CONTROLLING OSCILLATIONS TO TREAT ALZHEIMERS DISEASE TARGETING THE BASAL FOREBRAIN PARVALBUMINSYSTEM - ALZH…
Federal financial assistance recorded from USAspending. This is not a procurement contract.
Assistance award details
- Assistance award identifier
- ASST_NON_R00AG066819_075
- FAIN
- R00AG066819
- Recipient
- THE GENERAL HOSPITAL CORPORATION
- Awarding agency
- Department of Health and Human Services
- Funding agency
- Department of Health and Human Services
- Assistance listing (CFDA)
- 93.866
- Total obligated
- $741,919
- Period
- Jun 1, 2021 – Jul 31, 2027
- Fiscal year
- 2024
- Place of performance state
- MA
- Source file
- FY2024_All_Assistance_Full_20261006.zip
Description
CONTROLLING OSCILLATIONS TO TREAT ALZHEIMERS DISEASE TARGETING THE BASAL FOREBRAIN PARVALBUMINSYSTEM - ALZHEIMER'S DISEASE (AD) IS A NEUROGENERATIVE DISORDER CHARACTERIZED BY EARLY DEPOSITION OF AMYLOID-BETA PROTEIN (AÎ) FOLLOWED BY TAUOPATHY AND IMPAIRED COGNITION. INNOVATIVE TREATMENT STRATEGIES ARE NEEDED. RECENT STUDIES IN AMYLOIDOSIS AND TAUOPATHY MODEL MICE HAVE SHOWN THAT CHRONIC 40HZ GAMMA ENTRAINMENT USING SENSORY STIMULI (GENUS) IMPROVES PATHOLOGICAL AND BEHAVIORAL OUTCOMES. HOWEVER, THESE EXCITING STUDIES HAVE NOT BEEN INDEPENDENTLY REPLICATED AND OPTIMAL METHODS TO REDUCE PATHOLOGY BY GAMMA ENTRAINMENT ARE UNKNOWN. THUS, HERE, WE TEST WHETHER OPTOGENETIC EXCITATION OF NON-CHOLINERGIC BASAL FOREBRAIN PARVALBUMIN NEURONS (BF PV) ENABLES WIDESPREAD CONTROL OF GAMMA OSCILLATIONS THROUGHOUT CORTEX AND HIPPOCAMPUS TO TREAT AMYLOIDOSIS/TAUOPATHY AND RESTORE HIPPOCAMPAL-CORTICAL OSCILLATORY FUNCTIONS THAT SUPPORT MEMORY. THE MENTORED (K99) PHASE OF THIS PROPOSAL WILL USE 5XFAD MICE TO TEST BENEFITS OF 40HZ OPTOGENETIC BF PV EXCITATION IN PREVENTING AMYLOIDOSIS. ALL EXPERIMENTS RECORD IPSILATERAL LOCAL FIELD POTENTIALS (LFP) IN MEDIAL PREFRONTAL CORTEX (MPFC) AND HIPPOCAMPUS (HPC). THE FIRST EXPERIMENT DIRECTLY COMPARES THE EFFICACY OF 40HZ BF PV EXCITATION TREATMENT AGAINST GENUS IN REDUCING PLAQUE PATHOLOGY. THE SECOND EXPERIMENT USES CHEMOGENETICS TO MODEL PHARMACOLOGICALLY TARGETING OF BF PV AND TESTS WHETHER CHEMOGENETIC BF PV EXCITATION AND GENUS SYNERGIZE TO IMPROVE OUTCOME. THE THIRD EXPERIMENT ASSESSES THE HYPOTHESIS THAT CHRONIC 40HZ BF PV EXCITATION REPAIRS GAMMA GENERATING MECHANISMS IN HIPPOCAMPUS AND CORTEX TO RESTORE OSCILLATORY COMMUNICATION AND RESCUE WORKING MEMORY. THE FOURTH EXPERIMENT WILL USE A CLOSED-LOOP STIMULATION METHOD TO DELIVER TWO BRIEF (10MS) LASER PULSES AT THE PEAK OR TROUGH OF HIPPOCAMPAL THETA PHASE TO ASSESS WHETHER THETA-PHASE SPECIFIC TIMING OF BF PV EXCITATION MATTERS. THE INDEPENDENT (R00) PHASE STUDIES WILL APPLY METHO