organism/neuron/appunti/2026-01-18-Neuron-Geneosophic-Expression.md

Neuron Geneosophic Expression

Qui la timescale la inseriamo per la verifica dei comportamenti. Ma quello che conta e’ RF, che rappresenta nella espressione G, la possibilita’ di verificare la timescale.

Spiking Neuron Behavior

Container: N-SPK
- Expands: 1 AXO, 1 SOMA, 3 DB
- Modulability: 
  - TUN: None
  - DEV: None

Qui mettiamo i comportamenti che generalmente associamo al fare “diretto” neuronale. In N-TUN-(MTP-MTD) e N-MOD-(LTP-LTD) mettiamo le modulazioni di questi comportamenti.

Presynaptic Behavior

Container: PRE
Behavior: Presynaptic Behavior
- ContainedBy: AXO
- Expands: 10 VGCC
- Modulability: 
  - TUN: PRE # Possible <-> Actual, Synapting
  - DEV: None

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.

Milliseconds Time Scale

AP Arrives
Time: t = 0 ms
Trigger: Depolarization from axon hillock
Mechanism: Na⁺/K⁺ voltage-gated channel cascade
State: Terminal depolarizes from -70 mV to +30 mV
Duration: ~1 ms

VGCC Open - Ca2+ Influx

Container: VGCC
Behavior: VGCC Open - Ca2+ Influx
- ContainedBy: PRE
- Tubs: 
  - Source:
    - Ca+ #FULLNESS = 50 questo va messo nel Destination?
  - Yellow:	 
    - ATP #FULLNESS = 50
- Context: AP
  - RF: 1
  - IF NOT (Ca+ FULLNESS) AND NOT (ATP EMPTY)
    - Consequence: (Ca+ increase)
    - Consequence: (ATP decrease)
    - Traces: # le tracce di CaFullnessTraces le lasciamo quando vediammo im contesti a RF piu' alto
- Modulability: 
  - TUN: VGCC # Possible <-> Actual, Postsynapsis channel tuning
  - DEV: VGCC # Possible increase/descrease

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.

Se Ca+FULLNESS, lascio tracce di overflow per modulazione DOWN, da capire UP

VGCC Open
Time: t = 0.2-0.5 ms after AP arrival
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

Vesicle Release

Behavior: Vesicle Release
- ContainedBy: PRE
- Tubs: 
  - Source:
    - Ca+
    - RRP, 
  - Yellow:
    - NT
    - ATP 
    - TagRelease ?
- InContext: CaFull
  - RF: 6
  - Condition: IF (Ca+ FULLNESS) AND NOT (RRP EMPTY) AND NOT (ATP EMPTY)
    - Consequence: (RRP decrease)
    - Consequence: (NT increase) # vedi nota sotto
    - Consequence: (Ca+ decrease) # ?
    - Consequence: (TagRelease increase) # check di rilascio fatto (pensiamo ad una sola vescica per AP?)
    - Consequence: (ATP decrease)
	  - Traces: ?
  - Modulability: 
    - TUN: None
    - DEV: RRP, (Ca+ FULLNESS) # increase/decrease RPP, increase/decrease level of (Ca+ FULLNESS)

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
Decision:
1. [Ca²⁺]microdomain > 10-25 µM
2. Vesicle in RRP (docked & primed)
Release latency: 0.1-1.0 ms after Ca²⁺ threshold reached
Release synchrony: Multiple vesicles can release simultaneously

Ca+ Clearance

Behavior: Ca+ Clearance
- ContainedBy: PRE
- Blocks: Ca+, ATP
- InContext: CaMedium
  - RF: 6
  - Condition: IF NOT (Ca+ EMPTY) AND NOT (Ca+ FULLNESS) AND NOT (ATP EMPTY)
    - Consequence: (Ca+ decrease)
    - Consequence: (ATP decrease)
    - Tracce: None
  - Modulability:
    - TUN: None
    - DEV: RF
- InContext: CaFull
  - RF: 1
  - Condition: IF (Ca+ FULLNESS)
    - Consequence: (Ca+ decrease)
    - Consequence: (ATP decrease)
    - Tracce: None
  - Modulability: 
    - TUN: None
    - DEV: RF

