816 lines
23 KiB
Markdown
816 lines
23 KiB
Markdown
# Multi-Timescale Neural Component Analysis
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## PRESYNAPSE
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### Timescale 1: Fast (<1ms - 100ms)
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**Incoming Signals:**
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- Action potential depolarization (to \~+30 mV)
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- Voltage-gated calcium channel (VGCC) opening
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**Actions:**
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- Vesicle docking and priming (SNARE complex assembly)
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- Ca²⁺ influx
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- Glutamate vesicle release (stochastic, probability P_r)
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**Outgoing Signals:**
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- Glutamate release into synaptic cleft
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**Modulation:**
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- **Upregulation (Facilitation):** Residual Ca²⁺ from previous spikes increases P_r for next release
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- **Downregulation (Depression):** High-frequency firing depletes readily releasable vesicle pool, decreasing P_r
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---
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### Timescale 2: Medium (100ms - 10s)
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**Incoming Signals:**
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- Buildup of residual Ca²⁺
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- Volume transmission neuromodulators (dopamine, acetylcholine, noradrenaline)
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**Actions:**
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- Accumulation/depletion of Ca²⁺ stores
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- Modulation of release machinery sensitivity
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**Outgoing Signals:**
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- Sustained or diminished glutamate release patterns (STF/STD)
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**Modulation:**
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- **Short-Term Facilitation (STF):** Residual Ca²⁺ increases P_r over spike trains
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- **Short-Term Depression (STD):** Vesicle pool depletion reduces P_r
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- **Augmentation:** Calcium-sensing proteins (Munc13) alter release probability (1-10s range)
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**Notes:**
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This active clearance happens rapidly, within tens to hundreds of milliseconds. It serves two vital functions:
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- **Termination of Signal:** It rapidly lowers Ca²⁺ to end the release command, ensuring neurotransmitter release is brief and precise.
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- **Prevention of Toxicity:** Sustained high intracellular Ca²⁺ is cytotoxic and can trigger apoptosis (cell death). Efficient clearance is essential for neuronal health.
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- **Facilitation:** If Ca²⁺ clearance is slightly slower than the arrival of the next action potential, residual Ca²⁺ accumulates near the release sites. This "leftover" Ca²⁺ adds to the influx from the next spike, making vesicle fusion more likely (increasing P<sub>r</sub>).
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- **Depression:** If firing is very rapid, the pumps and exchangers cannot keep up, and Ca²⁺ levels remain elevated for longer in a more diffuse manner. This can paradoxically activate processes that inhibit release or simply outpace the recycling of vesicles, leading to depletion.
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---
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### Timescale 3: Slow (seconds - minutes)
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**Incoming Signals:**
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- Retrograde NO (nitric oxide) from postsynapse
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- Retrograde BDNF (brain-derived neurotrophic factor)
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- Retrograde endocannabinoids (eCBs, e.g., 2-AG)
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- Astrocyte gliotransmitters (ATP, D-serine, glutamate)
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**Actions:**
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- Enzymatic cascade activation/suppression
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- CB1 receptor activation (by eCBs)
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- VGCC modulation
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- Potassium channel modulation
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**Outgoing Signals:**
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- Modified P_r affecting subsequent releases
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**Modulation:**
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- **Upregulation:** NO/BDNF activates cascades that increase P_r, promote synaptic growth (facilitates LTP)
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- **Downregulation:** eCBs bind CB1 receptors, inhibit VGCCs, activate K⁺ channels → profound decrease in P_r (DSE/DSI - depolarization-induced suppression)
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### Timescale 4: Metabolic (minutes - hours)
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**Incoming Signals:**
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- Astrocyte-supplied lactate (via monocarboxylate transporters)
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- Glutamine from astrocytes (glutamate-glutamine cycle)
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- Metabolic state indicators (ATP levels, NAD/NADH ratio)
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**Actions:**
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- ATP-dependent vesicle cycling
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- Glutamine→glutamate conversion (via glutaminase)
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- Vesicle refilling with glutamate
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- Maintenance of ion gradients
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**Outgoing Signals:**
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- Sustained neurotransmitter release capacity
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- Metabolic demand signals to astrocyte
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**Modulation:**
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- **Metabolic veto:** Insufficient ATP prevents vesicle release despite adequate Ca²⁺
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- Lactate availability determines sustained release capacity during high activity
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---
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### Timescale 5: Structural (hours - days+)
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**Incoming Signals:**
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- Retrograde trophic factors (BDNF, sustained)
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- Homeostatic scaling signals from soma
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**Actions:**
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- Structural growth/retraction of presynaptic bouton
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- Changes in active zone size
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- Alterations in vesicle pool size
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**Outgoing Signals:**
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- Modified synaptic strength through structural change
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**Modulation:**
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- Terminal size increases/decreases
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- Vesicle pool capacity changes
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- Active zone protein composition changes
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---
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## POSTSYNAPSE (Dendritic Spine)
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### Timescale 1: Fast (<1ms - 100ms)
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**Incoming Signals:**
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- Glutamate binding to AMPA receptors (<1ms)
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- Glutamate binding to NMDA receptors (Mg²⁺-blocked initially)
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- Local depolarization from AMPA activation
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- GABA from inhibitory interneurons
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**Actions:**
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- AMPA receptor opening → Na⁺ influx → local depolarization (EPSP)
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- NMDA receptor Mg²⁺ unblock (requires depolarization > -40mV)
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- NMDA receptor opening → Ca²⁺ influx
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- AMPA receptor desensitization (if glutamate lingers)
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**Outgoing Signals:**
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- EPSP propagating to dendritic branch
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- Local Ca²⁺ concentration changes
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**Modulation:**
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- **Upregulation:** Depolarization relieves NMDA Mg²⁺ block → Ca²⁺ influx amplification
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- **Downregulation:** AMPA desensitization acts as low-pass filter
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---
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### Timescale 2: Medium (100ms - 10s)
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**Incoming Signals:**
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- Sustained glutamate exposure
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- Metabotropic glutamate receptor (mGluR) activation
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- GABA-B receptor activation (slow inhibition)
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**Actions:**
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- G-protein coupled signaling cascades
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- Second messenger activation
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- Modulation of local excitability
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**Outgoing Signals:**
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- Modified EPSP amplitude based on recent history
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- Preparation for plasticity events
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**Modulation:**
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- mGluR-mediated changes in spine excitability
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- GABA-B provides prolonged shunting inhibition (100ms-1s)
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---
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### Timescale 3: Slow (seconds - minutes)
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**Incoming Signals:**
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- Sustained high Ca²⁺ influx through NMDARs
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- Back-propagating action potential (bAP) from soma/AIS
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- D-serine co-agonist from astrocyte
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**Actions:**
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- CaMKII (calcium/calmodulin-dependent protein kinase II) autophosphorylation
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- Synaptic tagging: Ca²⁺ creates local molecular "tag" marking synapse as recently active
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- Synthesis and release of retrograde messengers:
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- **NO synthesis** (from high Ca²⁺)
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- **BDNF release**
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- **Endocannabinoid (eCB) synthesis** (from sustained Ca²⁺)
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- AMPA receptor trafficking from extrasynaptic pool into PSD (early-LTP)
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**Outgoing Signals:**
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- Retrograde NO (diffuses to presynapse)
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- Retrograde BDNF (travels to presynapse)
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- Retrograde eCBs (diffuse to presynapse)
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**Modulation:**
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- **Upregulation (LTP):** High Ca²⁺ (>10 μM) → CaMKII activation → spine head expansion → AMPAR insertion → increased synaptic weight
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- **Downregulation (LTD):** Low/sustained Ca²⁺ (0.5-1.0 μM) → phosphatase activation → spine shrinkage → AMPAR endocytosis → decreased weight
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- Tag duration: CaMKII phosphorylation state acts as \~1-2 hour memory tag
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---
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### Timescale 4: Metabolic (minutes - hours)
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**Incoming Signals:**
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- Astrocyte D-serine (NMDA co-agonist, essential for late-LTP)
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- Astrocyte TNF-α, cholesterol (permissive factors)
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- Metabolic substrates for local protein synthesis
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**Actions:**
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- Local protein synthesis in dendrites (responds to "tags")
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- Structural spine remodeling
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- Transition from early-LTP to late-LTP (L-LTP)
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**Outgoing Signals:**
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- Demand signals for continued metabolic support
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**Modulation:**
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- D-serine availability gates transition to L-LTP
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- Metabolic state determines whether tagged synapses can undergo structural consolidation
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---
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### Timescale 5: Structural (hours - days+)
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**Incoming Signals:**
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- Persistent synaptic tags combined with eligibility signals
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- Homeostatic scaling signals from soma
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- Neuromodulator-driven metaplasticity signals
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**Actions:**
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- Spine volume changes (0.01-1.0 μm³ range)
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- Receptor number changes (AMPAR density)
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- Structural consolidation or elimination
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- PSD protein composition changes
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**Outgoing Signals:**
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- Stable changes in synaptic weight
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**Modulation:**
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- Successful spines grow and strengthen
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- Weak/unused spines shrink or are eliminated
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- Homeostatic scaling adjusts all synapses proportionally
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---
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## DENDRITE
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### Timescale 1: Fast (10-100ms)
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**Incoming Signals:**
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- Multiple EPSPs from spines on the branch
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- Back-propagating action potential (bAP) from soma
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- IPSPs from inhibitory synapses
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- Neuromodulator influence on dendritic K⁺ channels
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**Actions:**
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- Spatial summation: EPSPs from different spines add together
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- Temporal summation: EPSPs from successive spikes add together
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- NMDA spike generation (local Ca²⁺ spike if threshold reached)
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- Dendritic Na⁺/Ca²⁺ spike generation
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**Outgoing Signals:**
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- Integrated EPSP to soma
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- Dendritic spike (amplified signal)
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- bAP propagation modulated by local K⁺ channels
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**Modulation:**
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- **Upregulation:** Dendritic spikes amplify signals; coincidence of local EPSP + bAP enhances NMDA activation
