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@@ -64,207 +64,220 @@ The astrocyte's perisynaptic wall distance is the variable that makes both outco
```Gen ```Gen
global state variables
// ── Fast (ms–s): wave propagation ─────────────────────────────
// Presynapse
pre_Ca_residual // leftover Ca²⁺ between spikes — short-term trace
vesicle_release_prob // P(0.1–1.0) per docking slot
RRP_pool // readily-releasable vesicle pool
reserve_pool // chained vesicles in deep storage
// Postsynapse ## global state variables
membrane_potential // Vm — depolarization state
NMDA_Mg_block // bool — mechanical clamp on/off
post_Ca_amplitude // peak [Ca²⁺] rise in spine
post_Ca_rise_speed // d(Ca)/dt — fast=LTP signal, slow=LTD signal
// Astrocyte // ── Fast (ms–s): wave propagation ─────────────────────────────
glutamate_cleft // [glu] in synaptic cleft // Presynapse
glutamate_spillover // extrasynaptic [glu] — saturates mGluRs pre_Ca_residual // leftover Ca²⁺ between spikes — short-term trace
astro_Ca_local // IP3-triggered local rise near synapse vesicle_release_prob // P(0.1–1.0) per docking slot
astro_Ca_global // soma-wide wave — network overload flag RRP_pool // readily-releasable vesicle pool
D_serine_release // gliotransmitter — NMDA co-agonist pulse reserve_pool // chained vesicles in deep storage
lactate_output // fuel export rate to pre and post
// ── Intermediate (s–min): temporary tuning ──────────────────── // Postsynapse
mGluR2_3_activation // presynaptic Gi — autoinhibitory brake membrane_potential // Vm — depolarization state
mGluR5_activation // astrocytic Gq — IP3→Ca²⁺→D-serine cascade NMDA_Mg_block // bool — mechanical clamp on/off
cAMP_level // set by dopamine/NE via Gs → adenylyl cyclase post_Ca_amplitude // peak [Ca²⁺] rise in spine
PKA_activity // downstream of cAMP post_Ca_rise_speed // d(Ca)/dt — fast=LTP signal, slow=LTD signal
GluA1_Ser845_primed // bool — AMPA insertion threshold lowered by PKA
DARPP32_phospho // bool — PP1 (LTD phosphatase) silenced by PKA
CREB_active // bool — structural gene expression enabled
// ── Slow (h–weeks): structural architecture ─────────────────── // Astrocyte
AMPA_count // surface receptors — postsynaptic sensitivity glutamate_cleft // [glu] in synaptic cleft
spine_volume // physical size of dendritic spine glutamate_spillover // extrasynaptic [glu] — saturates mGluRs
active_zone_size // docking slot count astro_Ca_local // IP3-triggered local rise near synapse
RRP_pool_capacity // max readily-releasable pool astro_Ca_global // soma-wide wave — network overload flag
VGCC_clustering // Ca²⁺ channels beneath active zone D_serine_release // gliotransmitter — NMDA co-agonist pulse
perisynaptic_distance // how close astrocyte walls are to synapse lactate_output // fuel export rate to pre and post
ECM_integrity // extracellular matrix density
D_serine_tonic_level // baseline co-agonist supply (sustained)
glutamate_clearance_rate // EAAT transporter density
fast time scale — wave propagation (ms → s)
function fire_action_potential(input_freq):
// Presynapse: launch wavefront // ── Intermediate (s–min): temporary tuning ────────────────────
pre_Ca_residual += spike_influx(input_freq) mGluR2_3_activation // presynaptic Gi — autoinhibitory brake
pre_Ca_residual *= decay(τ ≈ 100ms) // fades unless spikes keep arriving mGluR5_activation // astrocytic Gq — IP3→Ca²⁺→D-serine cascade
vesicle_release_prob *= facilitation(pre_Ca_residual) cAMP_level // set by dopamine/NE via Gs → adenylyl cyclase
released_vesicles = binomial(RRP_pool, vesicle_release_prob) PKA_activity // downstream of cAMP
