tFUS Targeting EC-II SST Interneurons Restores Hippocampal-Prefrontal Gamma Sync in hAPP-J20 Mice

In_Vivo Score: 0.744 Price: $0.50 Alzheimer's disease hAPP-J20 mice (n=10/group x 3 groups) with chronic LFP implants in CA1, mPFC, and EC-II Status: proposed

What This Experiment Tests

In_Vivo experiment designed to assess clinical efficacy targeting SST in hAPP-J20 mice (n=10/group x 3 groups) with chronic LFP implants in CA1, mPFC, and EC-II. Primary outcome: CA1-mPFC gamma coherence (30-80 Hz) >=2x vehicle during theta phase; Y-maze alternation >=65%

Description

Determine whether closed-loop transcranial focused ultrasound (tFUS, 250 kHz, 500 ms pulses phase-locked to hippocampal theta) targeting entorhinal cortex layer II SST+ interneurons restores hippocampal-prefrontal gamma synchrony and improves spatial working memory in hAPP-J20 AD mice.

TARGET GENE

SST (Score: 0.527)

MODEL SYSTEM

hAPP-J20 mice (n=10/group x 3 groups) with chronic LFP implants in CA1, mPFC, and EC-II

ESTIMATED COST

$110,000

TIMELINE

22 months

PATHWAY

EC-II SST interneuron -> theta-gamma coupling -> hippocampal-prefrontal synchrony

SOURCE

task:a989715e-c687-4558-91ca-74fce1474bd2

PRIMARY OUTCOME

CA1-mPFC gamma coherence (30-80 Hz) >=2x vehicle during theta phase; Y-maze alternation >=65%

Scoring Dimensions

Protocol

Implant LFP/unit recording arrays in EC-II, CA1, mPFC at 3 months hAPP-J20. 2. Closed-loop tFUS system: real-time theta detection (Hilbert transform, 4-12 Hz), trigger tFUS pulse (250 kHz, 0.3 MPa, 500 ms) at theta trough targeting EC-II. 3. 20 daily sessions (1 h each) vs sham-tFUS controls. 4. Endpoints: - LFP coherence spectral analysis (CA1-mPFC, 30-80 Hz) - Single-unit SST interneuron firing (juxtasomal recording) - Y-maze, novel object location (NOL) - IHC: SST+/cFos+ co-labelling, c-Fos in EC-II - Safety: Evans blue BBB permeability, H+E histology. 5. Primary: coherence; secondary: SST firing rate, Y-maze, BBB integrity.

Expected Outcomes

Closed-loop tFUS will increase gamma coherence >=2x, drive SST interneuron firing phase-locked to theta, restore Y-maze alternation to >=65%, and produce no BBB disruption.

Success Criteria

Primary: CA1-mPFC gamma coherence >=2x vehicle (paired t-test p<0.05). Secondary: Y-maze alternation >=65%; Evans blue negative (no BBB disruption).

Related Hypotheses (6)

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