diff --git a/elements/neuron/appunti/2026-06-26-biological-reference_v14.md b/elements/neuron/appunti/2026-06-26-biological-reference_v14.md deleted file mode 100644 index e1466cf..0000000 --- a/elements/neuron/appunti/2026-06-26-biological-reference_v14.md +++ /dev/null @@ -1,360 +0,0 @@ -# Tripartite Synapse — Biological Reference (companion to v14 pseudocode) - -> Companion to `tripartite_synapse_v14_pseudocode.md` · principle: `logic_principles_v3` (The -> Timescale Ladder). Explains the biology each variable and behavior conflates. v14 adds -> per-component plain-language intros, regroups budget refill under RECOVER, adds presynaptic -> short-term potentiation (possible_tag → VGCC coupling occupancy, the presynaptic parallel to -> postsynaptic AMPA-surface occupancy), and surfaces four timescale tiers — FAST (ms–s, traces), -> MEDIUM (s–min, occupancy + evidence), SLOW (hr, tag), PERSISTENT (NIGHT-written capacity). - ---- - -## The three synaptic components and their support structures - -A SYNAPSE is composed of three first-class components: -- **PRE** — presynaptic bouton (the axon's terminal at this synapse) -- **POST** — postsynaptic spine (the dendrite's terminal at this synapse) -- **ASTRO** — astrosynapse, the perisynaptic astrocytic process (the astrocyte's terminal) - -Each has an upstream support structure that supplies it: -- **AXON** supplies PRE (transmission + transport from soma) -- **DEND** supplies POST (integration + transport from soma) -- the **astrocyte cell body** supplies ASTRO (energy + ECM material) -- **SOMA** is the integrating center and the root of neuronal material - -The compartment analogy: AXON:PRE = DEND:POST = astrocyte-body:ASTRO = supply line : terminal. - ---- - -## Resource variables - -### DAY budget (one per component) -Aggregates fast energy AND fast consumables — everything needed to run moment-to-moment. - -- **pre_budget** — ATP for VGCC gating, vesicle fusion (SNARE), VATPase vesicle refill, - plus fast consumables: vesicle membrane lipids, synaptotagmin recycling. -- **post_budget** — ATP for the NaK pump (membrane reset after current), NMDA current - handling, plus fast actin monomers for transient spine changes and receptor-recycling lipids. -- **dend_budget** — ATP for bAP propagation (NaK reset along branch), local translation - (ribosome running cost), SERCA Ca²⁺ resequestration, plus fast mRNA consumed by translation. -- **soma_budget** — ATP for AP generation (Na⁺/K⁺ currents + NaK reset), CREB - phosphorylation, nuclear Ca²⁺ handling, plus shipping running costs. -- **axon_budget** — ATP for AP propagation at nodes of Ranvier, kinesin/dynein motor - running cost, fast myelin maintenance. -- **astro_central_budget** — ATP from glycolysis at the astrocyte cell body; funds EAAT - clearance, serine→D-serine synthesis, lactate export, fast process motility. - -### astro_lactate[i] -Lactate exported from the astrocyte cell body to synapse i. Biologically: glucose → -(glycolysis) → lactate, released into extracellular space, absorbed by neuronal MCT2 -transporters, converted to pyruvate → TCA → ATP in the neuron's mitochondria. The astrocyte -is the primary fast-energy supplier to pre, post, and dend. - -### NIGHT energy (one per component) — NOT recoverable -ATP for structural assembly. Distinct from DAY budget because it is spent on building, and -the work of assembly is thermodynamically gone once done (cannot be recovered by disassembly). -- pre_energy: RIM/Munc13 incorporation, VGCC clustering. -- post_energy: CaMKII anchoring, actin polymerization, PSD scaffold remodeling. -- dend_energy: mitochondria incorporation, cytoskeletal reinforcement. -- soma_energy: ribosome biogenesis, ion-channel incorporation. -- axon_energy: myelination, microtubule stabilization. -- astro_energy: process retraction, ECM secretion, racemase upregulation. - -### NIGHT material (one per component) — RECOVERABLE -Slow structural proteins. Recoverable because disassembly (LTD) returns the proteins to a -reusable pool (ubiquitin-proteasome → amino acids; internalized receptors → endosomal reserve). -- **soma_material** (root) — all neuronal structural proteins from CREB-driven synthesis: - AMPA subunits, PSD scaffold, AZ scaffold, mRNA transcripts (Arc, BDNF), organelles. -- **dend_material** — from soma: Arc/plasticity mRNA, mitochondria, cytoskeletal proteins, - AMPA subunits in transit to spines. -- **post_material** — from dend: AMPA receptor subunits (GluA1/2), PSD scaffold (PSD-95, - SHANK, Homer), structural actin, CaMKII. -- **axon_material** — from soma: kinesin/dynein motors, microtubule components, myelin proteins. -- **pre_material** — from axon: RIM, Munc13, VGCC