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- **Downregulation:** K⁺ channels limit bAP propagation; strong inhibition can veto dendritic spikes
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- bAP amplitude and spread actively modulated by dendritic K⁺ channels → regulated teaching signal
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---
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### Timescale 2: Medium (100ms - 10s)
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**Incoming Signals:**
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- Patterns of dendritic spikes
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- Neuromodulator tone affecting dendritic excitability
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**Actions:**
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- Branch-level integration over short time windows
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- Modulation of dendritic spike threshold
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**Outgoing Signals:**
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- Pattern-classified signals to soma
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**Modulation:**
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- Dendritic excitability adjusted by neuromodulator context
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- Short-term changes in integration properties
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---
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### Timescale 3: Slow (seconds - minutes)
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**Incoming Signals:**
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- Sustained patterns of activity
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- Astrocyte gliotransmitters affecting dendritic excitability
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**Actions:**
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- Coincidence detection for STDP (spike-timing-dependent plasticity)
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- Branch acts as pattern classifier
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**Outgoing Signals:**
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- Timing information (pre-post spike timing) determining LTP/LTD sign
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**Modulation:**
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- Timing of pre- and postsynaptic activity determines sign (LTP vs LTD) and magnitude of plastic change
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- Branch-specific computation and learning rules
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---
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### Timescale 4: Metabolic (minutes - hours)
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**Incoming Signals:**
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- Metabolic support from astrocytes
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- Proteins synthesized locally in dendrites
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**Actions:**
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- Local protein synthesis in response to activity
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- Maintenance of ion gradients
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- Support for sustained dendritic spike generation
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**Outgoing Signals:**
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- Metabolic demand signals
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**Modulation:**
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- Availability of metabolic substrates determines capacity for local plasticity
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- Local translation enables rapid structural changes without waiting for somatic gene expression
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---
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### Timescale 5: Structural (hours - days+)
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**Incoming Signals:**
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- Homeostatic scaling signals
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- Structural plasticity factors
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**Actions:**
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- Dendritic branch growth/retraction
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- Changes in spine density
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- Alterations in dendritic arbor complexity
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**Outgoing Signals:**
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- Modified dendritic integration capacity
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**Modulation:**
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- Experience-dependent dendritic remodeling
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- Branch-specific structural changes based on activity history
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---
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## SOMA
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### Timescale 1: Fast (1-100ms)
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**Incoming Signals:**
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- Thousands of filtered EPSPs and IPSPs from all dendritic branches
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- Direct perisomatic inhibition from basket cells and chandelier cells
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- HCN channel (Ih current) activity at rest
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**Actions:**
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- Final spatial/temporal summation of all inputs
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- Voltage-gated channel activity (HCN channels stabilize membrane potential)
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- Integration toward or away from spike threshold
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**Outgoing Signals:**
