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Modulation of serotonin levels during development produce long-lasting changes in dopaminergic function

Award Number: R01HD095966
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/11/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Modulation of serotonin levels during development produce long-lasting changes in dopaminergic function - Project Summary The perinatal period is marked by intense plasticity, making it vulnerable to environmental factors that can derail normal brain development and lead to maladaptive behaviors in the adult. High levels of serotonin during development resulting from genetic manipulations, maternal inflammation or administration of selective- serotonin-reuptake-inhibitors (SSRIs) lead to alterations in brain development and/or to behavioral deficits in adult rodents such as anhedonia, anxiety-like behaviors and social interaction deficits. In our preliminary work, we have found that increasing serotonergic tone during the perinatal period leads to decreased exploration, decreased response to an amphetamine challenge and motivation deficits. Interestingly, these behaviors are dependent on the dopaminergic system, a known regulator of mood, reward seeking and motivated behavior. During development, the serotonergic system develops earlier than the dopaminergic one and the Dorsal Raphe nucleus projects strongly to the Ventral Tegmental Area, enabling the serotonergic system to modulate the dopaminergic one. While most studies have focused on the effects of abnormal developmental serotonin levels on the serotonergic system itself or on cortical development, how it affects the dopaminergic system and function is unknown. We hypothesize, based on preliminary data, that high levels of serotonin during development disturb dopaminergic function through the Dorsal Raphe > Ventral Tegmental Area > Nucleus Accumbens pathway resulting in behavioral deficits in the adult. Using a combination of behavioral testing, optogenetics and electrophysiology, we will assess how elevated serotonin levels during development affect our target dopaminergic circuit. In Aim 1, we expand on our preliminary data to characterize the extent to which dopamine- dependent behaviors are affected in mice exposed to SSRIs during the perinatal period. In Aim 2, we delineate the molecular, cellular and circuit bases of the deficits in dopamine-dependent tasks observed in our preliminary data. Understanding the regulation and the interactions between serotonin and dopamine in this key monoaminergic circuit can have clinical implications spanning from mood disorders to autism and motivational aspects of behavior. Furthermore, although our serotonergic manipulation is optimal from experimental and neurobiological perspectives, it is also potentially relevant to real-world clinical situations. Indeed, some pregnancies require the use of antidepressants, which typically increase fetal serotonin levels. An enhanced understanding of the behavioral consequences and the mediating mechanisms of early elevations in serotonergic levels may have substantial implications for improving the lifelong outcomes of the offspring of such pregnancies in the future.


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: 2025 ( Subtotal = $0 )
2025	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD BLDG 35	ORANGEBURG	NY	10962	ROCKLAND	USA	Child Health and Human Development Extramural Research	000	5	3/20/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $394,406 )
2023	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Child Health and Human Development Extramural Research	000	5	4/11/2023	NON-COMPETING CONTINUATION	$394,406
														Subtotal = $394,406

Issue Date FY: 2022 ( Subtotal = $408,150 )
2022	2022	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Child Health and Human Development Extramural Research	001	4	5/27/2022	NON-COMPETING CONTINUATION	$40,817
2022	2022	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Child Health and Human Development Extramural Research	000	4	4/14/2022	NON-COMPETING CONTINUATION	$367,333
														Subtotal = $408,150

Issue Date FY: 2021 ( Subtotal = $406,722 )
2021	2021	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Child Health and Human Development Extramural Research	000	3	3/26/2021	NON-COMPETING CONTINUATION	$406,722
														Subtotal = $406,722

Issue Date FY: 2020 ( Subtotal = $415,022 )
2020	2020	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Child Health and Human Development Extramural Research	000	2	4/6/2020	NON-COMPETING CONTINUATION	$415,022
														Subtotal = $415,022

Issue Date FY: 2019 ( Subtotal = $417,771 )
2019	2019	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	140 OLD ORANGEBURG RD	ORANGEBURG	NY	10962	ROCKLAND	USA	Child Health and Human Development Extramural Research	000	1	4/11/2019	NEW	$417,771
														Subtotal = $417,771

Grand Total All Awards = $2,042,071

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Modulation of serotonin levels during development produce long-lasting changes in dopaminergic function

Award Number: R01HD095966

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/11/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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