearance with the Ca²⁺ loop — pump failure is what connects ATP depletion to VGCC inactivation. It shares the glutamine shuttle with the NT loop — when the astrocyte is energy-starved, conversion efficiency falls and RP replenishment slows, making vesicle depletion more severe and prolonged. ATP depletion is therefore the single point of failure that can cascade across all three loops simultaneously, which is why it is the mechanistic basis of excitotoxic protection. + +## The four pillars + +This framework describes a system that is not a static processor, but a living entity that balances high-speed pattern extraction based on expectations with allostatic balancing and physical transformation. + +### Pillar 1: The Electrical Pillar (The Integration Layer) + +- Function & Reason: Pattern Extraction. The neuron acts as a spatiotemporal filter. It integrates thousands of tiny inputs across its dendritic tree (space) and within narrow windows of time. Its "output" is a declaration that a specific relevant pattern has been recognized. +- Timescale: Milliseconds (ms). +- Behaviors: Summation of Excitatory/Inhibitory Post-Synaptic Potentials (EPSPs/IPSPs), the "Tug-of-War" at the soma, and the propagation of the "Success" signal (the Spike). +- Elements Involved: + \-- Ions: Na+ (The "Yes" current), K+ (The "No/Reset" current). + \-- Hardware: Dendritic tree (The Space), VGSC/VGKC (The Timers). + +### Pillar 2: The Metabolic Pillar (The Constraint Layer) + +* **Function & Reason:** Sustainability and Gradient Maintenance. This pillar provides the energy required for all other behaviors. It sets the "Hard Limit" on how much work the neuron can do. +* **Timescale:** **Seconds to Minutes.** +* **Behaviors:** Active transport of ions, ATP production, and "Metabolic Silencing" (shutting down to prevent death when energy is low). +* **Elements Involved:** + * **Molecules:** ATP, Glucose, Oxygen. + * **Hardware:** Na/K-ATPase Pump (the "Battery Recharger"), Mitochondria. + * **Constraint:** The $Na^+/K^+$ ratio. + +### Pillar 3: The Calcium Pillar (The Logic / Information Keeper) + +* **Function & Reason:** Adaptation and Translation. This pillar acts as the "sensor" that monitors electrical activity and translates it into chemical signals. It keeps the "history" of the cell's workload. +* **Timescale:** **Minutes to Hours.** +* **Behaviors:** **Homeostatic Scaling** (tuning the master volume), Synaptic Plasticity (LTP/LTD), and Gain Control. +* **Elements Involved:** + * **Ions:** Calcium ($Ca^{2+}$). + * **Hardware:** Somatic VGCCs (L-type), NMDA receptors. + * **Software:** Calmodulin, CaMKIV (signaling proteins that "count" the calcium). + +### Pillar 4: The Structural Pillar (The Renovation Layer) + +* **Function & Reason:** Physical Transformation. This pillar is the actual rebuilding of the "factory" to change the neuron's fundamental capabilities. It is the physical manifestation of long-term memory and health. +* **Timescale:** **Days to Weeks.** +* **Behaviors:** **Axon Initial Segment (AIS) translocation** (moving the trigger zone), dendritic branch growth/pruning, and changes in total channel/receptor count via gene expression. +* **Elements Involved:** + * **Structural Proteins:** Actin, Microtubules, Ankyrin-G (the "anchor"). + * **Genetics:** mRNA, Ribosomes, Transcription Factors (e.g., CREB). + +### What is Achieved by This Entity? + +By combining these four pillars, the neuron becomes a Non-Static Adaptive Engine: + +- Selective Attention: It doesn't just pass signals; it ignores noise and only "speaks" when its specific spatial and temporal requirements are met. +- Self-Regulating Sensitivity: If the patterns it is expecting become too frequent or too rare, the Calcium and Structural pillars adjust the Electrical hardware to find a new "sweet spot." +- Metabolic Wisdom: It balances the "desire" to extract patterns against the "cost" of ATP. It is an engine that tunes itself to be as efficient as possible. +- Hardware-Software Unity: Unlike a computer, where the software cannot change the CPU, the neuron's "software" (the activity patterns) physically rewrites its "hardware" (the pillars) every single day. + +This is the portrait of a system that isn't just "running a program"—it is a biological machine constantly sculpting itself to become a better filter for the world it perceives. + +## Comprehensions ### Axon @@ -34,35 +118,7 @@ The presynapse does not release blindly. Its behaviour is governed by three inte --- -**The NT loop** is the supply chain of the synapse, operating across all three timescales. - -- On the millisecond scale, action potentials trigger Ca²⁺-driven release of NT from the RRP into the cleft. NT in the cleft feeds back on itself within the same millisecond — high cleft concentration suppresses further release, acting as a local brake. -- On the seconds scale, the astrocyte's EAATs actively clear NT from the cleft, and the accumulated clearance load drives the IP3 signal that tells the astrocyte how hard the synapse has been working. EEATs only captures 30% of NT?. The rest is dispersed. -- On the minutes scale, the astrocyte converts the captured glutamate into glutamine and ships it back to the presynapse, which repackages it into vesicles and restores the RP. The RP then feeds the RRP on the seconds scale via Ca²⁺-trace-gated recruitment. -- The loop closes when those recycled vesicles are released again at the next burst. -- The critical asymmetry is timescale: release takes milliseconds, full replenishment takes minutes. Sustained firing depletes faster than the loop can replenish. - -**The Ca²⁺ loop** is the timing and intensity controller of the synapse, operating entirely within the millisecond scale with a slow integration tail that reaches into seconds. - -- Ca²⁺ enters through VGCCs at every spike and immediately drives two things in parallel: - - vesicle release (the higher the Ca²⁺, the more vesicles fuse) - - the Tr_Ca trace integrator (which accumulates the recent Ca²⁺ history). -- Ca²⁺ is then cleared by a single slow decay term, returning toward baseline between spikes. -- The loop closes through Tr_Ca: a high trace — reflecting a recent burst — accelerates RP→RRP recruitment in the seconds loop, meaning that Ca²⁺ activity directly speeds up the resupply of the very vesicles that Ca²⁺ triggered. -- The Ca²⁺ loop is also where the eCB retrograde signal from the postsynapse intersects: sustained postsynaptic depolarisation generates eCB on the seconds scale, which travels back and suppresses VGCC opening at the next spike, reducing Ca²⁺ influx. This makes the Ca²⁺ loop the primary interface between the presynapse and the postsynapse — it is the channel through which the receiving neuron tells the sending terminal to ease off. - -**The ATP loop** (not included in the coprehension yet) is the metabolic backbone of the synapse, operating on the minutes scale but with consequences that reach back into every millisecond. - -- 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. -- The creation side of the loop runs on the minutes scale and is entirely astrocyte-dependent. The astrocyte delivers glucose from the bloodstream to both itself and the presynapse. Glucose enters glycolysis and the mitochondrial oxidative phosphorylation chain, producing ATP. The astrocyte also produces lactate as an intermediate, which it shuttles directly to the presynaptic terminal as an additional fuel source. The rate of ATP production is therefore set by glucose availability — the root input of the loop. -- The loop closes through Ca²⁺ clearance. If firing is sustained long enough that ATP demand outpaces glucose-driven production, ATP falls, the PMCA and SERCA pumps slow, and residual Ca²⁺ builds between spikes. This elevated residual Ca²⁺ suppresses CDI recovery, causing VGCCs to gradually lock shut and silencing the synapse. Silence stops consuming ATP, allowing the production side to catch up and ATP to recover. The ATP loop therefore has a natural self-resetting property: the same mechanism that causes silence also triggers recovery. -- The ATP loop intersects both other loops. It shares Ca²⁺ clearance with the Ca²⁺ loop — pump failure is what connects ATP depletion to VGCC inactivation. It shares the