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- Integrated voltage (Vm) to AIS
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- Decision point: spike or no spike
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**Modulation:**
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- **Upregulation:** Excitatory inputs sum toward threshold; depolarization
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- **Downregulation:** Perisomatic inhibition exerts powerful veto control; HCN channels act as "voltage clamp" resisting large swings
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- Direct somatic inhibition can clamp voltage below threshold, overriding all excitatory input
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---
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### Timescale 2: Medium (100ms - seconds)
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**Incoming Signals:**
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- Spike afterhyperpolarization (sAHP) from recent spike
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- Neuromodulator receptor activation (ACh, noradrenaline, serotonin, dopamine)
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**Actions:**
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- Ca²⁺-activated K⁺ (SK) channel opening (from sAHP)
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- Kv7 (M-type) K⁺ channel modulation
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- Adjustment of input resistance and excitability
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**Outgoing Signals:**
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- Modified excitability state
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- Spike frequency adaptation
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**Modulation:**
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- **Upregulation:**
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- Inactivation of Kv7 channels (by ACh or prior depolarization) → lower threshold, increased input resistance
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- Reduced sAHP (by noradrenaline) → allows higher sustained firing rates
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- **Downregulation:**
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- sAHP produces prolonged hyperpolarization (hundreds of ms) → potently suppresses further firing → spike frequency adaptation
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---
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### Timescale 3: Slow (seconds - minutes)
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**Incoming Signals:**
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- Sustained neuromodulatory tone
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- Integrated Ca²⁺ signals from dendritic activity
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**Actions:**
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- Modulation of global neuronal excitability
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- Preparation for plasticity events
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- Ca²⁺/CaMKIV signaling integration
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**Outgoing Signals:**
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- Somatic Ca²⁺ state influencing gene expression pathways
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- Modified neuronal gain
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**Modulation:**
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- Neuromodulators set global "mood" of neuron
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- Somatic state gates whether dendritic tags will be consolidated
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---
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### Timescale 4: Metabolic (minutes - hours)
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**Incoming Signals:**
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- Mean firing rate (F_avg) integrated over hours
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- Metabolic state indicators (ATP, lactate availability)
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- Astrocyte metabolic support signals
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**Actions:**
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- Somatic Ca²⁺/CaMKIV signaling senses mean activity
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- Initiation of homeostatic responses
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- Gene expression programs triggered
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**Outgoing Signals:**
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- Demand for metabolic support
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- Signals initiating homeostatic adjustments
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**Modulation:**
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- Metabolic state determines capacity for sustained firing
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- Energy availability gates neuronal operations
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---
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### Timescale 5: Structural (hours - days+)
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**Incoming Signals:**
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- Integrated activity history (hours-days)
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- Neuromodulator-driven metaplasticity signals
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- CREB, BDNF transcription activation
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**Actions:**
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- Global synaptic scaling: AMPA receptor transcription/trafficking changes across all synapses
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- Homeostatic plasticity (typically 12-48 hours)
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- Metaplasticity: changes in plasticity rules themselves
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- Gene expression establishing new baseline excitability
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**Outgoing Signals:**