subunits, structural vesicle proteins. -- **astro_material** (root: astrocyte cell body) — EAAT proteins, serine racemase, ECM - proteins (Glypicans, Thrombospondins), process cytoskeleton. - -**Why energy and material are separate in NIGHT but combined in DAY:** during DAY both are -fast consumables replenished on the same timescale, so one `budget` variable suffices. During -NIGHT they diverge — material is recoverable after LTD, energy is not — so they must be two -variables. This asymmetry (material returns to the pool, energy is gone) is what makes one -synapse's depression genuinely fund another's potentiation. - ---- - -## Structural variables (strength ceilings — written in NIGHT) - -Each aggregates several correlated structural properties into one capacity. - -- **pre_structure** — active zone capacity: - slot_ceiling (number of vesicle docking slots) + VGCC_coupling (Ca²⁺-channel proximity to - slots, sets release efficiency) + refill_ceiling (max RRP replenishment rate). -- **post_structure** — spine sensitivity capacity: - slot_ceiling (number of PSD anchoring slots for AMPA) + spine_volume (local reserve and - actin machinery) + reserve_ceiling (endosomal AMPA pool size). -- **dend_structure** — branch capacity: - bAP_fidelity(position) (mitochondrial density sets propagation strength, attenuates with - distance) + translation_ceiling (local mRNA capacity) + transport_speed (cytoskeletal integrity). -- **soma_structure** — somatic output capacity: - baseline_threshold (inverse: ion-channel density at axon initial segment) + AP_reliability - (Na⁺ channel density) + synthesis_ceiling (ribosome density + CREB machinery). -- **axon_structure** — axonal capacity: - propagation reliability (myelination density) + transport_ceiling (motor density + microtubule - integrity) + mitochondrial density. -- **astro_structure** — astrosynaptic environmental capacity: - perisynaptic_distance⁻¹ (wall proximity — closer = more glutamate contained) + EAAT_density - (clearance ceiling) + Dserine_tonic (baseline co-agonist) + ECM_integrity. - **Self-reinforcing both directions:** tighter wrap + more tonic D-serine make future - potentiation easier; looser wrap + zero tonic D-serine make future depression easier. - ---- - -## Budget ceilings (endurance ceilings — written in NIGHT) - -- **{component}_budget_ceiling** — the maximum fuel the component can hold / the maximum - duration of sustained behavior. Biologically: mitochondrial density and local fuel-storage - capacity. Built by activity-driven mitochondrial biogenesis; lost by mitophagy when idle. - Parallel to structure: structure is strength capacity, budget_ceiling is endurance capacity. - ---- - -## Trace variables - -### fast_trace (one per component) — DAY only, decays automatically -The local record of recent activity that biases the next behavior. -- **pre_fast_trace** — residual presynaptic Ca²⁺ after spikes (τ≈100ms). Biases NT release - (facilitation) and provides tagging eligibility. -- **post_fast_trace** — spine Ca²⁺ amplitude × rise-speed (τ≈tens ms). Encodes the LTP-vs-LTD - instruction (fast rise → CaMKII → potentiation; slow rise → phosphatase → depression). -- **dend_fast_trace** — branch Ca²⁺ from bAP + spine spillover (τ≈300ms). Integrates branch co-activity. -- **soma_fast_trace** — nuclear Ca²⁺ from each AP (τ≈seconds). Drives toward CREB activation. -- **axon_fast_trace** — propagation load (τ≈seconds). High load → Na⁺ inactivation at branch - points → propagation failure (this is axonal short-term depression). -- **astro_fast_trace** — perisynaptic Ca²⁺ from mGluR5 activation by glutamate spillover - (τ≈seconds). Drives D-serine release. - -### soma timing traces (emergent refractory + adaptation + alignment) -- **soma_Na_inactivation** (τ≈ms) — sodium-channel inactivation after an AP. Its recovery IS - the refractory period (emergent, not a hardcoded timer). High → absolute refractory; decaying - → relative refractory; recovered → normal. -- **soma_adaptation** (τ≈100s of ms) — slow K⁺ channel (SK/M-type) activation accumulating - over a spike train, raising threshold. This is spike-frequency adaptation. -- **soma_refractory_alignment** — deposited when a suprathreshold input arrives during - refractoriness (a missed coincidence). Speeds future recovery so the soma aligns to its input - rhythm. Bottom-up: no rhythm is represented; alignment emerges from accumulated local - mismatches and decays when mismatches stop (self-limiting). - -### possible_tag (one per component) — intermediate, τ≈s–min -Graded accumulation of tagging eligibility. For POST, this is the CANDIDATE tag lifetime. - -### endurance_need (one per component) — intermediate, τ≈s–min -Deposited when budget depletion interrupts a behavior that was on a LOCALLY successful -trajectory. Records that fuel — not structure, not significance — was the binding constraint -on a forming success. Requires NO dopamine (homeostatic, not associative). -**Local success proxy per component** (each uses only its own state + arrived signals): -- PRE: own fast_trace high (was releasing strongly), optionally amplified by retrograde - messenger (endocannabinoid / NO / BDNF) that has arrived. -- POST: own Ca²⁺ climbing toward tagging threshold (naturally local). -- DEND: own branch strongly active (high branch voltage/Ca²⁺) when propagation fell short. -- SOMA: own nuclear Ca²⁺ climbing toward CREB. -- AXON: own propagation load high (was carrying a strong train). -- ASTRO: own local glutamate/Ca²⁺ high (was under heavy clearance/D-serine demand). - -### tag (one per component) — DAY→NIGHT bridge, τ≈hours -The validated record of significance that survives to NIGHT and gates strength commits. -Formed by coincidence of local eligibility + non-local validation (dopamine). -**POST is special — two-phase, three coincidences:** -- CANDIDATE: local Ca²⁺ above threshold + astrosynapse D-serine present (coincidence 1). -- amplified when bAP confirms soma fired (coincidence 2). -- STABLE: CANDIDATE + dopamine within stabilization window (coincidence 3). -Biologically: early CaMKII creates a labile tag (early-LTP); PKA driven by dopamine via D1R -stabilizes it (late-LTP). Without dopamine, the candidate degrades — early-LTP reverses. - ---- - -## Behaviors — biological meaning - -### PRE | AP — neurotransmitter release -`NT_flux = RRP × sat(pre_fast_trace, K_release)` models continuous NT release proportional to -the readily-releasable pool and a saturating Ca²⁺ drive (synaptotagmin's cooperative Ca²⁺ -sensitivity, simplified to a saturating curve). RRP depletes as released (short-term depression -as a consequence) and refills via VATPase (energy-throttled, so low budget deepens depression). -The mGluR2/3 brake is presynaptic autoinhibition by spillover (Gi → reduced VGCC opening). - -### POST | NOT_bAP — three calcium sources, two plasticity cases -- **Source 1 (AMPA):** glutamate opens AMPA → depolarizing current + small Ca²⁺; the - depolarization begins ejecting the NMDA Mg²⁺ block. -- **Source 2 (NMDA):** if depolarized enough (Mg²⁺ ejected) AND D-serine present (astrocyte - co-agonist) AND glutamate bound → large Ca²⁺ influx. This is the coincidence detector. -- **Source 3 (bAP, separate context):** back-propagating AP adds depolarization + Ca²⁺, - amplifying an existing signal supralinearly. -- **Case 1 (STP):** high Ca²⁺ drives AMPA receptors from the local reserve to the surface, - bounded by the anchoring-slot ceiling. Fast, reversible, NO dopamine. When Ca²⁺ falls, - receptors drift back — short-term depression as a passive consequence, never signaled. -- **Case 2 (LTP tag):** high Ca²⁺ + (later) dopamine sets the tag that NIGHT uses to raise the - slot ceiling. NIGHT builds slots; DAY fills them. - -### DEND | bAP — bidirectional signaling -Propagates the bAP from soma toward spines (fidelity attenuates with distance — distal spines -get weaker confirmation, are harder to potentiate) and integrates spine signals toward the soma. - -### SOMA | AP — integration, firing, emergent timing -Fires when integrated branch input exceeds a threshold that is the baseline (from structure) -raised by adaptation and modulated by neuromodulators, gated by the emergent refractory state. -Each AP deposits three traces (inactivation → refractory, adaptation → threshold rise, nuclear -Ca²⁺ → plasticity). The soma is the coincidence detector at the cellular scale (nuclear Ca²⁺ + -dopamine → CREB), and the production bottleneck: its tag gates how much material all downstream -components get in NIGHT. - -### AXON | AP — reliable propagation with frequency-dependent failure -Propagation reliability is set by myelination and degraded by high-frequency load (Na⁺ -inactivation at branch points = axonal STD). The axon also transports material to boutons and -sets the timescale of presynaptic structural commits. - -### ASTRO | CONTINUOUS — gatekeeper and energy hub -Clears glutamate (EAAT), supplies D-serine (the NMDA co-agonist that gates postsynaptic LTP), -and distributes lactate to the territory by demand-weighting (active synapses generating more -clearance load pull more fuel; slow synapses get less). The same spillover that excites the -astrocyte (mGluR5 → Ca²⁺ → D-serine) also brakes the presynapse (mGluR2/3 → Gi) — one signal, -opposite effects via different receptors. The astrocyte is the energy root and the gain control -of the