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+

Time: t = 1-50 ms after influx
Clearance mechanisms (in order of speed):

1. Fast buffers (calbindin, parvalbumin): <1 ms
2. Plasma membrane Ca²⁺ ATPase (PMCA): 10-100 ms
3. Na⁺/Ca²⁺ exchanger (NCX): 10-100 ms
4. Mitochondrial uptake: 10-1000 ms
5. Endoplasmic reticulum uptake: 100-1000 ms
   Residual Ca²⁺: 0.1-0.5 µM persists for 10-1000 ms

Observed 1 - STP - Upregulation of Pr

Timing: > 10 ms

• Upregulation (Facilitation): Residual Ca²⁺ from previous spikes increases P_r for next release

Observed 2 - STD - Downregulation of Pr

Timing: > 10 ms

• Downregulation (Depression): High-frequency firing depletes readily releasable vesicle pool, decreasing P_r

Tens-ms to seconds Time Scale

Vescicles Recycling

Time: t = 10 ms - 10 s (depending on activity)
Sequential steps:

1. Endocytosis (clathrin-mediated, kiss-and-run, bulk)
2. Vesicle re-acidification (v-ATPase)
3. Neurotransmitter reloading (vesicular transporters)
4. Priming (SNARE assembly, docking)
5. Return to RRP
   Recycling rate: Limited by ATP availability

Vescicle from RP to RRP

Behavior: Vescicle from RP to RRP
- ContainedBy: PRE
- Blocks: RP, RRP, Ca+, ATP
- InContext: CaEmpty
  - RF:  30
  - Condition: IF NOT (ATP EMPTY) AND NOT (RP EMPTY)
    - Consequence: (RP decrease) # moved VERY slow
    - Consequence: (RRP increase) # moved VERY slow
    - Consequence: (ATP decrease) # Very low ATP consumption
    - Tracce: ? # se non c’e’ abbastanza ATP o non ci sono abbastanza RP, lascio tracce per la modulazione UP, devo capire modulazione DOWN
    - Modulability: 
      - TUN: None
      - DEV: RF
- InContext: CaMedium
  - RF:  15
  - Condition: IF NOT (ATP EMPTY) AND NOT (RP EMPTY)
    - Consequence: (RP decrease) # moved slow
    - Consequence: (RRP increease) # moved slow
    - Consequence: (ATP decrease) # low ATP consumption
    - Tracce: ? # se non c’e’ abbastanza ATP o non ci sono abbastanza RP, lascio tracce per la modulazione UP, devo capire modulazione DOWN
    - Modulability: 
      - TUN: None
      - DEV: RF
- InContext: CaFull
  - # 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)
  - RF:  5
  - Condition: IF NOT (ATP EMPTY) AND NOT (RP EMPTY)
    - Consequence: (RP decrease) # moved fast
    - Consequence: (RRP increease) # moved fast
    - Consequence: (ATP decrease) # fast ATP consumption
    - Tracce: ? # se non c’e’ abbastanza ATP o non ci sono abbastanza RP, lascio tracce per la modulazione UP, devo capire modulazione DOWN
    - Modulability: 
      - TUN: None
      - DEV: RF

From The Reserve Pool and Recently Endocytosed Vesicles

Check Ca+ Concentration

Behavior: Check Ca+ Concentration
- ContainedBy: PRE
- Blocks: Ca+, Ca+MediumTraces, Ca+HighTraces
- Context-fixed
  - RF: 60
    - Condition: IF (Ca+ EMPTY)
      - OutContext: CaEmpty
      - Consequence: None
      - Traces: None 
    - Condition: IF (NOT Ca+ EMPTY) AND (NOT Ca+ FULLNESS)
      - OutContext: CaMedium
      - Consequence: None
      - Traces: (Ca+MediumTraces increase) # Add to traces Ca+Medium (Questo per la modulazione, quanti giri e’ rimasto in questa condizione)
    - Condition: IF (Ca+ FULLNESS)
      - OutContext: CaFull
      - Consequence: None
      - Traces: (Ca+HighTraces increase) # Add to traces Ca+Medium (Questo per la modulazione, quanti giri e’ rimasto in questa condizione)
  - Modulability: 
    - TUN: None
    - DEV: (Ca+ FULLNESS)

Il controllo su Ca+ viene fatto anche nel contesto spike, ma li e’ con RF1. Qui lo facciamo sempre ma con RF50 o maggiore, per limitare check e comunque siamo in un timescale molto piu’ alta.

Non deve andare in overlap con Action Potential

Seconds-Minutes Time Scale

Questi comportamenti si possono fare anche controllando che non ci sia alta concentrazione di Ca+ per essere sicuri che il neurone sia in un momento di calma. Quindi devo cambiare e mettere context fixed?

Vesicles Filling RP ?

Behavior: Vesicles Filling RP ?
- ContainedBy: PRE
- Blocks: Vescicle, ATP
- InContext: Fixed
  - RF: 300
  -
  -
  - Modulability: 
    - TUN: None
    - DEV: None (credo vada con DEV di RP)

Qui riempiamo le vesciche. Fino ad un numero massimo, che viene modulato in DEV

Lactate-ATP

Behavior: Lactate-ATP
- ContainedBy: PRE
- Blocks: Lactate, ATP, Ca+
- InContext: Fixed
  - RF: 300
  - Condition: ??? IF NOT (Ca+ FULLNESS) AND NOT EMPTY AND IF AstroLactate NOT EMPTY AND ATP NOT FULL
    - Consequence: get Lactate
    - Consequence: Increase ATP
    - Tracce: 
  - Modulability: 
    - TUN: None
    - DEV: RF

Il Lactate viene mandato da Astro che ha fatto re-uptake di Glutamate, trasformato in Glutamine e poi Lactate. Il Lactate serve a fare ATP. Astrocyte gliotransmitters (ATP, D-serine, glutamate).

Postsynaptic behavior

Container: POST
- ContainedBy: BD
- Expands: 100 POST-CHAN
- Modulability: 
  - TUN: # POST Possible <-> Actual, Synapting
  - DEV: None

Milliseconds Time Scale

AMPA Opening

• Timing: < 1 ms
• InContext: Glutamate > FULLNESS
• OutContext: AMPA receptor opening

Ca+ influx by AMPA

• Timing: < 1 ms
• InContext: AMPA receptor opened
• Consequence: Na⁺ influx
• Consequence: addition to local depolarization (EPSP) from AMPA activation

Limited Ca+ influx by NMDA

• Timing: > 1 ms

• InContext: local depolarization (EPSP) NOT FULLNESS (requires depolarization > -40mV)

• Consequence: Glutamate binding to NMDA receptors (Mg²⁺-blocked initially)

• Consequence: limited NMDA receptor opening → Ca²⁺ influx

• Consequence: limited addition to local depolarization (EPSP) from NMDA activation

Depolarization by bAP

• Timing: > 1 ms
• InContext: bAP backpropagating action potential
• Consequence: addition to local depolarization (EPSP) from bAP

Mg²⁺ NMDA unblock

• Timing: > 1 ms

• InContext: local depolarization (EPSP) > FULLNESS (requires depolarization > -40mV)

• OutContext: NMDA Mg²⁺ unblock

Full Ca+ influx by NDMA

• Timing: < 1 ms
• InContext: NMDA Mg²⁺ unblock
• Consequence: Na⁺ influx
• Consequence: addition to local depolarization (EPSP) from Full NMDA activation

Observed 1 - Upregulation

• Upregulation: Depolarization relieves NMDA Mg²⁺ block → Ca²⁺ influx amplification

Observed 2 - Downregulation

• Downregulation: AMPA desensitization acts as low-pass filter

Dendritic behavior

Container: BD
- ContainedBy: N-SPK
- Expands: 100 POST
- Modulability: 
  - TUN: None
  - DEV: None

