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Changing the neuromodulation game: ultrasound fenestration of the blood brain barrier for noninvasive viral transfection of primate CNS neurons

Award Number: R34NS122272
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Changing the neuromodulation game: ultrasound fenestration of the blood brain barrier for noninvasive viral transfection of primate CNS neurons - Summary Genetic technologies have revolutionized the way scientists can dissect out brain circuitry by inserting G protein-coupled receptors that enable selective modulation of neurons in target structures. Amongst them, a promising tool,DREADDS (designer receptors exclusively activated by designer drugs) is used to modulate neural activity pharmacologically in targeted brain regions. Unfortunately, DREADDS also require invasive methods to deliver the genes that express the receptor. Focused Ultrasound (FUS) is a novel approach that focuses an ultrasound beam through the skull and meninges to reach deep brain structures and directly stimulate or inhibit neurons in the targeted region. Combined with lipid microbubbles, focused ultrasound can be used to open the blood-brain barrier (BBB) in targeted brain regions. This method is non-invasive, but spatially precise. Focused ultrasound mediated BBB opening has been used to deliver optogenetic viruses in rodent models. Here, we propose to test if this approach can be used to express DREADDS in targeted brain regions in nonhuman primates (rhesus monkeys). We will open the BBB using FUS with microbubbles. The BBB remains open for 24 to 48 hours. During this time, a viral delivery system will be used to introduce DREADDS by intravenous injection. The DREADDS should circulate through the bloodstream and enter the brain only in the region where the BBB has been opened. This entire procedure is completely noninvasive. We will test the functional effects of DREADDS using a fMRI and electrophysiology. We will then confirm DREADD expression using post-mortem histology. The development of FUS-based DREADD delivery could make deep brain neuromodulation available for patients who are not candidates for surgical approaches. The proposed experiments are essential for establishing the efficacy of focused ultrasound mediated DREADD delivery to treat psychiatric illnesses that affect cognition and motivation. FUS-based chemogenetic therapy could become a non-surgical alternative for patients with psychiatric disorders who would benefit from DBS


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/17/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/10/2023	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $752,571 )
2021	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/29/2021	NEW	$752,571
														Subtotal = $752,571

Grand Total All Awards = $752,571

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Changing the neuromodulation game: ultrasound fenestration of the blood brain barrier for noninvasive viral transfection of primate CNS neurons

Award Number: R34NS122272

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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