# 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)](https://cl.splindex.net/apps/files/files/1160115?dir=/code-server/G-notes/neuron&editing=false&openfile=true#h-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](https://cl.splindex.net/apps/files/files/1160115?dir=/code-server/G-notes/neuron&editing=false&openfile=true#h-4-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