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- Homeostatic scaling factors to all synapses
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- Modified intrinsic excitability parameters
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- Changed plasticity thresholds
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**Modulation:**
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- "Corporate-wide audit": soma ensures network stability by proportionally adjusting all synaptic strengths
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- Chronic high activity → global downscaling
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- Chronic low activity → global upscaling
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- Neuromodulators broadcast "global strategy" (e.g., "be alert and learn" vs "sleep and consolidate")
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---
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## AIS (Axon Initial Segment)
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### Timescale 1: Fast (1-100ms)
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**Incoming Signals:**
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- Somatically integrated voltage (Vm) from soma
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- Direct chandelier cell inhibition (targeting proximal axon)
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**Actions:**
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- Threshold detection (AIS has lowest spike threshold in neuron)
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- Explosive opening of high-density voltage-gated Na⁺ (NaV) channels
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- All-or-none action potential initiation
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- Analog-to-digital conversion: graded somatic voltage → binary spike
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**Outgoing Signals:**
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- Action potential propagating down axon
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- Action potential back-propagating into soma/dendrites (bAP)
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**Modulation:**
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- **Upregulation:** If Vm crosses AIS threshold, reliable spike initiation
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- **Downregulation:**
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- Absolute/relative refractory periods enforce maximum firing rate
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- Chandelier cell inhibition can completely block spike generation
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- High-fidelity trigger: faithfully converts somatic voltage to timed output
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---
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### Timescale 2: Medium (seconds - minutes)
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**Incoming Signals:**
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- Recent spike history
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- Neuromodulator influence on AIS excitability
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**Actions:**
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- Refractory period enforcement
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- Spike timing precision maintenance
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**Outgoing Signals:**
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- Precisely timed spike trains
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**Modulation:**
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- Refractory periods control maximum firing frequency
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- Spike timing precision maintained by AIS properties
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---
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### Timescale 3: Slow (minutes - hours)
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**Incoming Signals:**
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- Activity-dependent signals
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- Metabolic state information
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**Actions:**
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- Subtle modulation of threshold
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- Preparation for structural adjustments
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**Outgoing Signals:**
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- Modified spike generation parameters
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**Modulation:**
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- Activity-dependent threshold adjustments
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---
|
||
|
||
### Timescale 4: Structural (hours - days+)
|
||
|
||
**Incoming Signals:**
|
||
|
||
- Chronic activity patterns
|
||
- Homeostatic signals from soma
|
||
|
||
**Actions:**
|
||
|
||
- AIS location can be plastically adjusted (moves closer/farther from soma)
|
||
- Channel composition changes (NaV channel density/subtypes)
|
||
- Cytoskeletal matrix reorganization
|
||
|
||
**Outgoing Signals:**
|
||
|
||
- Modified intrinsic neuronal gain
|
||
|
||
**Modulation:**
|
||
|
||
- AIS repositioning effectively changes neuron's input-output function
|
||
- Chronic high activity → AIS moves away from soma (decreased excitability)
|
||
- Chronic low activity → AIS moves toward soma (increased excitability)
|
||
- Changes in AIS properties alter neuronal gain and excitability
|
||
|
||
---
|
||
|
||
## ASTROCYTE
|
||
|
||
### Timescale 1: Fast (milliseconds)
|
||
|
||
**Incoming Signals:**
|
||
|
||
- Extracellular glutamate spillover from synapses
|
||
- K⁺ efflux from neuronal firing
|
||
- Sensing via mGluRs on astrocyte processes
|
||
|
||
**Actions:**
|
||
|
||
- Rapid glutamate uptake via EAAT1/2 transporters
|
||
- K⁺ uptake via Kir4.1 channels
|
||
|
||
**Outgoing Signals:**
|
||
|
||
- Glutamate clearance (prevents excitotoxicity)
|
||