whole synapse. - ---- - -## NIGHT operations — biological meaning - -- **Step 1 (replenish/distribute):** overnight protein synthesis peaks (CREB-driven, gated by - soma_tag — corresponds to slow-wave-sleep replay). Soma material flows to branches/axon then - spines/boutons; astrocyte material flows to astrosynapses, tag-weighted. -- **Step 2 (strength commits):** tagged components build structure — more slots, tighter - coupling, tighter astrosynaptic wrap. Coherence bonus when pre+post+astro all tagged (the - whole synapse agrees). astro_structure self-reinforces. -- **Step 2b (endurance commits):** components with high endurance_need build budget_ceiling — - mitochondrial biogenesis. Competes with step 2 for the same material/energy. -- **Step 3 (passive decay):** both ceilings decay; maintenance from the remaining pool resists - decay only where sufficient. Depotentiation and endurance-loss are both by neglect — no - signal weakens anything; unmaintained capacity simply drifts down. Recovered material (not - energy) returns to pools. -- **Step 4 (homeostatic scaling):** if the soma fired too much overall, all synapses scale down - proportionally (sleep-associated global downscaling), preserving relative differences. -- **Step 5 (clear traces):** fast traces, possible tags, endurance needs, and soma timing traces - reset; tags below expiry clear, above-expiry tags carry forward (multi-night consolidation); - structure and budget_ceiling persist. - -### Shockwave lockdown -Emergency global astrocytic Ca²⁺ wave → GABA + ATP release → mass AMPA internalization and -hyperpolarization. Bypasses budget gates. A circuit breaker against runaway excitation. - ---- - -## Pool-filling: private reserve vs contested supply - -The pseudocode uses two filling primitives, distinguished by where the resource comes from. - -**`fill` (private reserve).** The pool is replenished from a source the component owns -outright, uncontested by siblings, bounded by the component's own ceiling and a rate cap. -- RRP refill — vesicles mobilized from the bouton's own reserve pool toward the docking-slot - ceiling, rate-limited by VATPase. The reserve is private to the bouton. -- SOMA self-replenish — the soma fuels itself from its own mitochondria toward its budget - ceiling. No other component draws on it. - -**`refill` (contested supply).** The pool is replenished from a supply that multiple -components compete for, rationed by demand (gap to ceiling). -- pre/post/dend/axon budgets — drawn from astrocytic lactate (shared across all synapses the - astrocyte wraps) plus shipment from soma/axon/dendrite (shared across downstream targets). - -**Neither primitive (their own forms).** Some inflows are not fills toward a ceiling: -- AMPA surface insertion — Ca²⁺-driven rate from the spine's private endosomal reserve, with - an explicit passive drift-back (short-term depression) when Ca²⁺ is low. Not a steady fill. -- D-serine release — demand-driven (saturating in astro Ca²⁺) and budget-limited, like NT - release; a release process, not a pool top-up. -- Root productions — `glycolysis(glucose)` at the astrocyte and `CREB_synth(soma_tag)` at the - soma are the system's energy and material roots: raw inflows capped only by the external - vascular supply, not fills toward an internal ceiling. - -The distinction matters biologically: a private reserve guarantees a component some autonomy -(the bouton can refill its RRP from its own vesicles even when lactate is scarce), while a -contested supply couples a component's fate to its neighbours' demands (operational budget -fails first where many active synapses compete for the same lactate). - ---- - -## PRE ↔ POST interaction: local computation, message-only coupling - -The presynapse and postsynapse never read each other's internal state. They interact only -by writing to and reading from shared cleft channels. Each side computes entirely locally on -what it has: its own variables plus whatever signals have arrived in the cleft. This is the -message-passing realization of the locality principle. - -**Forward channel — glutamate (PRE → POST and ASTRO).** The presynapse writes glutamate via -NT_flux. The postsynapse reads it (AMPA, NMDA) and the astrosynapse reads it (clearance, -mGluR5). The astrosynapse clears it. PRE never knows whether POST responded — it only emits. - -**Gate channel — astro_Dserine (ASTRO → POST).** The astrosynapse writes D-serine; the -postsynapse reads it as the obligatory NMDA co-agonist. POST cannot open NMDA without this -arrived signal, but it does not read the astrocyte's state — only the delivered D-serine. - -**Backward channel + — retro_NO (POST → PRE).