Hypothesis Comparison

graph TD
    A["TREK-1 Channel
(KCNK2)
Mechanosensitive K+ Channel"] --> B["Potassium Efflux
K+ Current Activation"]
    B --> C["Membrane Potential
Hyperpolarization
-70 to -90 mV"]
    C --> D["Lipid Raft
Reorganization
Cholesterol Clustering"]
    D --> E["Phospholipid
Asymmetry Changes
PS and PIP2 Distribution"]
    E --> F["alpha-Syntrophin
Membrane Association
PDZ Domain Binding"]
    F --> G["Dystrophin-Associated
Protein Complex
(DAPC) Assembly"]
    G --> H["AQP4 Tetramer
Anchoring
M1 and M23 Isoforms"]
    H --> I["Perivascular Endfoot
Polarization
Directional Clustering"]
    I --> J["Glymphatic
Flow Enhancement
CSF-ISF Exchange"]
    
    K["Arachidonic Acid
Lipid Mediator
TREK-1 Activator"] --> A
    L["Mechanical Stretch
Astrocyte Swelling
Osmotic Stress"] --> A
    
    M["Neurodegeneration
AQP4 Depolarization
Waste Accumulation"] --> N["Impaired Clearance
Amyloid beta
Tau Proteins"]
    
    I --> O["Neuroprotection
Enhanced Clearance
Reduced Inflammation"]
    J --> P["Cognitive Function
Restoration
Memory Improvement"]
    
    Q["Calcium Signaling
Astrocyte Networks
Gap Junction Coupling"] --> C
    
    classDef normal fill:#4fc3f7
    classDef therapeutic fill:#81c784
    classDef pathology fill:#ef5350
    classDef outcome fill:#ffd54f
    classDef molecular fill:#ce93d8
    
    class A,B,C,D,E,F,G,H,K,L,Q molecular
    class I,J therapeutic
    class M,N pathology
    class O,P outcome

graph TD
    A["Orexin neurons in
lateral hypothalamus
circadian dysregulation"] -->|"reduced signaling"| B["OX1R and OX2R
orexin receptors
decreased activation"]
    
    B -->|"targeted modulation"| C["Orexin receptor
antagonist therapy
suvorexant/lemborexant"]
    
    C -->|"promotes"| D["Enhanced sleep
consolidation and
NREM sleep stages"]
    
    D -->|"activates"| E["Noradrenergic locus
coeruleus suppression
during sleep"]
    
    E -->|"reduces"| F["Astrocytic AQP4
water channel
polarization enhanced"]
    
    F -->|"facilitates"| G["CSF influx along
periarterial spaces
Virchow-Robin spaces"]
    
    G -->|"drives"| H["CSF-ISF mixing
in brain parenchyma
convective flow"]
    
    H -->|"mobilizes"| I["Amyloid-beta and
tau protein aggregates
from interstitium"]
    
    I -->|"clearance via"| J["Perivenous drainage
pathways activated
during sleep"]
    
    J -->|"exits to"| K["Cervical lymphatic
vessels and
systemic circulation"]
    
    A -->|"disrupts"| L["Circadian clock genes
Per1/Per2/Clock/Bmal1
expression altered"]
    
    L -->|"affects"| M["Glymphatic system
circadian regulation
10-20 fold variance"]
    
    M -->|"impairs"| N["Sleep-dependent
protein aggregate
clearance capacity"]
    
    N -->|"leads to"| O["Alzheimer pathology
progression and
neurodegeneration"]
    
    K -->|"reduces"| P["Brain toxic protein
burden and
oxidative stress"]
    
    P -->|"slows"| Q["Cognitive decline
and memory
impairment"]
    
    D -->|"strengthens"| R["Circadian rhythm
restoration and
sleep architecture"]
    
    R -->|"enhances"| M
    
    O -->|"without treatment"| S["Progressive
neuronal loss
and dementia"]

    classDef normal fill:#4fc3f7,stroke:#2196f3
    classDef therapeutic fill:#81c784,stroke:#4caf50
    classDef pathology fill:#ef5350,stroke:#f44336
    classDef outcome fill:#ffd54f,stroke:#ff9800
    classDef molecular fill:#ce93d8,stroke:#9c27b0

    class A,B,F,L,M pathology
    class C,D,E therapeutic
    class G,H,I,J,K,P,R normal
    class N,O,S pathology
    class Q,S outcome
    class A,B,F,I molecular