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PET imaging of dynorphin/kappa-opioid reactivity to stress in depression

Award Number: K01MH129780
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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PET imaging of dynorphin/kappa-opioid reactivity to stress in depression - PROJECT SUMMARY/ABSTRACT: Major depressive disorder (MDD) is a leading cause of disability worldwide with a paucity of personalized, efficacious treatments. Life stressors have long been shown to potently predict depressive symptomatology and onset of major depressive episodes. Despite this, the neurobiological mechanisms underlying stress regulation in depression are not yet fully understood in humans. Preclinical and initial human studies implicate kappa-opioid receptor (KOR) deficits in the pathogenesis of MDD and suggest that stress reactivity might contribute to these KOR deficits. The innovative study proposed in this K01 represents a first step to determine if KOR binding deficits and heightened dynorphin/KOR-mediated stress reactivity are observed in MDD relative to healthy controls (HCs). If shown to be so, then the second step will be to determine whether these deficits represent a state effect that it is present in currently depressed and not in euthymic subjects with MDD or a trait effect present in both currently depressed and remitted MDD (to be tested in a follow-up R01). Therefore, we seek to evaluate KOR binding at rest and endogenous dynorphin release to a laboratory stressor in unmedicated, currently depressed participants with MDD vs. HCs. KOR binding and dynorphin release will be quantified in vivo in humans with functional positron emission tomography (PET) with the new tracer [11C]EKAP, already reliably synthesized and used in rodents at the Columbia PET Center, that targets KOR with high sensitivity and specificity. A brief, validated stress task with physiologic and psychologic components will be given during the PET scan that elicits hypothalamic-pituitary-adrenal (HPA) axis activation. Physiologic markers of HPA activation will be acquired proximal to the task, e.g., cortisol, to be compared with KOR binding at rest and stress-induced endogenous dynorphin release in MDD vs. HCs. Further, the Principal Investigator’s (PI) preliminary studies suggest that smartphone-administered ecological momentary assessment (EMA) of daily stressors is greater in depressed relative to control participants and has distinct structural and functional neural correlates. In this study, EMA of daily stressors will be acquired and evaluated to determine if daily stress preceding the PET scan, as well as preceding a structural magnetic resonance imaging (MRI) scan, modulate brain structure, KOR binding, and stress-induced endogenous dynorphin release in depression. This will be the first study to investigate KOR’s role in stress-reactivity in vivo in MDD, and will combine multimodal neuroimaging, peripheral markers of HPA activation, and EMA daily stress. Regardless of the outcome of this study, it will increase our understanding of KOR’s role in MDD and in dysregulated stress reactivity in MDD, potentially suggesting KOR-regulated, stress-sensitive depression subtypes. This award will measurably advance the PI’s training in conducting highly impactful research studies and understanding the neurobiology of mood disorders. This will propel the PI toward research independence, launching her research program aimed at elucidating the consequences of stress in mood disorders and developing interventions to mitigate them.


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 = $181,332 )
2026	2026	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	001	3	8/19/2026	NON-COMPETING CONTINUATION	$181,332
2026	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	2	1/26/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $181,332

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	2	8/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	2	8/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $181,331 )
2023	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	001	2	8/18/2023	NON-COMPETING CONTINUATION	$181,331
2023	2023	RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC.	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	002	2	9/27/2023	NON-COMPETING CONTINUATION	$0
2023	2022	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	1	5/24/2023	NEW	$0
														Subtotal = $181,331

Issue Date FY: 2022 ( Subtotal = $181,332 )
2022	2022	RESEARCH FOUNDATION FOR MENTAL HYGIENE INC	1051 RIVERSIDE DR	NEW YORK	NY	10032	NEW YORK	USA	Mental Health Research Grants	000	1	9/15/2022	NEW	$181,332
														Subtotal = $181,332

Grand Total All Awards = $543,995

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PET imaging of dynorphin/kappa-opioid reactivity to stress in depression

Award Number: K01MH129780

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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