glutamine shuttle with the NT loop — when the astrocyte is energy-starved, conversion efficiency falls and RP replenishment slows, making vesicle depletion more severe and prolonged. ATP depletion is therefore the single point of failure that can cascade across all three loops simultaneously, which is why it is the mechanistic basis of excitotoxic protection. - -**VGCC Tuning** +#### VGCC Tuning **Short, medium and long time scale** 1. The Short-Term Mechanism: Local CDI @@ -231,57 +287,7 @@ Qui riportiamo la struttura della espressione G e una descrizione di come legger - RPShuttle - RefillRPGlutamine (sec) -```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 - -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 -``` ---- ---- -## 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 l’accumulo 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 +#### Comportamenti uscita NT (Rrp) @@ -301,9 +307,9 @@ ingresso Rp tuning VGCC -## Condizioni +#### Condizioni -### Rilascio NT - comportamento +##### Rilascio NT - comportamento Il comportamento principale che assegniamo al container Presinspse e’ quello del rilascio di NT all’arrivo di AP_ctx dal SOMA. Il rilascio di NT all’arrivo di AP_ctx dal SOMA dipende da: @@ -311,11 +317,11 @@ Il comportamento principale che assegniamo al container Presinspse e’ quello d - Quantita’ di Rrp disponibile - ATP disponibile? -### Concentrazione di Ca2+ - condizione +##### Concentrazione di Ca2+ - condizione La concentrazione di Ca2+ dipende da: -#### Ingresso Ca2+ - comportamento +##### Ingresso Ca2+ - comportamento L’ingresso di Ca2+ avviene tramite i VGCC e dipende da: @@ -328,14 +334,14 @@ L’ingresso di Ca2+ avviene tramite i VGCC e dipende da: Ha un proprio refractory e dipende dalla concentrazione di Ca2+. Normalmente si attiva all’apertura dei VGCC, perche’ deve limitare l’ingresso di Ca2+, che altrimenti entrerebbero come in una cascata. Invece qui si gestisce anche la coincidenza temporale, ovvero AP deve arrivare quando non c’e’ CDI, altrimenti il sistema non funziona efficientemente. -#### Ristagno Ca2+ +##### Ristagno Ca2+ Il ristagno di Ca2+ e’ dovuto: - Alla mancanza di ATP che non permette l’eliminazione tramite le pompe - La alta frequenza di spike che non permette anche in presenza di ATP di eliminare CA2+ -#### Eliminazione Ca2+ +##### Eliminazione Ca2+ ATP is consumed continuously by three processes: @@ -345,13 +351,13 @@ ATP is consumed continuously by three processes: 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 +##### Permanenza di Ca2+ - Trace - medium/long period Questo serve per il medio/lungo periodo -### Quantita’ di Rrp disponibile +##### Quantita’ di Rrp disponibile -### ATP disponibile +##### ATP disponibile --- @@ -578,83 +584,3 @@ The simplification implies that: - Removing ATP removes the false eCB trigger mechanism entirely. The retrograde signal remains but it is always genuine — driven by real Ca_post elevation from NMDA coincidence, not pump failure. The synapse cannot enter the excitotoxic protection cascade. - Removing Desensitization_level means the postsynapse cannot fatigue under sustained NT exposure. Receptor availability is always at maximum, so the tenth burst produces the same AMPA response as the first. This preserves the short-term dynamics of V_post without the adaptation layer. - Removing Ca²⁺ clearance detail means Ca_post reflects the cumulative history of coincidence events with a single decay constant rather than the interplay of PMCA, NCX speed, and ATP availability. Ca_post will still accumulate under high-frequency coincident firing if the decay is slow relative to the event rate, which preserves the eCB trigger dynamic even without the full pump machinery. - ---- - ---- - -## Flussi e chiusure - -### Flusso da POST a SOMA - -- Gli NT che arrivano a BEH-POST-AMPA aprono i AMPA che fa entrare Na che vengono integrati nella POST -- Gli Na nella POST aprono NDMA che fanno entrare Ca2+ -- Ca2+ genera VPost nel DB -- L'integrazione di VPost nel DB genera VDB nel SOMA -- L'integrazione di VDB nel SOMA determina AP -- Si aprono i Canali ionici del SOMA, si genera VSOMA e