From 7149ca6850dc1f202e6a9341ea0fe8220af8fc90 Mon Sep 17 00:00:00 2001 From: ocrampal Date: Fri, 5 Jun 2026 13:42:53 +0200 Subject: [PATCH] Update 2026-06-04-modulation-of-future-behavior.md --- ...026-06-04-modulation-of-future-behavior.md | 215 ------------------ 1 file changed, 215 deletions(-) diff --git a/elements/astrocyte/appunti/2026-06-04-modulation-of-future-behavior.md b/elements/astrocyte/appunti/2026-06-04-modulation-of-future-behavior.md index 3178673..393ca86 100644 --- a/elements/astrocyte/appunti/2026-06-04-modulation-of-future-behavior.md +++ b/elements/astrocyte/appunti/2026-06-04-modulation-of-future-behavior.md @@ -267,221 +267,6 @@ key asymmetry — perisynaptic distance is bidirectional // potentiation becomes self-reinforcing; depression becomes self-reinforcing ``` - -## 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 -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 -glutamate_cleft // [glu] in synaptic cleft -glutamate_spillover // extrasynaptic [glu] — saturates mGluRs -astro_Ca_local // IP3-triggered local rise near synapse -astro_Ca_global // soma-wide wave — network overload flag -D_serine_release // gliotransmitter — NMDA co-agonist pulse -lactate_output // fuel export rate to pre and post - -### ── Intermediate (s–min): temporary tuning ──────────────────── -mGluR2_3_activation // presynaptic Gi — autoinhibitory brake -mGluR5_activation // astrocytic Gq — IP3→Ca²⁺→D-serine cascade -cAMP_level // set by dopamine/NE via Gs → adenylyl cyclase -PKA_activity // downstream of cAMP -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 ─────────────────── -AMPA_count // surface receptors — postsynaptic sensitivity -spine_volume // physical size of dendritic spine -active_zone_size // docking slot count -RRP_pool_capacity // max readily-releasable pool -VGCC_clustering // Ca²⁺ channels beneath active zone -perisynaptic_distance // how close astrocyte walls are to synapse -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 -pre_Ca_residual += spike_influx(input_freq) -pre_Ca_residual *= decay(τ ≈ 100ms) // fades unless spikes keep arriving -vesicle_release_prob *= facilitation(pre_Ca_residual) -released_vesicles = binomial(RRP_pool, vesicle_release_prob) -glutamate_cleft = released_vesicles × quantal_content -RRP_pool -= released_vesicles - -#### Astrocyte: overflow sensing and co-agonist release -glutamate_spillover = extrasynaptic_diffusion(glutamate_cleft) -if glutamate_spillover > spillover_threshold: -mGluR5_activation = True // Gq arm → IP3 → Ca²⁺ → D-serine -astro_Ca_local += IP3_cascade(PLC) -D_serine_release += proportional_to(astro_Ca_local) -mGluR2_3_activation = True // Gi arm → brake presynapse -cAMP_level -= Gi_inhibition(adenylyl_cyclase) -vesicle_release_prob -= VGCC_suppression() // autoinhibitory brake - -#### Astrocyte: check for network overload -astro_Ca_global = soma_wave(astro_Ca_local > OVERLOAD_threshold) -if astro_Ca_global: trigger(shockwave_lockdown) - -#### Postsynapse: wavefront strikes resonator -AMPA_current = glutamate_cleft × AMPA_count -membrane_potential += AMPA_current - -#### NMDA gate: coincidence check -if membrane_potential > -40mV and D_serine_release > threshold: -NMDA_Mg_block = False // Mg²⁺ ejected -post_Ca_amplitude += NMDA_influx(glutamate_cleft) -post_Ca_rise_speed = d(post_Ca_amplitude) / dt - -#### Astrocyte: vacuum trailing echoes + fuel pipeline -glutamate_cleft -= glutamate_clearance_rate × Δt -lactate_output += glycolysis_rate(glutamate_clearance_rate) -membrane_potential restored by NaK_ATPase(lactate_output) -RRP_pool refilled by VATPase(lactate_output) - -### intermediate time scale — temporary tuning (s → min) -function short_term_plasticity(input_freq, duration): - -#### Presynapse: facilitate or depress based on Ca²⁺ history -if input_freq > 20Hz: -vesicle_release_prob *= 1.3 // residual Ca²⁺ primes launchpad -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 -if input_freq >= 50Hz and duration > 1s: -NMDA_Mg_block = False // sustained depolarization -post_Ca_amplitude accumulates // early-LTP signal rises - -#### Astrocyte: sustained volume → escalate co-agonist -if astro_Ca_local > local_threshold: -D_serine_release += gliotransmitter_pulse() // widens NMDA window - -#### Neuromodulators: set context gate via Gs protein -if dopamine_level > D1_threshold or NE_level > β_threshold: -cAMP_level += Gs_activation(adenylyl_cyclase) -PKA_activity = proportional_to(cAMP_level) -phosphorylate(GluA1, site=Ser845) -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 -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 ────────────────────────────── -if event_detected and overflow_sensed and context_validated: - -##### Postsynapse: anchor receptors, enlarge spine -activate(CaMKII) -AMPA_count += receptor_insertion(CaMKII, GluA1_Ser845_primed) -spine_volume *= 1.5 - -##### Presynapse: expand launchpad, increase output reliability -active_zone_size *= 1.4 // more docking slots -RRP_pool_capacity += pool_expansion(active_zone_size) -VGCC_clustering += cluster_beneath_AZ() // tighter Ca²⁺ coupling -vesicle_release_prob += 0.1 // driven by VGCC clustering - -##### Astrocyte: seal and insulate the channel -perisynaptic_distance -= process_retraction() // walls move IN → tighter wrap -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" - -#### ── Branch 2: temporary only — Ca²⁺ rose, no save signal ───── -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 These are produced by small, anatomically concentrated nuclei that broadcast widely across the brain: