organism/neuron/DEV-N.md

# DEV-N: Modulator

Neuron Development - LTP-LTD Behavior:

Il DEV-N lavora durante Night a tempi lunghi rispetto a BEH-N. In pratica cambia la forma delle possibilita’ di BEH-N.

Il DEV contiene quei behavior di modulazione che cambiano la somma (fullness + active). La modulazione DEV aumenta/diminuisce (fullness + active). Ovvero c’e’ creazione di nuova “forma” di possibilita’.

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., un 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)

> Night Time Scale

```Gen
modulator: DEV-N
  contained_by: N
```

## DEV-RF: Modulator

Perche’ mettiamo RF in DEV e non in TUN?

```Gen
modulator: DEV-RF
  contained_by: DEV-N
```

### DEV-PRE-VesciclesRecycling-RF: Modulator

```Gen
modulator: DEV-PRE-VesciclesRecycling-RF
 contained_by: DEV-RF

 modulates: BEH-PRE/episode/VesciclesRecycling
# each BEH-PRE is modulated!
 
 tub_dev: 
  - fulMod ( fullness: None, active: rf/fullness, emptiness: 0x )
  - actMod ( fullness: None, active: rf/active, emptiness: 0x )

# qui stiamo modulando l'active di RF mantenendolo fra fullness e 
# emptiness dichiarato in VesciclesRecycling
 
 tub_local:

 tub_intricated:
  - Nox ( contained_by: BEH-POST )
  - Ecb ( contained_by: BEH-POST )
```

#### Context

#### Episode

### DEV-PRE-VesiclesFillingRP-RF: Modulator

```Gen
modulator: DEV-PRE-VesiclesFillingRP-RF
 contained_by: DEV-RF

 modulates:

 tub_local:

 tub_intricated:
  - Nox ( contained_by: BEH-POST )
  - Ecb ( contained_by: BEH-POST )
```

#### Context

#### Episode

### DEV-PRE-LactateAtp-RF: Modulator

```Gen
modulator: DEV-PRE-LactateAtp-RF
 contained_by: DEV-RF

 modulates:

 tub_local:

 tub_intricated:
  - Nox ( contained_by: BEH-POST )
  - Ecb ( contained_by: BEH-POST )
```

#### Context

#### Episode

## DEV-TUB-FLOOR: Modulator

Perche’ mettiamo Full in DEV e non in TUN?

```Gen
modulator: DEV-TUB-FLOOR
  contained_by: DEV-N
```

### DEV-PRE-CA2+-TUB: Modulator

```Gen
modulator: DEV-PRE-CA2+-TUB
 contained_by: DEV-TUB-FLOOR

 modulates: BEH-PRE/tub/Ca2+ # this is the tub whose "full" must be modulated
  
 tub_dev: 
   - fullMod ( fullness: 100x, active: Ca2+/fullness, emptiness: 50x ) # Ca2+Full "contains" a number of blocks equal to the current Full.
# qui stiamo modulando la fullness di Ca2+, associandola ad
# active di fullMod. Cambiando active di fullMod, 
# si cambia la fullness di Ca2+

 tub_local:

 tub_intricated:
  - Nox ( contained_by: BEH-POST )
  - Ecb ( contained_by: BEH-POST )
```

#### Context

***Tens Milliseconds Time Scale***

```Gen
context: CheckPreTubCa2+

  contained_by: DEV-PRE-FULL-CA2+
  in_context: Fixed
  rf: 60x

  condition: ( empty ) 
  out_context: DecreaseFull

  condition: NOT ( empty ) AND NOT ( Ca2+ full ) 
  out_context: Nothing

  condition: ( full) 
  out_context: IncreaseFull
```

#### Episode

```Gen
episode: VgccOpen
  contained_by: DEV-PRE-FULL-CA2+

  in_context: DecreaseFull
  rf: 1x

  hypothesis: NOT ( full ) AND NOT ( empty ) 
  action: [ increase,  decrease]
  trace: None
```

### DEV-PRE-RRP-TUB: Modulator

```Gen
modulator: DEV-PRE-RRP-TUB
 contained_by: DEV-TUB-FLOOR

 modulates: BEH-PRE/tub/Rrp # this is the tub whose "full" must be modulated
  
 tub_dev: 
   - fullMod ( fullness: 100x, active: Rrp/fullness, emptiness: 50x ) # RrpFull "contains" a number of blocks equal to the current Full.
# qui stiamo modulando la fullness di Rrp, associandola ad
# active di fullMod. Cambiando active di fullMod, 
# si cambia la fullness di Rrp

 tub_local:

 tub_intricated:
  - Nox ( contained_by: BEH-POST )
  - Ecb ( contained_by: BEH-POST )
```

#### Context

#### Episode

## DEV-TUB-CONCEPTUAL: Modulator

Qui la PRE e la POST si predispongono per dare le condizioni a SYN di stabilire o eliminare una sinapsi. Per ora questo comportamento lo mettiamo in TUN perche’ non si tratta di creare o distruggere PRE o POST, ma di rendere disponibile a SYN la possibilita’ di creare o distruggere una SYN. Durante il Day c’e’ il TUN che mette a disposizione, durante il Night SYN crea o distrugge gli accoppiamenti PRE POST.

ATTENZIONE: Questo e POST e’ da cambiare, perche’ c’e’ il passaggio da TubPoss a TubPossSyn a TubAct. E’ la SYN che passa in TubAct.

> Minutes/hours Time Scale

```Gen
modulator: DEV-TUB-CONCEPTUAL
 contained_by: DEV-N
```

### DEV-AXO-BEH-PRE-TUB: Modulator

Qui stiamo ragionanando sulla trasformazione fra bottone presinaptico inattivo e bottone attivo, pronto a diventare parte di una sinapsi. Il ragionamento e' locale, e mette a disposizione o toglie un bottone attivo che un altro ragionamento, credo in TUN-WTA, fara' su questo bottone, il bottone postisinaptico e una sinapsi disponibile.

```Gen
modulator: DEV-AXO-BEH-PRE-TUB
 contained_by: DEV-TUB-CONCEPTUAL
 
 modulates: BEH-AXO/expansion/BEH-PRE
# qui stiamo modulando fullness e actual del tub BEH-PRE associandoli 
# a tub_modulation prePos e PreAct. 

 tub_modulation: # in TUN agiamo su fullness <-> active
  - fulMod ( fullness: None, active: BEH-PRE/fullness, empty: 0x )  # riferimento a possible di BEH-PRE
  - actMod ( fullness: None, active: BEH-PRE/active, empty: BEH-PRE/emptiness )  # riferimento a active di BEH-PRE

 context_intricated:
  - TunPossible ( contained_by: TUN-N )

 tub_local:

 tub_intricated:
```

#### Context

```Gen
context: CheckTunSynAxoPrePossibility
 contained_by: TUN-SYN-AXO-PRE

 in_context: TunPossible
 rf: ( active: 60x )

 condition:
  out_context: 
```

#### Episode

```Gen
episode: TunSynAxoPre
  contained_by: TUN-SYN-AXO-PRE

  in_context: ??
  rf: 1x

  hypothesis: NOT () AND NOT ()
  action: [ increase,  decrease]
  trace: None
```

### DEV-BD-BEH-POST-TUB: Modulator

```Gen
modulator: DEV-BD-BEH-POST-TUB

 contained_by: DEV-TUB-CONCEPTUAL
...
```

#### Context

#### Episode