organism/neuron/BEH-BD.md

BEH-BD.md

Qui comprendiamo:

• BEH-BD: Dendritic Branch
• BEH-POST: Postsynapsis
• BEH-POST-AMPA: AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors)

BEH-BD: Container

Dendritic Branch: In questa prima fase, non consideriamo lo spike dendritico come comportamento. Questo limita molto il modello, perche' equipara tutte le Postsinapsi sui tre branch dendritici e non permette di fare in maniera che ad esempio due branch contestualizzino (base activity) e uno faccia scattare il threshold per lo spike somatico. Qui BEH-DB espande solo i BEH-POST, e' un cavo di collegamento come l'assone

Container: BEH-BD
 
 expansion:
  - BEH-POST ( full: 50x, active: 20x, empty: 10x ) 
    modulated_by: DEV-BD-BEH-POST-TUB from DEV-N.md

BEH-POST: Container

The postsynapse is the receiving terminal of a neuron — a specialised patch of membrane on the surface of a dendrite, sitting directly across the synaptic cleft from the presynapse. Its job is to detect the neurotransmitters (NT) released by the presynapse, convert that chemical signal back into an electrical response, and decide — based on the history and pattern of that activity — whether to strengthen or weaken the connection for the future.

To do this, the postsynapse maintains two types of receptor on its membrane surface. AMPA receptors are the fast responders: when NT binds them, they immediately open and allow sodium ions to rush in, raising the local membrane potential (V_post). NMDA receptors are the coincidence detectors: they can only open fully when two conditions are simultaneously true — NT must be present in the cleft, and the membrane must already be strongly depolarised. Under resting conditions a magnesium ion physically plugs the NMDA channel from the inside, blocking calcium entry. Only a sufficiently large depolarisation can eject this plug. This dual requirement makes NMDA receptors the central logic gate of the postsynapse.

The depolarisation that clears the NMDA block can come from two sources acting together. Local AMPA activation raises V_post from incoming NT. A back-propagating action potential (bAP) — an electrical echo of the postsynaptic neuron's own firing that travels backward up the dendrites from the cell body — provides an independent boost. When both arrive simultaneously, V_post reaches its maximum and the NMDA gate opens fully. When only one arrives, or when they arrive at different times, the gate stays partially or fully blocked. This coincidence detection is what gives the postsynapse its ability to distinguish meaningful coordinated activity from random noise.

When the NMDA gate does open, calcium (Ca²⁺) surges into the postsynaptic spine. The size of this surge is the key signal. A large surge — produced by strong, well-timed coincidence — activates molecular machinery that inserts more AMPA receptors into the membrane, making the synapse more sensitive to future NT release. This is long-term potentiation, or LTP: the postsynapse remembers that this connection was recently successful and strengthens it. A weak or poorly timed surge — produced when the presynapse fired but the postsynaptic neuron was not ready — activates a different pathway that removes AMPA receptors, weakening the connection. This is long-term depression, or LTD. The amplitude of Ca²⁺ in the spine is therefore the plasticity controller: it translates the timing of electrical events into lasting structural change.

But the postsynapse does not only look forward. If Ca²⁺ in the spine remains elevated for too long — a sign that incoming activity is excessive — the postsynapse synthesises a chemical called an endocannabinoid (eCB) and releases it retrogradely across the cleft. This signal travels backward to the presynapse and suppresses the very channels that are driving the excess activity. This is the postsynapse telling the presynapse to ease off: a retrograde brake, operating on the seconds timescale, that protects the spine from being overwhelmed.

After every response, ion gradients must be restored. Sodium that entered through AMPA receptors must be pumped back out by Na/K-ATPase. Calcium that entered through NMDA receptors must be pumped out of the spine by dedicated calcium pumps. Both processes consume ATP continuously, and their cost scales directly with how active the synapse has been.

The ATP supply comes from the same astrocyte that serves the presynapse — a shared glucose budget that both sides draw from simultaneously. Under sustained high-frequency activity, this shared supply can be exhausted. When postsynaptic ATP falls, the calcium pumps slow and Ca²⁺ begins to accumulate in the spine even between genuine coincidence events. This accumulation looks, to the postsynapse, indistinguishable from real overactivity: the eCB threshold is crossed, the retrograde signal fires, and the presynapse is silenced — not because it was genuinely excessive, but because the postsynapse has lost the ability to clear calcium fast enough to distinguish signal from noise. This false trigger is a desperate survival mechanism. By silencing the presynapse, NT input stops, NMDA gates close, the calcium load drops, the pumps have a chance to recover, and the synapse pulls back from the edge of excitotoxic collapse.

Like its presynaptic partner, the postsynapse is governed by three interlocking loops—the V_{post} loop, the Ca^{2+} loop, and the ATP loop—operating across three distinct timescales.

---

1.The V_{post} Loop: The Fast Gatekeeper (Milliseconds)

This is the primary electrophysiological response, where chemical signals are converted back into electricity.

• Activation: When NT arrives in the cleft, it binds to AMPA receptors. These act as the primary current drivers. If NT_cleft is Full and receptors are not in a Desensitization state, the Na^{+} influx causes the local membrane potential (V_{post}) to rise steeply.