glutamate_cleft = released_vesicles × quantal_content GluA1_Ser845_primed // bool — AMPA insertion threshold lowered by PKA
RRP_pool -= released_vesicles DARPP32_phospho // bool — PP1 (LTD phosphatase) silenced by PKA
CREB_active // bool — structural gene expression enabled
// Astrocyte: overflow sensing and co-agonist release // ── Slow (h–weeks): structural architecture ───────────────────
glutamate_spillover = extrasynaptic_diffusion(glutamate_cleft) AMPA_count // surface receptors — postsynaptic sensitivity
if glutamate_spillover > spillover_threshold: spine_volume // physical size of dendritic spine
mGluR5_activation = True // Gq arm → IP3 → Ca²⁺ → D-serine active_zone_size // docking slot count
astro_Ca_local += IP3_cascade(PLC) RRP_pool_capacity // max readily-releasable pool
D_serine_release += proportional_to(astro_Ca_local) VGCC_clustering // Ca²⁺ channels beneath active zone
mGluR2_3_activation = True // Gi arm → brake presynapse perisynaptic_distance // how close astrocyte walls are to synapse
cAMP_level -= Gi_inhibition(adenylyl_cyclase) ECM_integrity // extracellular matrix density
vesicle_release_prob -= VGCC_suppression() // autoinhibitory brake D_serine_tonic_level // baseline co-agonist supply (sustained)
glutamate_clearance_rate // EAAT transporter density
// Astrocyte: check for network overload ## fast time scale — wave propagation (ms → s)
astro_Ca_global = soma_wave(astro_Ca_local > OVERLOAD_threshold)
if astro_Ca_global: trigger(shockwave_lockdown)
// Postsynapse: wavefront strikes resonator function fire_action_potential(input_freq):
AMPA_current = glutamate_cleft × AMPA_count
membrane_potential += AMPA_current
// NMDA gate: coincidence check // Presynapse: launch wavefront
if membrane_potential > -40mV and D_serine_release > threshold: pre_Ca_residual += spike_influx(input_freq)
NMDA_Mg_block = False // Mg²⁺ ejected pre_Ca_residual *= decay(τ ≈ 100ms) // fades unless spikes keep arriving
post_Ca_amplitude += NMDA_influx(glutamate_cleft) vesicle_release_prob *= facilitation(pre_Ca_residual)
post_Ca_rise_speed = d(post_Ca_amplitude) / dt released_vesicles = binomial(RRP_pool, vesicle_release_prob)
glutamate_cleft = released_vesicles × quantal_content
RRP_pool -= released_vesicles
// Astrocyte: vacuum trailing echoes + fuel pipeline // Astrocyte: overflow sensing and co-agonist release
glutamate_cleft -= glutamate_clearance_rate × Δt glutamate_spillover = extrasynaptic_diffusion(glutamate_cleft)
lactate_output += glycolysis_rate(glutamate_clearance_rate) if glutamate_spillover > spillover_threshold:
membrane_potential restored by NaK_ATPase(lactate_output) mGluR5_activation = True // Gq arm → IP3 → Ca²⁺ → D-serine
RRP_pool refilled by VATPase(lactate_output) astro_Ca_local += IP3_cascade(PLC)
intermediate time scale — temporary tuning (s → min) D_serine_release += proportional_to(astro_Ca_local)
function short_term_plasticity(input_freq, duration): mGluR2_3_activation = True // Gi arm → brake presynapse
cAMP_level -= Gi_inhibition(adenylyl_cyclase)
vesicle_release_prob -= VGCC_suppression() // autoinhibitory brake
// Presynapse: facilitate or depress based on Ca²⁺ history // Astrocyte: check for network overload
if input_freq > 20Hz: astro_Ca_global = soma_wave(astro_Ca_local > OVERLOAD_threshold)
vesicle_release_prob *= 1.3 // residual Ca²⁺ primes launchpad if astro_Ca_global: trigger(shockwave_lockdown)
mobilize(reserve_pool → RRP_pool) // break storage chains
elif input_freq < 5Hz:
vesicle_release_prob *= 0.7 // RRP depleted faster than refill