** When the postsynapse's NMDA opens (Mg²⁺ -ejected, D-serine present, glutamate bound), nNOS — physically tethered to the NMDA receptor -through PSD-95 — synthesises nitric oxide (and, on a slower timescale, BDNF is released). -These diffuse retrogradely to the presynapse. Biologically this is the classic retrograde -messenger of LTP: it tells the bouton that its release landed on a postsynapse that genuinely -responded. In the model, POST emits `retro_NO` proportional to its own NMDA-driven calcium — -computed purely from POST's local state — and PRE reads it as `retro_NO_local`. - - `retro_NO_local` is exactly the grounding of the presynaptic endurance signal. The - presynapse's local success proxy is "I was releasing strongly" (`pre_fast_trace` high). On - its own that only says the bouton was working hard, not that the work mattered. `retro_NO` - adds the missing confirmation — that the postsynapse responded — without PRE ever reading - POST's calcium. So PRE deposits endurance need as `pre_fast_trace × (1 + retro_NO_local)`: - strong release that was confirmed effective makes the strongest claim that fuel, not - futility, was what interrupted a forming success. retro_NO is short-lived (NO degrades and - diffuses within seconds), so the channel decays fast — confirmation must be recent to count. - -**Backward channel − — retro_eCB (POST → PRE).** When the postsynapse is strongly -depolarised, it synthesises endocannabinoids (2-AG, anandamide) that diffuse retrogradely and -bind presynaptic CB1 receptors, suppressing release. This is depolarisation-induced -suppression of excitation (DSE) — a homeostatic negative feedback: an over-driven postsynapse -tells the presynapse to release less. In the model, POST emits `retro_eCB` from its own -membrane potential, and PRE reads it as `retro_eCB_local`, which reduces the release drive -`sat(...) × (1 - retro_eCB_local)`. Again POST computes from its own state; PRE adjusts from -the arrived signal; neither reads the other's interior. - -The two backward channels are opposite-signed messages the postsynapse sends about its own -condition: retro_NO says "your input was effective — worth sustaining," retro_eCB says "I am -saturated — ease off." Together with the forward glutamate and the D-serine gate, they make -the synapse a fully message-coupled system of locally-computing components. - -**Why RRP refill is in NOT_AP only.** During an AP the bouton releases — RRP depletes. Refill -(VATPase reloading vesicles from the reserve pool) is a recovery process that proceeds between -spikes. Placing `fill(RRP, ...)` only in the NOT_AP context makes the AP context pure -depletion and the NOT_AP context pure recovery. A consequence falls out for free: during -sustained high-frequency firing there are many AP steps and few NOT_AP steps, so RRP depletes -faster than it recovers — short-term depression deepens with frequency, with no explicit -depression rule. The release itself is throttled further when budget is low (VATPase refill -is energy-limited), coupling metabolic state to the depth of depression. - - ---- - -## Presynaptic short-term potentiation — VGCC coupling occupancy - -`VGCC_active` is the presynaptic parallel to the postsynaptic `AMPA_surface`. Both are MEDIUM-tier -occupancy variables: a current operating value filled toward a NIGHT-built ceiling, no dopamine, -reversible, drifting back when undriven. - -Biologically, `VGCC_active` represents the effective coupling between voltage-gated calcium -channels and the vesicle docking slots — how reliably each calcium influx is converted into -release. Repeated eligible activity (accumulated `pre_possible_tag`) transiently tightens this -coupling — through calcium-channel facilitation, active-zone protein phosphorylation, and -channel-to-sensor proximity changes — raising release efficiency without changing the number of -channels (which is the structural ceiling `pre_structure.VGCC_coupling`, written only at NIGHT). -When eligibility falls, the coupling relaxes back to baseline over seconds-to-minutes: presynaptic -short-term depression as the passive consequence of undriven coupling, never a signalled act. - -This gives the presynapse a genuine intermediate-timescale memory it previously lacked — a -"this bouton has been reliably active lately" state that outlasts individual spikes and bursts, -filling the gap between the fast trace (residual calcium, ~100 ms) and the tag (hours). It also -completes the capacity/occupancy symmetry across the synapse: both PRE and POST now fill a -MEDIUM occupancy variable toward a PERSISTENT structural ceiling, rather than PRE reading its -ceiling directly as if capacity and occupancy were the same thing.