• The bAP Feedback: The postsynapse does not work in isolation. It receives a back-propagating Action Potential (bAP)—an electrical "echo" sent from the cell body whenever the neuron fires.

• Coincidence Logic: On this millisecond scale, the loop computes a logical AND operation. If local AMPA-driven depolarization coincides with a somatic bAP, the total V_{post} becomes Full. This massive depolarization is the only thing strong enough to kick the magnesium "plug" out of the NMDA receptors, allowing the next loop to begin.

---

2.The Ca^{2+} Loop: The Plasticity Controller (Seconds)

This loop translates electrical timing into biological "memory."

• The NMDA Gate: Ca^{2+} entry is strictly gated by the NMDA receptor. Unlike the presynaptic VGCCs (which open with any spike), the NMDA channel only opens if it senses both NT (from the presynapse) and high V_{post} (from the bAP).

• Signaling Fate (LTP/LTD): The amplitude of the Ca^{2+} surge determines the synapse’s fate. A Full surge (perfect coincidence) triggers LTP, signaling the astrocyte to help strengthen the synapse. A Medium or poorly timed surge triggers LTD, weakening the connection.

• Retrograde Signaling (eCB): If Ca^{2+} levels remain high for too long, the postsynapse synthesizes endocannabinoids (eCB). This signal travels backward across the cleft to tell the presynapse to stop sending NT. This is the primary safety valve that prevents the postsynapse from being overwhelmed.

---

3.The ATP Loop: The Metabolic Backbone (Minutes)

This is the "Hidden Master" that determines if the other two loops are allowed to function.

• The Cost of Logic: The postsynapse is metabolically expensive. The Na/K pumps must work constantly to reset the V_{post} gradient, and the PMCA pumps must use ATP to flush out the Ca^{2+} that entered through NMDA channels.

• The Astrocyte Bridge: The astrocyte provides the glucose required to replenish ATP. It also performs a "janitorial" service: it clears excess Potassium (K^{+}) and Glutamate from the cleft. If the astrocyte is starved of glucose, the ATP_level_post drops to Empty.

• The False Trigger (Excitotoxic Protection): When ATP fails, the Ca^{2+} pumps stop. Even without an NMDA surge, Ca^{2+} begins to "leak" and accumulate in the spine. This creates a False Trigger: the high Ca^{2+} level initiates eCB synthesis, silencing the presynapse even though there was no "real" signal. This is a desperate survival mechanism; by tricking the presynapse into silence, the postsynapse stops the influx of ions and buys time for its ATP levels to recover.

The failure of the ATP loop in the postsynapse is arguably more dangerous; if the postsynaptic pumps fail and the eCB "False Trigger" doesn't fire, the spine will literally digest itself from Ca^{2+} overload.

---

The Critical Connection with the presynapse

The system is beautifully asymmetric. While the presynapse is built to supply signal, the postsynapse is built to filter it.

container: BEH-POST

 expansion: 
  - BEH-POST-AMPA ( full: 10x, active: 5x, empty: 2x )
   # modulated_by: TUN-POST-IC # possible/actual

 tub_local:
  - Ca2+ ( full: 60x, active: 30x, empty: 0x )
   # modulated_by: DEV-POST-???-FULL # Full 

  - Nox ( full: 100x, active: 20x, empty: 0x ) # Nitric Oxide (NO):  A gas that diffuses freely.

  - Ecb ( full: 100x, active: 20x, empty: 0x ) # Endocannabinoids (e.g., 2-AG)

 tub_intricated:
  - Nt ( contained_by: BEH-SYN )
  - bAp ( contained_by: BEH-SOMA )

ms: behaviors POST

CheckConditionsPostMs:Context

Contestualizziamo in maniera Fixed ogni mezzo secondo?

context: CheckConditionsPostMs
  contained_by: BEH-POST

  in_context: Fixed
  rf: ( active: 600x )

  condition: NOT (RP empty) AND NOT (RRP full)
    out_context: RPShuttle

  condition: NOT (CaTrace empty) 
    out_context: CaTracesNotEmpty

  condition: NOT (eCB empy) 
    out_context: eCBNotEmpty

:Episode

BEH-POST-AMPA: Container

container: BEH-POST-AMPA

 tub_intricated:
  - Nt ( contained_by: BEH-SYN )

 context_intricated:
  - bAp ( contained_by: BEH-SOMA )

sec: behaviors POST

min: behaviors POST

ms: behaviors AMPA

AmpaOpen: Episode

• Timing: < 1 ms
• InContext: Glutamate > FULLNESS
• OutContext: AMPA receptor opening
• Consequence: Na⁺ influx
• Consequence: addition to local depolarization (EPSP) from AMPA activation

episode: AmpaOpen
  contained_by: BEH-POST-AMPA

  in_context: NtCapured
  rf: ( active: 1x )

 hypothesis: NOT (Ca2+ full)
  action: [Ca2+ increase]
  trace: None # Se Ca+FULLNESS, lascio tracce di overflow per modulazione DOWN, da capire UP

Depolarization by bAP

Da ricordare i Dendritic VCGG che si aprono facendo entrare Ca2+ all'arrivo di bAP. In teoria abbiamo 3 Ion Channel.

• 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

Upregulation: Observable

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

Downregulation: Observable

• Downregulation: AMPA desensitization acts as low-pass filter