// Postsynapse: NMDA gate primed if frequency sustained // Postsynapse: wavefront strikes resonator
if input_freq >= 50Hz and duration > 1s: AMPA_current = glutamate_cleft × AMPA_count
NMDA_Mg_block = False // sustained depolarization membrane_potential += AMPA_current
post_Ca_amplitude accumulates // early-LTP signal rises
// Astrocyte: sustained volume → escalate co-agonist // NMDA gate: coincidence check
if astro_Ca_local > local_threshold: if membrane_potential > -40mV and D_serine_release > threshold:
D_serine_release += gliotransmitter_pulse() // widens NMDA window NMDA_Mg_block = False // Mg²⁺ ejected
post_Ca_amplitude += NMDA_influx(glutamate_cleft)
post_Ca_rise_speed = d(post_Ca_amplitude) / dt
// Neuromodulators: set context gate via Gs protein // Astrocyte: vacuum trailing echoes + fuel pipeline
if dopamine_level > D1_threshold or NE_level > β_threshold: glutamate_cleft -= glutamate_clearance_rate × Δt
cAMP_level += Gs_activation(adenylyl_cyclase) lactate_output += glycolysis_rate(glutamate_clearance_rate)
PKA_activity = proportional_to(cAMP_level) membrane_potential restored by NaK_ATPase(lactate_output)
phosphorylate(GluA1, site=Ser845) RRP_pool refilled by VATPase(lactate_output)
GluA1_Ser845_primed = True // lowers CaMKII threshold
phosphorylate(DARPP32)
DARPP32_phospho = True // silences PP1 — blocks LTD
translocate(PKA → nucleus) → phosphorylate(CREB)
CREB_active = True // enables structural gene expression
// Acetylcholine: lower LTP threshold globally
LTP_threshold *= (1 / (1 + ACh_level × mAChR_gain))
slow time scale — structural commit (h → weeks)
function commit_to_structural_change():
// Hierarchical filter: three conditions must align ## intermediate time scale — temporary tuning (s → min)
event_detected = post_Ca_amplitude > Ca_HIGH // layer 1: did something happen?
overflow_sensed = mGluR5_activation == True // layer 2: was it excessive?
context_validated = DARPP32_phospho and GluA1_Ser845_primed // layer 3: worth saving?
// ── Branch 1: LTP — potentiation ────────────────────────────── function short_term_plasticity(input_freq, duration):
if event_detected and overflow_sensed and context_validated:
// Postsynapse: anchor receptors, enlarge spine // Presynapse: facilitate or depress based on Ca²⁺ history
activate(CaMKII) if input_freq > 20Hz:
AMPA_count += receptor_insertion(CaMKII, GluA1_Ser845_primed) vesicle_release_prob *= 1.3 // residual Ca²⁺ primes launchpad
spine_volume *= 1.5 mobilize(reserve_pool → RRP_pool) // break storage chains
elif input_freq < 5Hz:
vesicle_release_prob *= 0.7 // RRP depleted faster than refill
// Presynapse: expand launchpad, increase output reliability // Postsynapse: NMDA gate primed if frequency sustained
active_zone_size *= 1.4 // more docking slots if input_freq >= 50Hz and duration > 1s:
RRP_pool_capacity += pool_expansion(active_zone_size) NMDA_Mg_block = False // sustained depolarization
VGCC_clustering += cluster_beneath_AZ() // tighter Ca²⁺ coupling post_Ca_amplitude accumulates // early-LTP signal rises
vesicle_release_prob += 0.1 // driven by VGCC clustering
// Astrocyte: seal and insulate the channel // Astrocyte: sustained volume → escalate co-agonist
perisynaptic_distance -= process_retraction() // walls move IN → tighter wrap if astro_Ca_local > local_threshold:
ECM_integrity += secrete(Glypicans, Thrombospondins) D_serine_release += gliotransmitter_pulse() // widens NMDA window
D_serine_tonic_level += upregulate_synthesis() // sustained NMDA priming
glutamate_clearance_rate *= 0.85 // tighter wrap → slower diffusion away