Somatic behavior

Container: SO
- ContainedBy: N-SPK
- Expands: 20 SO-CHAN
- Modulability: 
  - TUN: None
  - DEV: None

AIS behavior

Container: AXO
- ContainedBy: N-SPK
- Expands: 30 PRE
- Modulability: 
  - TUN: None
  - DEV: None

Tuning - MTP-MTD Behavior

Container: N-TUN
- Expands: None
- Modulability: 
  - TUN: None
  - DEV: None

Qui si modulano i canali ionici, sia quelli voltage (PRE/POST/SO/altro?) che quelli Neuro (POST/SO(inibitori)). Non si creano o si distruggono (lo si fa in Developing), ma si rendono attivi disattivi quelli presenti. Ovviamente potremmo aggiungere anche altri comportamenti di tuning che riguardano altri tipi di modulazione (RF?).

Presynaptic Behavior Tuning

Seconds Time Scale

VCGG Channel Tuning

- ContainedBy: N-TUN
- Tubs: 
  - Source:
    - 
  - Yellow:	 
    - 
- Context: ?
  - RF: 1
  - IF NOT 
    - Consequence: ()
    - Consequence: ()
    - Traces: # 
- Modulability: 
  - TUN: None
  - DEV: None

Lo possiamo fare sia con alterazione di RF che del volume Tub, di sicuro per Ca+ poi altro non so.

Inoltre devo vedere se farlo alla fine di spiketrain, quando il neurone e’ in rest stateM

This is critical for long-term presynaptic changes. The postsynaptic cell, upon detecting specific activity patterns (like those for LTP/LTD), releases chemical signals that travel backwards to the presynaptic terminal, instructing it to change.

• For Presynaptic Strengthening (e.g., LTP):
  • Nitric Oxide (NO):* A gas that diffuses freely. During postsynaptic LTP induction (strong NMDAR activation), neuronal NO synthase (nNOS) is activated. NO diffuses into the presynaptic terminal and activates soluble guanylyl cyclase (sGC), raising cGMP levels. This enhances vesicle release via PKG, contributing to presynaptic LTP.*
  • Endocannabinoid-Mediated LTP (eLTP):* In some synapses, a postsynaptic depolarization triggers production of endocannabinoids (e.g., 2-AG). These bind to presynaptic CB1 receptors, but surprisingly, can initiate a signaling cascade (involving cAMP/PKA) that increases Pr for a long period.*
  • Neurotrophins (BDNF):* Released from the postsynapse in an activity-dependent manner. Presynaptic TrkB receptors activate pathways (PI3K, MAPK) that enhance vesicle docking and Pr.*
• For Presynaptic Weakening (e.g., LTD):
  • Classical Endocannabinoid-Mediated LTD (eCB-LTD):* More common. Moderate postsynaptic activity (mGluR activation or moderate Ca²⁺ rise) triggers 2-AG release. 2-AG binds presynaptic CB1 receptors, which inhibit VGCCs and directly inhibit the release machinery via Gi/o protein signaling, reducing Pr for a long time.*
  • Other Lipid Mediators* (like LPA) can also act as retrograde signals for depression.*

Augmentation:

• Calcium-sensing proteins (Munc13) alter release probability (1-10s range). How?

Upregulation:

• NO/BDNF activates cascades that increase P_r, promote synaptic growth (facilitates LTP). How?
• VGCC TUN
• Potassium channel modulation ??

Downregulation:

• eCBs bind CB1 receptors, inhibit VGCCs, activate K⁺ channels → profound decrease in P_r (DSE/DSI - depolarization-induced suppression)

• CB1 receptor activation (by eCBs)

• Retrograde BDNF (brain-derived neurotrophic factor)

Postynaptic behavior Tuning

Seconds Time Scale

Postsynapsis channel tuning

- ContainedBy: N-TUN
- Tubs: 
  - Source:
    - 
  - Yellow:	 
    - 
- Context: ?
  - RF: 1
  - IF NOT 
    - Consequence: ()
    - Consequence: ()
    - Traces: # 
- Modulability: 
  - TUN: None
  - DEV: None