- Local K⁺ removal (prevents hyperexcitability)
|
||
|
||
**Modulation:**
|
||
|
||
- Immediate protection: prevents excitotoxicity and runaway excitation
|
||
- Maintains signal fidelity by clearing neurotransmitter
|
||
|
||
---
|
||
|
||
### Timescale 2: Medium (seconds)
|
||
|
||
**Incoming Signals:**
|
||
|
||
- Accumulated glutamate uptake
|
||
- Astrocytic internal Ca²⁺ waves (triggered by mGluR activation)
|
||
|
||
**Actions:**
|
||
|
||
- Ca²⁺ wave propagation through astrocyte syncytium
|
||
- Gliotransmitter release (ATP, D-serine, glutamate)
|
||
- K⁺ spatial redistribution via gap junctions
|
||
|
||
**Outgoing Signals:**
|
||
|
||
- Gliotransmitters to synapses (forming "tripartite synapse")
|
||
- D-serine as NMDA co-agonist
|
||
- ATP (can be converted to adenosine)
|
||
- Spatially redistributed K⁺
|
||
|
||
**Modulation:**
|
||
|
||
- Active modulation of synaptic dialogue
|
||
- Prevents local hyperexcitability through K⁺ buffering and spatial redistribution
|
||
- Can enhance or suppress synaptic transmission
|
||
|
||
---
|
||
|
||
### Timescale 3: Slow (minutes)
|
||
|
||
**Incoming Signals:**
|
||
|
||
- Sustained neuronal activity patterns
|
||
- Rising extracellular K⁺ and glutamate (sustained)
|
||
- Internal metabolic state changes (NAD/NADH ratio shifts)
|
||
|
||
**Actions:**
|
||
|
||
- Glutamate→glutamine conversion (via glutamine synthetase)
|
||
- Glucose uptake stimulation (triggered by glutamate uptake)
|
||
- Glycogenolysis (breakdown of glycogen stores)
|
||
- Glycolysis: glucose→lactate
|
||
|
||
**Outgoing Signals:**
|
||
|
||
- Glutamine export to neurons (for glutamate resynthesis)
|
||
- Lactate export to neurons (via MCTs - monocarboxylate transporters)
|
||
- Early gliotransmission adjustments
|
||
|
||
**Modulation:**
|
||
|
||
- Glutamate-glutamine cycle: "refueling loop" maintains neurotransmitter pool
|
||
- ANLS (astrocyte-neuron lactate shuttle): "turbocharger" provides rapid ATP synthesis fuel
|
||
- Metabolic buffering for burst neuronal activity
|
||
|
||
---
|
||
|
||
### Timescale 4: Metabolic (minutes - hours)
|
||
|
||
**Incoming Signals:**
|
||
|
||
- Chemical sensors: sustained high K⁺ and glutamate
|
||
- Internal Ca²⁺ waves (integrated over time)
|
||
- Metabolic redox state (NAD/NADH ratio)
|
||
- Energy depletion: falling glucose and glycogen levels
|
||
|
||
**Actions:**
|
||
|
||
- Sustained glucose uptake and glycolysis
|
||
- Glycogen replenishment
|
||
- Vasomodulation: astrocyte endfeet release vasoactive signals (prostaglandins, epoxyeicosatrienoic acids)
|
||
- pH buffering via bicarbonate transporters
|
||
- Volume regulation via Aquaporin-4 (AQP4) water channels
|
||
- ATP metabolism producing adenosine
|
||
- D-serine production for late-LTP support
|
||
- Release of metabolic substrates and factors (TNF-α, cholesterol) for local dendritic protein synthesis
|
||
|
||
**Outgoing Signals:**
|
||
|
||
- Sustained lactate supply (metabolic fuel)
|
||
- Glutamine for neurotransmitter recycling
|
||
- Vasoactive signals → local blood vessel dilation (neurovascular coupling)
|
||
- Adenosine accumulation (sleep pressure signal)
|
||
- pH regulation maintaining optimal enzyme function
|
||
- Modulated extracellular space volume and tortuosity (affects neurotransmitter diffusion)
|
||
- D-serine for late-LTP
|
||
- Permissive factors for local protein synthesis
|
||
|
||
**Modulation:**
|
||
|
||
- **Resource manager:** Maintains neurotransmitter pools and delivers emergency fuel
|
||
- **Environmental steward:** Homeostasis of ions (K⁺), pH, water balance
|
||
- **Systemic regulator:** Matches blood flow to metabolic demand; builds sleep pressure via adenosine
|
||
- **Plasticity enabler:** Provides D-serine and metabolic support to transition early-LTP to late-LTP
|
||
- Astrocyte microdomain (\~100,000 synapses) functions as local metabolic unit
|
||
- Prevents metabolic collapse during high-speed signaling
|
||
|
||
---
|
||
|
||
### Timescale 5: Structural (hours - days+)
|
||
|
||
**Incoming Signals:**
|
||
|
||
- Chronic activity patterns in local network
|
||
- Sleep-wake cycle signals
|
||
- Long-term metabolic demand patterns
|
||
|
||
**Actions:**
|
||
|
||
- Structural remodeling of astrocyte processes
|
||
- Glycogen storage capacity changes
|
||
- Glymphatic system clearance (during slow-wave sleep)
|
||
- Aquaporin-4 channel facilitation of CSF influx
|
||
- Metabolic support for neuronal gene expression programs
|
||
- Support for epigenetic modifications
|
||
|
||
**Outgoing Signals:**
|
||
|
||
- Changed coverage of synapses (physical enwrapment)
|
||
- Waste clearance (amyloid-β, tau) via glymphatic system
|
||
- Long-term metabolic support for structural plasticity
|
||
- Support for systems-level consolidation
|
||
|
||
**Modulation:**
|
||
|
||
- Astrocyte morphology adapts to network activity history
|
||
- Nightly glymphatic clearance prevents toxic protein accumulation
|
||
- Essential for transitioning labile memory traces to stable long-term form
|
||
- Supports neuronal structural rewiring and homeostatic adjustments
|
||
- Enables sustainable high-speed computation over lifetime
|
||
|
||
---
|
||
|
||
## SYNTHESIS
|
||
|
||
**Key Principles:**
|
||
|
||
1. **Traces propagate upward:** Fast processes leave traces (residual Ca²⁺, tags, metabolic demand) that persist into slower timescales
|
||
2. **Context flows downward:** Slower processes create context that reinterprets fast events (metabolic state determines if Ca²⁺ can trigger release; homeostatic scaling changes synaptic weights)
|
||
3. **The astrocyte is the multi-scale bridge:** Operates at every timescale from milliseconds (glutamate clearance) to lifetime (metabolic support for epigenetics)
|
||
4. **No component operates in isolation:** Each receives inputs from multiple timescales and sends outputs that affect multiple timescales
|
||
5. **Modulation is contextual:** The "same" signal (e.g., Ca²⁺ influx) has different effects depending on metabolic state, recent history, neuromodulatory tone, and structural configuration
|
||
6. **Metabolic veto is real:** Components can refuse to execute operations if metabolic resources are insufficient—this is not a bug but a feature of biological computation |