return "potentiated"
// ── Branch 2: temporary only — Ca²⁺ rose, no save signal ───── // Neuromodulators: set context gate via Gs protein
elif event_detected and not context_validated: if dopamine_level > D1_threshold or NE_level > β_threshold:
AMPA_count += transient_insertion() // early-LTP only — reverses in minutes cAMP_level += Gs_activation(adenylyl_cyclase)
vesicle_release_prob += transient_facilitation() PKA_activity = proportional_to(cAMP_level)
// No astrocyte structural change phosphorylate(GluA1, site=Ser845)
return "temporary facilitation only" GluA1_Ser845_primed = True // lowers CaMKII threshold
phosphorylate(DARPP32)
DARPP32_phospho = True // silences PP1 — blocks LTD
translocate(PKA → nucleus) → phosphorylate(CREB)
CREB_active = True // enables structural gene expression
// Acetylcholine: lower LTP threshold globally
LTP_threshold *= (1 / (1 + ACh_level × mAChR_gain))
// ── Branch 3: LTD — active forgetting ───────────────────────── ## slow time scale — structural commit (h → weeks)
elif event_detected and not overflow_sensed and not context_validated:
// Postsynapse: internalize receptors, shrink spine function commit_to_structural_change():
activate(PP1)
AMPA_count -= receptor_internalization(PP1)
spine_volume *= 0.7
// Presynapse: dismantle launchpad // Hierarchical filter: three conditions must align
active_zone_size -= docking_slot_removal() event_detected = post_Ca_amplitude > Ca_HIGH // layer 1: did something happen?
RRP_pool_capacity -= pool_contraction() overflow_sensed = mGluR5_activation == True // layer 2: was it excessive?
VGCC_clustering -= scatter_VGCCs() // decouple Ca²⁺ from AZ context_validated = DARPP32_phospho and GluA1_Ser845_primed // layer 3: worth saving?
vesicle_release_prob *= 0.6
// Astrocyte: dissolve matrix, pull away, cut support // ── Branch 1: LTP — potentiation ──────────────────────────────
ECM_integrity -= secrete(MMPs) // molecular scissors if event_detected and overflow_sensed and context_validated:
D_serine_tonic_level = 0 // co-agonist supply cut
perisynaptic_distance += process_extension() // walls move OUT → loose wrap
glutamate_clearance_rate *= 1.2 // looser wrap → faster spillover
return "depressed"
// ── Branch 4: baseline ──────────────────────────────────────── // Postsynapse: anchor receptors, enlarge spine
else: activate(CaMKII)
// All structural variables unchanged — system holds current state AMPA_count += receptor_insertion(CaMKII, GluA1_Ser845_primed)
return "baseline — no change" spine_volume *= 1.5
special case — shockwave lockdown (>100Hz uncoordinated)
function shockwave_lockdown():
astro_Ca_global = GLOBAL_WAVE // soma-level flood
release(GABA, ATP) // gel floods postsynapse
AMPA_count -= mass_internalization()
membrane_potential = HYPERPOLARIZED
cluster(VGCC → beneath_active_zone) // ensures signal survives chaos
energy supply chain — metabolic gating (continuous)
function metabolic_loop(Δt):
// Astrocyte: glucose → lactate pipeline
glucose_uptake = blood_capillary_supply()
lactate_output = glycolysis(glucose_uptake, glutamate_clearance_rate)
lactate_output *= load_factor(glutamate_clearance_rate)
// Pre + post absorb lactate → power their pumps // Presynapse: expand launchpad, increase output reliability
RRP_pool refill rate ∝ VATPase(lactate_output) active_zone_size *= 1.4 // more docking slots
membrane_potential reset ∝ NaK_ATPase(lactate_output) RRP_pool_capacity += pool_expansion(active_zone_size)
key asymmetry — perisynaptic distance is bidirectional VGCC_clustering += cluster_beneath_AZ() // tighter Ca²⁺ coupling
