# neuron-dev.md

Neuron Development - LTP-LTD Behavior:

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)

```Gen

NEURON-DEV

  type: developer # ??? (container)

  contained_by: NEURON
```

## CA2-PRESYNAPSE-DEV: Developer

```Gen
CA2-PRESYNAPSE-DEV

  type: developer
  contained_by: NEURON-DEV

  develops: NEURON/NEURON-BEH/AXON/PRESYNAPSE/tub/Ca2+ 
    # this is the tub whose "full" must be modulated

  tub_dev: fullMod ( fullness: 100x, active: Ca2+/full, emptiness: 50x ) 
    # qui stiamo modulando il full di Ca2+, associandolo ad
    # active di fullMod. Cambiando active di fullMod, 
    # si cambia la full di Ca2+

  tub_local:

  tub_intricated:
    - Nox ( contained_by: NEURON/NEURON-DAY/AXON/PRESYNAPSE )
    - Ecb ( contained_by: NEURON/NEURON-DAY/AXON/PRESYNAPSE )
```

### CheckPreCa2: Contextor

***Tens Milliseconds Time Scale***

```Gen
CheckPreCa2: ( active: 60x )

  type: contextor
  contained_by: NEURON-DEV

  in_context: Fixed

    condition: ( empty ) 
      out_context: DecreaseCa2Full_ctx

    condition: NOT ( empty ) AND NOT ( Ca2+ full ) ???
      out_context: Nothing_ctx

    condition: ( full) 
      out_context: IncreaseFull_ctx
```

### DecreasePreCa2Full: Accumulator

```Gen
DecreasePreCa2Full: ( active: 1x )

  type: accumulator
  contained_by: NEURON-DEV

  in_context: DecreaseCa2Full_ctx

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

### IncreasePreCa2Full: Accumulator

```Gen
IncreasePreCa2Full: ( active: 1x )

  type: accumulator
  contained_by: NEURON-DEV

  in_context: IncreaseCa2Full_ctx

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

## RRP-PRESYNAPSE-DEV: Developer

```Gen
RRP-PRESYNAPSE-DEV

  type: developer
  contained_by: NEURON-DEV

  develops: NEURON/NEURON-BEH/AXO/PRESYNAPSE/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: NEURON/NEURON-BEH/DENDRITIC-BRANCH/POSTSYNAPSE )
  - Ecb ( contained_by: NEURON/NEURON-BEH/DENDRITIC-BRANCH/POSTSYNAPSE )
```

### Contextor

### Accumulator

## PRESYNAPSE-AXO-DEV: Developer

Qui stiamo ragionanando sull'aggiunta o eliminazione di bottoni presynaptici. Il TUN della PRESYNAPSE e' fatto in WINNERTAKEALL/EXCITATION.


## POSTSYNAPSE-DENDRITIC-BRANCH-DEV: Developer

Qui stiamo ragionanando sull'aggiunta o eliminazione di bottoni postsynaptici. Il TUN della POSTSYNAPSE e' fatto in WINNERTAKEALL/EXCITATION.