--- **What needs adjustment** `Voltage-Context` is labelled as an Episode but contains sub-episodes — it should be a Context. Same for `NMDA-Coincidence` and `Ca-Dynamics & ATP-Drain`. You have used Episode and Context interchangeably in a few places; the distinction matters for the specification: a Context sets the conditions, an Episode is a named outcome within those conditions. `Vpost_Maximum` lists `V_bAP full OR (g_AMPA full AND V_bAP medium)` — this is correct Boolean logic and should be kept exactly as written. It captures the two ways the postsynapse can reach maximum depolarisation: the bAP alone if it is strong enough, or AMPA plus a partial bAP together. `AMPA_Population_Increase` correctly gates on `ATP_level_post NOT empty` — LTP requires ATP for CaMKII phosphorylation and receptor trafficking. LTD does not have the same gate in your spec. This is slightly asymmetric — LTD (receptor internalisation via endocytosis) is also ATP-dependent, though less so than LTP. Worth noting. `Plasticity_LTD` covers `Ca_post_history medium` but does not cover the case where `Ca_post_history` is empty — a completely silent synapse also weakens over time (homeostatic depression). This can be left as a gap or named explicitly. `Astrocyte_Supply_Crises` has a typo (Crises → Crisis). The bAP needs new parameters and state variables in the model before it can be expressed as a fully implemented behavior. I will add those inline as `[GAP — to implement]` markers so the spec is complete even where the code is not yet written. --- **Final restructured specification** ``` BEH-POST-UNIFIED: The Integrated Postsynaptic Model ===================================================== Three loops, three timescales, one shared astrocyte supply. Each loop feeds the next: V_post enables NMDA, NMDA drives Ca_post, Ca_post determines plasticity and eCB, ATP sustains all three. Failure of ATP does not silence the postsynapse (unlike the presynapse) — it corrupts it, triggering false retrograde signals and risking excitotoxic Ca2+ accumulation. Variables: V_bAP — back-propagating AP amplitude (0→1) [GAP — requires bAP_train input, analogous to presynaptic spike_train] g_AMPA — AMPA receptor conductance (= receptor_conductance) V_post — total postsynaptic membrane potential (0→1) NT_cleft — glutamate in cleft (from presynapse) Desensitization — fraction of AMPA receptors desensitized (0→1) Ca_post — free Ca2+ in postsynaptic spine (0→...) Ca_post_history — 2 s rolling mean of Ca_post ATP_level_post — normalised postsynaptic ATP (0→1) ATP_demand_post — accumulated ATP cost since last metabolic cycle g_AMPA_baseline — long-term AMPA receptor density set by plasticity [GAP — not yet in model; LTP/LTD would write this] eCB_level — endocannabinoid retrograde signal (0→1) written here, read by presynapse Loop 1 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ms: behaviors — Fast Kinetics and Gate Logic ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Voltage-Context: Context Determines the total depolarisation (V_post) available to lift the NMDA Mg block. Two independent sources contribute: AMPA-driven local depolarisation (g_AMPA) and the somatic back-propagating AP (V_bAP). Either alone can partially depolarise; both together reach maximum. Vpost_Maximum: Episode — V_bAP full OR — g_AMPA full AND V_bAP medium — Result: V_post high enough for complete Mg block removal. NMDA gate can open fully. Both ATP costs charged at maximum rate. Vpost_Attenuated: Episode — g_AMPA medium AND V_bAP empty/low OR — g_AMPA low AND V_bAP medium — Result: V_post sub-threshold. Mg block partially remains. NMDA gate opens partially or not at all. This is the most common state during low-rate firing without a coincident bAP. Vpost_Passive: Episode — g_AMPA empty AND V_bAP empty — Result: V_post at rest. Mg block fully intact. No Ca_post entry possible. Na/K-ATPase cost minimal. Desensitization-Context: Context Modulates g_AMPA independently of NT_cleft. Sustained NT exposure drives receptors into a closed state that persists even when NT remains present. DesensitizationRising: Episode — NT_cleft sustained high (multiple consecutive ms) — Desensitization rises each ms — g_AMPA effectively reduced despite NT presence — attenuates Vpost_Maximum toward Vpost_Attenuated DesensitizationRecovering: Episode — NT_cleft low or empty — Desensitization decays with tau_desensitization = 500 ms — g_AMPA ceiling restored gradually NMDA-Coincidence: Context Strict AND gate: both NT (ligand) and V_post (voltage) must be simultaneously non-zero for Ca_post to rise. Unlike presynaptic VGCCs which open with any spike, NMDA requires coincidence. This makes Ca_post a detector of coordinated pre+post activity, not just input rate. NMDA_Open: Episode — NT_cleft full AND V_post maximum (Vpost_Maximum active) — Mg block fully lifted — Ca_post surges — LTP territory — ATP_demand_post rises sharply (PMCA must clear Ca_post) — if sustained → Ca_post_history crosses eCB threshold NMDA_LogicBlocked: Episode — NT_cleft full BUT V_post attenuated or passive — Mg block partially or fully intact — Ca_post does not rise despite NT presence — Result: presynapse fired but postsynapse was not ready No plasticity signal generated This is the mechanism for input selectivity: only synapses active during postsynaptic firing produce a Ca_post signal NMDA_LigandBlocked: Episode — V_post maximum BUT NT_cleft empty — No glutamate to open the channel — Ca_post entry zero despite full depolarisation — Result: bAP arrived but presynapse was silent Again no plasticity signal The AND logic enforces true coincidence Ca-Dynamics-Context: Context Ca_post clearance rate depends entirely on ATP_level_post. This is the bridge from the ATP loop into the Ca2+ loop. When ATP fails, Ca_post clearance fails, and the Ca2+ loop becomes corrupted — Ca_post reflects pump state rather than genuine coincidence events. Clearance_Optimal: Episode — ATP_level_post full → pump_scale_post near 1 — PMCA (ATP-gated) + NCX (always on) both clearing — Ca_post returns to baseline between events — Each coincidence event is temporally isolated — ATP_demand_post increases proportionally to Ca_post load Clearance_Reduced: Episode — ATP_level_post medium → pump_scale_post reduced — Ca_post clears more slowly — Residual elevation begins accumulating between events — Ca_post_history starts drifting upward — eCB threshold may be approached during heavy firing Clearance_Failing: Episode — ATP_level_post low or empty → pump_scale_post near 0 — Only NCX clearing (floor, not rescue) — Ca_post accumulates regardless of coincidence activity — False Trigger conditions: Ca_post_history crosses eCB threshold without genuine NMDA overactivity — Excitotoxicity risk if Ca_post elevation is sustained ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ sec: behaviors — Signal Integration and Fate ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Synaptic-Weight-Decision: Context Ca_post_history (2 s rolling mean of Ca_post) determines the plasticity signal. The threshold logic is graded: the same variable produces opposite outcomes depending on whether it is above or below the LTP/LTD boundary. ATP_level_post gates LTP expression but not LTD — strengthening requires energy, weakening does not. Plasticity_LTP: Episode — Ca_post_history full (above Ca_post_LTP threshold) — High-frequency or high-amplitude coincidence detected — Tags synapse for AMPA receptor insertion — Requires ATP_level_post NOT empty for expression (CaMKII phosphorylation and receptor trafficking are ATP-dependent — energy failure blocks LTP even if the Ca_post signal is correct) — [GAP] LTP expression writes g_AMPA_baseline upward in the minutes loop Plasticity_Boundary: Episode — Ca_post_history medium — Poorly timed or low-frequency coincidence — Neither LTP nor LTD threshold crossed — Synapse weight unchanged this cycle Plasticity_LTD: Episode — Ca_post_history low but non-zero — Weak or mistimed coincidence — presynapse fired but postsynapse was not sufficiently depolarised — Tags synapse for AMPA receptor removal — Less ATP-dependent than LTP; can proceed under mild energy stress — [GAP] LTD expression writes g_AMPA_baseline downward in the minutes loop Plasticity_Silent: Episode — Ca_post_history empty (prolonged absence of activity) — Homeostatic depression: unused synapses weaken — [GAP] not yet modelled; would require Ca_post_trace integration over hours Retrograde-Feedback: Context eCB synthesis is triggered by Ca_post_history, not V_post. It is Ca2+ in the spine — not voltage — that activates the enzymes (DAGL, PLC) that produce endocannabinoids. The model cannot distinguish internally between the two causes of elevated Ca_post_history (genuine vs pump failure) but the