// LTP: astrocyte moves IN → tighter diffusion barrier vesicle_release_prob += 0.1 // driven by VGCC clustering
// → glutamate_clearance_rate ↓ (signal contained, not diluted)
// → D_serine_tonic_level ↑ (NMDA gate chronically primed)
// LTD: astrocyte moves OUT → looser diffusion barrier // Astrocyte: seal and insulate the channel
// → glutamate_clearance_rate ↑ (signal bleeds away faster) perisynaptic_distance -= process_retraction() // walls move IN → tighter wrap
// → D_serine_tonic_level = 0 (NMDA gate chronically starved) ECM_integrity += secrete(Glypicans, Thrombospondins)
D_serine_tonic_level += upregulate_synthesis() // sustained NMDA priming
glutamate_clearance_rate *= 0.85 // tighter wrap → slower diffusion away
return "potentiated"
// Result: astrocyte amplifies both directions simultaneously // ── Branch 2: temporary only — Ca²⁺ rose, no save signal ─────
// potentiation becomes self-reinforcing; depression becomes self-reinforcing elif event_detected and not context_validated:
AMPA_count += transient_insertion() // early-LTP only — reverses in minutes
vesicle_release_prob += transient_facilitation()
// No astrocyte structural change
return "temporary facilitation only"
// ── Branch 3: LTD — active forgetting ─────────────────────────
elif event_detected and not overflow_sensed and not context_validated:
// Postsynapse: internalize receptors, shrink spine
activate(PP1)
AMPA_count -= receptor_internalization(PP1)
spine_volume *= 0.7
// Presynapse: dismantle launchpad
active_zone_size -= docking_slot_removal()
RRP_pool_capacity -= pool_contraction()
VGCC_clustering -= scatter_VGCCs() // decouple Ca²⁺ from AZ
vesicle_release_prob *= 0.6
// Astrocyte: dissolve matrix, pull away, cut support
ECM_integrity -= secrete(MMPs) // molecular scissors
D_serine_tonic_level = 0 // co-agonist supply cut
perisynaptic_distance += process_extension() // walls move OUT → loose wrap
glutamate_clearance_rate *= 1.2 // looser wrap → faster spillover
return "depressed"
// ── Branch 4: baseline ────────────────────────────────────────
else:
// All structural variables unchanged — system holds current state
return "baseline — no change"
## special case — shockwave lockdown (>100Hz uncoordinated)
function shockwave_lockdown():
astro_Ca_global = GLOBAL_WAVE // soma-level flood
release(GABA, ATP) // gel floods postsynapse
AMPA_count -= mass_internalization()
membrane_potential = HYPERPOLARIZED
cluster(VGCC → beneath_active_zone) // ensures signal survives chaos
## energy supply chain — metabolic gating (continuous)
function metabolic_loop(Δt):
// Astrocyte: glucose → lactate pipeline
glucose_uptake = blood_capillary_supply()
lactate_output = glycolysis(glucose_uptake, glutamate_clearance_rate)
lactate_output *= load_factor(glutamate_clearance_rate)
// Pre + post absorb lactate → power their pumps
RRP_pool refill rate ∝ VATPase(lactate_output)
membrane_potential reset ∝ NaK_ATPase(lactate_output)
## key asymmetry — perisynaptic distance is bidirectional
// LTP: astrocyte moves IN → tighter diffusion barrier
// → glutamate_clearance_rate ↓ (signal contained, not diluted)
// → D_serine_tonic_level ↑ (NMDA gate chronically primed)
// LTD: astrocyte moves OUT → looser diffusion barrier
// → glutamate_clearance_rate ↑ (signal bleeds away faster)
// → D_serine_tonic_level = 0 (NMDA gate chronically starved)
// Result: astrocyte amplifies both directions simultaneously
// potentiation becomes self-reinforcing; depression becomes self-reinforcing
``` ```
# Neuromodulators # Neuromodulators