refractory period (emergente) - -### Flusso da SOMA a POST - -bAP - -### Flusso da SOMA a PRE - -AP - -Based on the computational model provided, here is the complete breakdown of all simulated behaviors, categorized by functional compartment. - -## The four pillars - -This framework describes a system that is not a static processor, but a living entity that balances high-speed pattern extraction based on expectations with allostatic balancing and physical transformation. - -### Pillar 1: The Electrical Pillar (The Integration Layer) - -- Function & Reason: Pattern Extraction. The neuron acts as a spatiotemporal filter. It integrates thousands of tiny inputs across its dendritic tree (space) and within narrow windows of time. Its "output" is a declaration that a specific relevant pattern has been recognized. -- Timescale: Milliseconds (ms). -- Behaviors: Summation of Excitatory/Inhibitory Post-Synaptic Potentials (EPSPs/IPSPs), the "Tug-of-War" at the soma, and the propagation of the "Success" signal (the Spike). -- Elements Involved: - \-- Ions: Na+ (The "Yes" current), K+ (The "No/Reset" current). - \-- Hardware: Dendritic tree (The Space), VGSC/VGKC (The Timers). - -### Pillar 2: The Metabolic Pillar (The Constraint Layer) - -* **Function & Reason:** Sustainability and Gradient Maintenance. This pillar provides the energy required for all other behaviors. It sets the "Hard Limit" on how much work the neuron can do. -* **Timescale:** **Seconds to Minutes.** -* **Behaviors:** Active transport of ions, ATP production, and "Metabolic Silencing" (shutting down to prevent death when energy is low). -* **Elements Involved:** - * **Molecules:** ATP, Glucose, Oxygen. - * **Hardware:** Na/K-ATPase Pump (the "Battery Recharger"), Mitochondria. - * **Constraint:** The $Na^+/K^+$ ratio. - -### Pillar 3: The Calcium Pillar (The Logic / Information Keeper) - -* **Function & Reason:** Adaptation and Translation. This pillar acts as the "sensor" that monitors electrical activity and translates it into chemical signals. It keeps the "history" of the cell's workload. -* **Timescale:** **Minutes to Hours.** -* **Behaviors:** **Homeostatic Scaling** (tuning the master volume), Synaptic Plasticity (LTP/LTD), and Gain Control. -* **Elements Involved:** - * **Ions:** Calcium ($Ca^{2+}$). - * **Hardware:** Somatic VGCCs (L-type), NMDA receptors. - * **Software:** Calmodulin, CaMKIV (signaling proteins that "count" the calcium). - -### Pillar 4: The Structural Pillar (The Renovation Layer) - -* **Function & Reason:** Physical Transformation. This pillar is the actual rebuilding of the "factory" to change the neuron's fundamental capabilities. It is the physical manifestation of long-term memory and health. -* **Timescale:** **Days to Weeks.** -* **Behaviors:** **Axon Initial Segment (AIS) translocation** (moving the trigger zone), dendritic branch growth/pruning, and changes in total channel/receptor count via gene expression. -* **Elements Involved:** - * **Structural Proteins:** Actin, Microtubules, Ankyrin-G (the "anchor"). - * **Genetics:** mRNA, Ribosomes, Transcription Factors (e.g., CREB). - -### What is Achieved by This Entity? - -By combining these four pillars, the neuron becomes a Non-Static Adaptive Engine: - -- Selective Attention: It doesn't just pass signals; it ignores noise and only "speaks" when its specific spatial and temporal requirements are met. -- Self-Regulating Sensitivity: If the patterns it is expecting become too frequent or too rare, the Calcium and Structural pillars adjust the Electrical hardware to find a new "sweet spot." -- Metabolic Wisdom: It balances the "desire" to extract patterns against the "cost" of ATP. It is an engine that tunes itself to be as efficient as possible. -- Hardware-Software Unity: Unlike a computer, where the software cannot change the CPU, the neuron's "software" (the activity patterns) physically rewrites its "hardware" (the pillars) every single day. - -This is the portrait of a system that isn't just "running a program"—it is a biological machine constantly sculpting itself to become a better filter for the world it perceives. - ----