consequences differ: one is communication, the other is survival. eCB_Synthesis_Active: Episode — Ca_post_history > eCB_threshold (0.7) — Logic A (Genuine Protection): Cause : sustained NMDA_Open events — real overactivity Effect : appropriate retrograde stop signal Outcome : presynapse reduces NT → NT_cleft falls → NMDA closes → Ca_post load drops → Ca_post_history falls → eCB synthesis subsides Loop closes correctly — Logic B (False Trigger — Excitotoxic Protection): Cause : Clearance_Failing — Ca_post elevated by pump failure, not genuine coincidence Effect : presynapse silenced without real overactivity Outcome : NT_cleft falls → NMDA closes → Ca_post load drops → ATP_demand_post falls → ATP_level_post recovers → pumps restart → Ca_post clears → Ca_post_history falls → eCB synthesis subsides Desperate survival loop — buys time for metabolic recovery eCB_Synthesis_Idle: Episode — Ca_post_history < eCB_threshold — eCB_level decays with tau_eCB_decay = 10000 ms — Presynaptic suppression lifts gradually — 10 s decay means suppression outlasts the trigger — prevents immediate re-engagement before Ca_post has stabilised ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ min: behaviors — Bioenergetics and Structural Change ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Metabolic-Recovery: Context ATP_level_post is computed from Glucose_level (shared supply) minus ATP_demand_post (postsynaptic-specific cost). The shared supply creates the coupling: both pre and post deplete the same astrocyte glucose budget simultaneously. Presynaptic silence is therefore metabolically beneficial to the postsynapse — less NT means less NMDA activation means less Ca_post means less PMCA cost. Astrocyte_Supply_Active: Episode — Glucose_level full — ATP_demand_post within supply capacity — ATP_level_post replenished each cycle — All three loops operating normally Astrocyte_Supply_Stressed: Episode — Glucose_level medium OR ATP_demand_post elevated — ATP_level_post partially reduced — Clearance_Reduced begins — Plasticity_LTP at risk (ATP dependency) Astrocyte_Supply_Crisis: Episode — Glucose_level low OR ATP_demand_post chronically high — ATP_level_post near empty — Clearance_Failing — only NCX clearing Ca_post — False Trigger likely → eCB_Synthesis_Active (Logic B) — Presynaptic silence indirectly reduces postsynaptic ATP demand — the coupled protection mechanism Structural-Update: Context Long-term changes to AMPA receptor density. These are the physical substrate of learning and memory. [GAP] g_AMPA_baseline not yet implemented in the model. Would be written in Loop 3 and read by Loop 1 as the ceiling of receptor_conductance. AMPA_Population_Increase: Episode — Triggered by Plasticity_LTP — AND ATP_level_post NOT empty — g_AMPA_baseline shifts higher for next cycle — More AMPA receptors → stronger Vpost_Maximum — Easier to reach NMDA_Open in future events — Positive feedback: LTP makes future LTP more likely AMPA_Population_Decrease: Episode — Triggered by Plasticity_LTD or Plasticity_Silent — g_AMPA_baseline shifts lower — Fewer AMPA receptors → Vpost_Attenuated more common — Harder to reach NMDA_Open → weakens synapse further — Negative feedback: LTD stabilises by reducing future coincidence probability ``` --- --- ## short term Short-term potentiation (STP) and short-term depression (STD) are distinct from LTP/LTD in a fundamental way: they are **temporary** changes that last seconds to minutes and leave no lasting structural trace. They do not require the postsynapse at all — they are entirely presynaptic phenomena in most cases, and they operate on a completely different mechanism. --- **What they are and where they live** Short-term plasticity is driven by the **history of presynaptic Ca²⁺** and **vesicle pool state**, not by postsynaptic coincidence detection. The table we just built describes long-term plasticity — structural changes to AMPA density driven by Ca_post. Short-term plasticity describes transient changes to **how much NT the presynapse releases** on the next spike, driven by what happened on the last few spikes. There are two opposing forms: **Short-term potentiation / facilitation** — if a spike arrives shortly after the previous one, residual Ca²⁺ from the first spike has not fully cleared. The next spike adds to this residual, producing a larger Ca_post microdomain and therefore a higher release