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The orexin system as a novel mediator of depression-like outcomes in female rats exposed to an endocrine disrupting compound during the peripubertal period

Award Number: R21ES035848
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: 02/09/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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The orexin system as a novel mediator of depression-like outcomes in female rats exposed to an endocrine disrupting compound during the peripubertal period - Project Summary Age of puberty is one the most reliable predictors of later mental health outcomes in girls, with early menarche greatly increasing the risk of depression in early adulthood. Environmental exposure to endocrine disrupting compounds (EDCs) has been linked with early puberty onset in girls. Despite this, the neurobiological consequences of EDC exposure, and how they might predispose to depression, remain poorly understood. In a series of preliminary studies, we showed that peripubertal exposure to a model EDC, bisphenol-A (BPA), accelerates puberty onset in female rats, and predisposes to behaviors in early adulthood that are reminiscent of anhedonia, a core symptom of clinical depression. These changes were associated with a persistent impairment in the functioning of the orexin neuropeptide system, the activity of which is normally important for translating motivational states into reward behaviors. Specifically, BPA was associated with reduced reactivity of orexin neurons to reward-predictive stimuli, as well as reduced orexin terminals in ventral tegmental area (VTA), a key region through which orexins initiate reward-directed actions. Based on these data, we hypothesize that: at doses that promote early puberty onset, BPA produces a persistent impairment in the functioning of the orexin-VTA circuit. We predict that these changes are causally linked to the anhedonia-like phenotype observed in early adulthood in BPA-exposed rats. Here, we propose three distinct, yet interrelated aims to begin testing our hypothesis. In Aim 1, we will characterize the baseline activity (using electrophysiology) of VTA-projecting orexin neurons in BPA-exposed rats and determine how this is related to the expression of anhedonia-like behavior in early adulthood. In Aim 2, we will use fiber photometry recordings of a novel orexin sensor to measure orexin signaling in VTA in response to reward-predictive stimuli. Finally, in Aim 3, we will use chemogenetics to stimulate the orexin-VTA circuit to test its causal role in the expression of anhedonia-like behavior following BPA. These studies will be the first to determine the effect of EDC exposure on orexin neurons and their circuits, and will determine their mechanistic involvement in depression outcomes in a model of early puberty onset. The proposed project is thus highly relevant to the goal of NIEHS to understand the impact of environmental chemical exposures on psychiatric illness. Moreover, these studies are a critical first step for developing novel strategies to improve mental health outcomes in young women.


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 = $0 )
2026	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Environmental Health	000	2	11/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $196,250 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Environmental Health	000	2	3/5/2025	NON-COMPETING CONTINUATION	$196,250
														Subtotal = $196,250

Issue Date FY: 2024 ( Subtotal = $235,500 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Environmental Health	000	1	2/9/2024	NEW	$235,500
														Subtotal = $235,500

Grand Total All Awards = $431,750

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The orexin system as a novel mediator of depression-like outcomes in female rats exposed to an endocrine disrupting compound during the peripubertal period

Award Number: R21ES035848

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: 02/09/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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