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: 0x, empty: 10x ) 
    # managed_by: BEH-EXH or BEH-INH from winnertakeall
    # developed_by: DEV-BD-BEH-POST-TUB from DEV-N

BEH-POST: Container

Discursive description:

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.

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.

---

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.

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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.

---

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.

---

Behaviors:

— ms:

• NT arrives in cleft → AMPA receptors bind NT, gated by Desensitization_level
• V_post rises with AMPA conductance, decays passively each ms
• bAP arrives → V_post receives additional depolarisation boost
• NMDA gate checks coincidence: NT_cleft AND V_post both non-zero
• Ca²⁺ enters spine via NMDA — amount determined by NT_cleft × Mg_block_removal
• Ca²⁺ cleared slowly from spine (single decay term, ATP detail not modelled)
• V_post history updated every ms (rolling buffer, feeds seconds loop)
• Desensitization_level rises with NT_cleft exposure, recovers during silence
• ATP cost charged per V_post level (Na/K-ATPase recharge, continuous)
• ATP cost charged per unit Ca²⁺ cleared (PMCA cost, continuous)

— seconds:

• Ca_post_history computed (2 s rolling mean of Ca_post)
• eCB synthesised when Ca_post_history exceeds threshold
• eCB_level decays when Ca_post_history falls below threshold
• eCB_level written → read by presynapse as retrograde brake on VGCCs
• Ca_post_history compared to LTP/LTD thresholds → plasticity tag set
• Desensitization recovery continues passively

— mins:

• ATP_demand_post (accumulated from ms loop) reduces ATP_level_post
• ATP_demand_post resets to zero
• Glucose level (shared with presynapse) sets ATP_level_post
• If ATP_level_post low → Ca²⁺ clearance slows → false eCB trigger risk
• If Plasticity_LTP tagged AND ATP_level_post not empty → AMPA density increases
• If Plasticity_LTD tagged → AMPA density decreases
• AMPA density feeds back into receptor_conductance ceiling for next cycle

---

Simplified comprehension:

In this comprehension we decide to simplify:

• We do not model ATP — the postsynaptic energy loop is removed
• We do not model Desensitization_level — receptor availability is assumed constant
• We do not model Ca²⁺ clearance detail — Ca_post decays with a single slow term

The simplification implies that:

• Removing ATP removes the false eCB trigger mechanism entirely. The retrograde signal remains but it is always genuine — driven by real Ca_post elevation from NMDA coincidence, not pump failure. The synapse cannot enter the excitotoxic protection cascade.
• Removing Desensitization_level means the postsynapse cannot fatigue under sustained NT exposure. Receptor availability is always at maximum, so the tenth burst produces the same AMPA response as the first. This preserves the short-term dynamics of V_post without the adaptation layer.
• Removing Ca²⁺ clearance detail means Ca_post reflects the cumulative history of coincidence events with a single decay constant rather than the interplay of PMCA, NCX speed, and ATP availability. Ca_post will still accumulate under high-frequency coincident firing if the decay is slow relative to the event rate, which preserves the eCB trigger dynamic even without the full pump machinery.

---

Simplified Behaviors:

— ms:

• NT arrives in cleft → AMPA receptors bind NT (receptor availability constant, no desensitization)
• V_post rises with AMPA conductance, decays passively each ms
• bAP arrives → V_post receives additional depolarisation boost
• NMDA gate checks coincidence: NT_cleft AND V_post both non-zero
• Mg_block_removal = V_post / (V_post + V_NMDA_half) — sigmoid of V_post
• Ca²⁺ enters spine via NMDA: Ca_post += k_NMDA × NT_cleft × Mg_block_removal
• Ca_post decays slowly each ms (single exponential, no pump detail)
• Ca_post_history updated every ms (feeds seconds loop)
• V_post_history updated every ms (retained for reference)

— seconds:

• Ca_post_history mean computed over past 2 s
• eCB synthesised when Ca_post_history mean exceeds eCB threshold
• eCB_level decays when Ca_post_history mean falls below threshold
• eCB_level written → read by presynapse as retrograde brake on VGCCs
• Ca_post_history compared to LTP/LTD thresholds → plasticity tag set

— mins:

• If Plasticity_LTP tagged → AMPA density increases
• If Plasticity_LTD tagged → AMPA density decreases
• AMPA density feeds back into receptor_conductance ceiling for next cycle

---

Tubs:

• Na: Ioni entranti tramite AMPA receptors

• NT:

• Ca2+: Ioni entranti tramite NMDA

• eCB:

• Nox:?

---

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 )

  - Na ( full: 60x, active: 30x, empty: 0x )

  - 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? Oppure possiamo ricevere un contesto da SYN? Cmq anche li dovrebbe girare?

context: CheckConditionsPostMs
  contained_by: BEH-POST

  in_context: Fixed
  rf: ( active: 60x )

  condition: (Na fullness)
    out_context: NaMax

  condition: (Na mediumness)
    out_context: NaMedium 

  condition: (Na emptiness)
    out_context: NaLow

NDMAOpenMaximum: Episode

episode: NDMAOpenMaximum
  contained_by: BEH-POST

  in_context: bAp AND (NaMax OR NaMedium)
  rf: ( active: 2x )

 hypothesis: NOT (ca2+ full)
  action: [Ca2+ increase]
  trace: 

NDMAOpenMedium: Episode

episode: NDMAOpenMedium
  contained_by: BEH-POST

  in_context: (bAp AND NaLow) OR (NOT bAP AND NaMax) 
  rf: ( active: 4x )

 hypothesis: NOT (ca2+ full)
  action: [Ca2+ increase]
  trace: 

NDMAOpenLow: Episode

episode: NDMAOpenLow
  contained_by: BEH-POST

  in_context: NOT bAP AND NaMedium 
  rf: ( active: 12x )

 hypothesis: NOT (ca2+ full)
  action: [Ca2+ increase]
  trace: 

sec: behaviors POST

:Context

:Episode

min: behaviors POST

BEH-POST-AMPA: Container

container: BEH-POST-AMPA

 tub_intricated:
  - Nt ( contained_by: BEH-SYN )

 context_intricated:
  - Na ( contained_by: BEH-POST )

ms: behaviors AMPA

CheckNTPost: Context

context: CheckNTPost
  contained_by: BEH-POST

  in_context: Fixed
  rf: ( active: 8x )

  condition: (NT mediumness) 
    out_context: NTMedium

  condition: (NT fullness) 
    out_context: NTFull

AmpaOpenMaximum: Episode

episode: AmpaOpenMaximum
  contained_by: BEH-POST-AMPA

  in_context: NTFull
  rf: ( active: 2x )

 hypothesis: (NT mediumness)
  action: [Na increase]
  trace: 

AmpaOpenMedium: Episode

episode: AmpaOpenMedium
  contained_by: BEH-POST-AMPA

  in_context: NTMedium
  rf: ( active: 4x )

 hypothesis: (NT mediumness)
  action: [Na increase]
  trace: