A 5-HTERGIC DRN VCA1 CIRCUIT AND ALZHEIMER'S DISEASE - PROJECT SUMMARY DESPITE THE TREMENDOUS EFFORTS IN AL…

Assistance award details

Assistance award identifier

ASST_NON_R00AG078903_075

FAIN

R00AG078903

Recipient

THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.866

Total obligated

$492,929

Period

Jul 15, 2023 – Jun 30, 2028

Fiscal year

2025

Place of performance state

NY

Source file

FY2025_All_Assistance_Full_20261006.zip

Description

A 5-HTERGIC DRN VCA1 CIRCUIT AND ALZHEIMER'S DISEASE - PROJECT SUMMARY DESPITE THE TREMENDOUS EFFORTS IN ALZHEIMER’S DISEASE (AD) RESEARCH, WE HAVE NOT MADE MUCH PROGRESS IN UNDERSTANDING THE PATHOPHYSIOLOGY OF AD OR INHIBITING/CORRECTING AD-RELATED BEHAVIORAL SYMPTOMS. THE RECENT FDA-APPROVED ADUCANUMAB DEMONSTRATED SIGNIFICANT EFFICACY IN REDUCING AMYLOID Β (AΒ). STILL, IT SHOWED A LIMITED EFFECT IN IMPROVING AD-RELATED MEMORY IMPAIRMENTS. THE SPECIFIC NEURAL CIRCUITS THAT MEDIATE THESE COGNITIVE PROCESSES BUT ARE ALTERED PROGRESSIVELY IN THE AD BRAINS MAY SERVE AS A TREATMENT TARGET AFTER THE REMOVAL OF AΒ PLAQUES. IN MY PREVIOUS STUDIES, I DEMONSTRATED THAT DORSAL RAPHE NUCLEUS (DRN) SEROTONIN (5- HT) NEURONS PROVIDE MONOSYNAPTIC INPUTS TO THE HIPPOCAMPAL VENTRAL CA1 (VCA1). FURTHER, GENETIC ABLATION OF 5-HT SYNTHESIS SELECTIVELY IN THESE VCA1-PROJECTING DRN NEURONS IMPAIRED SPATIAL MEMORY IN YOUNG MICE. IN ADDITION, GENETIC DELETION OF THE 5-HT 2C RECEPTOR (5-HT2CR) IN THE VCA1 LED TO SPATIAL MEMORY DEFICITS IN YOUNG MICE. I ALSO OBSERVED THAT LORCASERIN, A SELECTIVE AGONIST OF 5-HT2CR, CAN AMELIORATE SPATIAL MEMORY DEFICITS IN A 6-MONTH-OLD KNOCK-IN AD MOUSE MODEL (APPNL-G-F), ASSOCIATED WITH RESTORATION OF SYNAPTIC PLASTICITY IN VCA1 NEURONS. TOGETHER, I DEVELOPED A HYPOTHESIS THAT A 5-HTERGIC DRN TO VCA1 CIRCUIT REGULATES SPATIAL MEMORY VIA 5-HT2CR, A THERAPEUTIC TARGET FOR MEMORY SYMPTOMS IN ALZHEIMER’S DISEASE. THE K99 PHASE WILL FOCUS ON THE UPSTREAM NODE OF THIS CIRCUIT, THE VCA1-PROJECTING 5-HT NEURONS. FIBER PHOTOMETRY EXPERIMENTS WILL BE USED TO MONITOR THE REAL-TIME ACTIVITY OF THESE VCA1-PROJECTING 5-HT NEURONS, AS WELL AS 5-HT RELEASE IN THE VCA1, CORRESPONDING TO MEMORY ACQUISITION AND RETRIEVAL BEHAVIORS. THE INTERSECTIONAL RETROGRADE CHEMOGENETIC APPROACH WILL BE USED TO FURTHER TEST WHETHER INHIBITION OF THE VCA1-PROJECTING 5-HT NEURONS WOULD INHIBIT MEMORY FUNCTION AND WHETHER ACTIVATING THESE NEURONS WOULD RESCUE MEMORY IMPAIRMENTS IN