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Mechanisms and therapies for the neurobehavioral deficits from early Mn exposure

Award Number: R01ES028369
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2018
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Mechanisms and therapies for the neurobehavioral deficits from early Mn exposure - Project Summary Studies in children/adolescents have linked developmental environmental manganese (Mn) exposure to inattention, impulsivity, hyperactivity, oppositional behaviors, and fine motor deficits, though these studies are limited by their cross-sectional designs and limited control of confounding that make it impossible to demonstrate that Mn causes these deficits. Our recent studies have shown that developmental Mn exposure causes lasting deficits in attention, impulse control, and fine motor function, providing the first causal evidence supporting the human studies. Our initial studies of the potential benefits of chronic oral methylphenidate (Ritalin) treatment revealed that the one dose studied alleviated the Mn-induced impulse control and fine motor dysfunctions, but impaired attentional performance in the Mn animals. We propose to build upon these findings to elucidate the neural mechanisms underlying the lasting attentional, impulse control, and fine motor dysfunction caused by developmental Mn exposure, and test potential therapeutic interventions (methylphenidate, guanfacine), in our established rodent model of childhood Mn exposure. Our testable hypotheses are 1) Oral MPH and/or guanfacine treatment will alleviate the lasting fine motor, attention and impulse control deficits caused by developmental Mn exposure; and 2) These lasting deficits caused by Mn exposure are due to changes levels of catecholaminergic system proteins in the pre-frontal cortex - striatal pathway. We will test these hypotheses via the following aims: Aim 1 will (i) Identify a clinically-relevant therapeutic regimen of MPH for the Mn deficits in attention, impulse control, and fine motor function by determining the dose-response relationship with MPH in male and female control vs Mn animals, and (ii) Determine involvement of DA D1, D2, and α2A adrenoreceptors in the Mn deficits and in the therapeutic efficacy of MPH, using administration of selective receptor antagonists during behavioral testing. Aim 2 will use PET neuroimaging and quantitative immunohistochemistry to further elucidate changes in catecholaminergic system proteins implicated in the attention/impulse control/fine motor Mn deficits, and the association of these measures with the attention/impulse control/fine motor outcomes. Aim 3 will test the hypotheses that guanfacine alleviates the attention/impulse control deficits produced by Mn. These studies will be the first to identify potentially efficacious therapies for the treatment/prevention of attentional and co-morbid fine motor deficits due to developmental Mn exposure, and to elucidate their neural mechanisms.


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: 2026 ( Subtotal = -$7,220 )
2026	2023	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Environmental Health	000	5	1/28/2026	NON-COMPETING CONTINUATION	-$7,220
														Subtotal = -$7,220

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Environmental Health	000	5	8/28/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $386,440 )
2023	2023	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Environmental Health	000	5	8/9/2023	NON-COMPETING CONTINUATION	$386,440
														Subtotal = $386,440

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF CALIFORNIA SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Environmental Health	000	4	8/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $551,255 )
2021	2021	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Environmental Health	000	4	8/30/2021	NON-COMPETING CONTINUATION	$551,255
														Subtotal = $551,255

Issue Date FY: 2020 ( Subtotal = $585,062 )
2020	2020	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Environmental Health	000	3	8/31/2020	NON-COMPETING CONTINUATION	$585,062
														Subtotal = $585,062

Issue Date FY: 2019 ( Subtotal = $738,995 )
2019	2019	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Environmental Health	000	2	8/26/2019	NON-COMPETING CONTINUATION	$596,148
2019	2019	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Environmental Health	001	2	9/17/2019	SUPPLEMENT FOR EXPANSION	$142,847
														Subtotal = $738,995

Issue Date FY: 2018 ( Subtotal = $571,410 )
2018	2018	UNIVERSITY OF CALIFORNIA, SANTA CRUZ	1156 HIGH ST	SANTA CRUZ	CA	95064	SANTA CRUZ	USA	Environmental Health	000	1	9/19/2018	NEW	$571,410
														Subtotal = $571,410

Grand Total All Awards = $2,825,942

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Mechanisms and therapies for the neurobehavioral deficits from early Mn exposure

Award Number: R01ES028369

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2018

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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