Dendritic-branch behavior Tuning

Soma behavior Tuning

Seconds Time Scale

SO Channel tuning

- ContainedBy: N-TUN
- Tubs: 
  - Source:
    - 
  - Yellow:	 
    - 
- Context: ?
  - RF: 1
  - IF NOT 
    - Consequence: ()
    - Consequence: ()
    - Traces: # 
- Modulability: 
  - TUN: None
  - DEV: None

AIS behavior Tuning

Development - LTP-LTD Behavior

Container: N-DEV
- Expands: None
- Modulability: 
  - TUN: None
  - DEV: None

Attivazione/disattivazione di possibilita’

Qui si incrementa/decrementa:

• Il numero possibile di canali ionici.
• la capacita’ di Vescice in RP e RPP
• la capacita’ di spostare vesciche da RP a RPP
• la capacita’ di riempire vesciche

Presynaptic behavior Development

Day Time Scale

Qui si modula la possibilita’ di potenza di fuoco, sia come nuovi recettori (voltage e neuro) sia come grandezza di RP, RRP e velocita’ di spostamento.

Long-lasting presynaptic strengthening requires new proteins:

• More vesicles
• More active zone proteins (e.g., RIM, Munc13)
• More mitochondria (for energy)
• More synaptic vesicle components (synaptobrevin, synaptotagmin)
• More cytoskeletal elements for structure

The neuron must detect a sustained need for strengthening at a specific synapse, send a signal to its nucleus, transcribe genes, and then deliver the new proteins back to that specific presynaptic bouton.

1. Detection:* Sustained high-frequency firing at the presynaptic terminal → elevated Ca²⁺ and/or neuromodulator release (dopamine, norepinephrine).*
2. Signal to Nucleus:* Activation of kinases (PKA, CaMKIV) and retrograde importin signaling → CREB phosphorylation in the nucleus.*
3. Transcriptional Program:* CREB induces expression of:*
   • Immediate Early Genes* (e.g., c-Fos, Arc) that regulate further transcription.*
   • Effector Genes:* Presynaptic proteins (synapsins, RIM, Munc13), BDNF, cytoskeletal proteins.*
4. Delivery:* Newly synthesized mRNAs/proteins are actively transported down the axon, targeted to the active synapses that initiated the signal.*
5. Local Implementation:
   • Assembly of new active zones.
   • Expansion of vesicle pools.
   • Possible local translation.
   • Bouton enlargement or new bouton formation.
6. Stabilization:* Epigenetic modifications and continued autocrine/paracrine signaling (BDNF→TrkB) lock in the changes.*

In essence, the neuron "knows" to strengthen a presynapse long-term because the synapse's own sustained activity creates a biochemical signature that reaches the nucleus, triggering a gene program specifically designed to build a bigger, better release machine. This is a fundamental mechanism underlying long-term memory storage at the synaptic level.

• ATP-dependent vesicle cycling

• Metabolic veto: Insufficient ATP prevents vesicle release despite adequate Ca²⁺

• Glutamine→glutamate conversion (via glutaminase). Glutamine from astrocytes (glutamate-glutamine cycle)

• Vesicle refilling with glutamate

• Maintenance of ion gradients

Incoming Signals:

• Astrocyte-supplied lactate (via monocarboxylate transporters)
• Metabolic state indicators (ATP levels, NAD/NADH ratio)

Outgoing Signals:

• Metabolic demand signals to astrocyte ??

Modulation:

• Lactate availability determines sustained release capacity during high activity ??

VCGG channel development

- ContainedBy: N-DEV
- Tubs: 
  - Source:
    - 
  - Yellow:	 
    - 
- Context: ?
  - RF: 1
  - IF NOT 
    - Consequence: ()
    - Consequence: ()
    - Traces: # 
- Modulability: 
  - TUN: None
  - DEV: None

RRP development

Ca+ FULLNESS

Ca+ Clearance RF

RP to RPP RF

Lactate to ATP RF

Postynaptic Behavior Development

Dentric-branch Behavior Development

Soma Behavior Development

AIS Behavior Development