probability. The synapse releases more NT on the second spike than the first. This is already partially captured in the presynaptic model through `Tr_Ca` — elevated calcium trace from recent activity speeds up RRP recruitment and effectively increases release efficiency. **Short-term depression** — if spikes arrive rapidly, the RRP depletes faster than it can be refilled. Each successive spike releases fewer vesicles because there are fewer available. NT release drops with each spike in a burst. This is already the core of CASCADE 1 in the presynaptic model — RRP depletion under high firing rate. --- **Where they fit in the model** Both are already implicitly present in the presynaptic ms and seconds loops: ``` Short-term facilitation: Residual Ca_micro from spike N → elevated Ca_micro at spike N+1 → higher release fraction in deterministic_release (Hill curve) → more NT per spike → decays as Ca_micro clears between spikes (tau ~100-200 ms) Short-term depression: Rapid firing depletes N_RRP → fewer vesicles available per spike → released_NT falls → recovers as RP→RRP recruitment refills (seconds timescale) ``` The timescale of each depends on parameters already in the model: | Form | Timescale | Driven by | Recovery | |--------------|------------|-------------------|-------------------------| | Facilitation | 100-500 ms | residual Ca_micro | Ca²⁺ clearance rate | | Depression | seconds | RRP depletion | RP→RRP recruitment rate | --- **What is missing from the current model** The model captures both implicitly but does not name them as behaviours. Two things are genuinely absent: **Augmentation** — a slower form of facilitation lasting 5-10 seconds, driven by residual Ca²⁺ accumulating in the presynaptic terminal across many spikes. It is distinct from spike-by-spike facilitation and would require a second, slower Ca²⁺ trace with `tau ~5000 ms`. The current `Tr_Ca` with `tau = 1000 ms` is between the two — it captures some augmentation but not cleanly. **Post-tetanic potentiation (PTP)** — an even slower presynaptic enhancement lasting minutes after a high-frequency burst, driven by protein kinase C activation from sustained Ca²⁺ elevation. This is a presynaptic phenomenon that looks like LTP from the outside but has no postsynaptic component and no structural change. It would require a third, very slow trace variable. --- **How they interact with the LTP/LTD table** Short-term and long-term plasticity operate on the same synapse simultaneously but independently: ``` Spike arrives → short-term: how much NT releases THIS spike (presynaptic, ms-seconds) → long-term: does the synapse get stronger or weaker PERMANENTLY (postsynaptic, mins-hours) ``` A synapse can be undergoing LTD (slowly losing AMPA receptors over minutes) at the same time as it is showing short-term facilitation (releasing more NT per spike due to residual Ca²⁺). The two processes do not interfere — they act on different variables through different mechanisms. The important implication for your model is that **the LTP/LTD table we built describes what happens to** `g_AMPA_baseline` **over minutes**. Short-term potentiation/depression describes what happens to `released_NT` over milliseconds to seconds. They are different outputs of the same synapse, running in parallel. If you want to add short-term plasticity explicitly to the behaviour specification it would live entirely in the presynaptic ms and seconds loops as named episodes of existing variables: ``` — ms (presynapse, short-term plasticity): ShortTermFacilitation: Episode — residual Ca_micro > 0 at next spike arrival — release_frac in deterministic_release elevated above baseline — decays as Ca_micro clears (tau ~100-500 ms) — more NT per spike than at rest ShortTermDepression: Episode — N_RRP depleted by rapid successive spikes — release_frac unchanged but N_RRP reduced — fewer absolute vesicles released per spike — recovers via RP→RRP recruitment (seconds) — seconds (presynapse, short-term plasticity): Augmentation: Episode [GAP — not yet modelled] — requires second slow Ca2+ trace (tau ~5000 ms) — elevated release probability for 5-10 s after burst — distinct from spike-by-spike facilitation PostTetanicPotentiation: Episode [GAP — not yet modelled] — requires very slow trace (tau ~minutes) — elevated release probability for minutes after tetanus — presynaptic only, no postsynaptic component ```