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Pre and post-synaptic pathways underlying the stress response in the adrenal medulla

Award Number: R01NS122534
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: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Pre and post-synaptic pathways underlying the stress response in the adrenal medulla - ABSTRACT The “fight-or-flight” response refers to the state of heightened physiological and mental arousal triggered by a physical threat, emotionally charged event, or metabolic disturbance. Although the precise reaction to each stressor may vary, all share some basic characteristics of sympathetic nervous system activation. Adrenomedullary chromaffin cells are core effectors of the sympathetic response in the periphery. When activated during stress, they discharge a cocktail of hormones into the suprarenal vein for circulation throughout the body. These hormones modulate cardiac, pulmonary, and metabolic functions in ways that favor survival or maintain internal conditions when they are threatened. Secretion from the adrenal medulla is dependent on input from preganglionic splanchnic fibers, which release acetylcholine (ACh) and pituitary adenylate cyclase-activating polypeptide (PACAP) onto chromaffin cells. What remains poorly understood is how ACh and PACAP tune hormone release to accommodate the range of splanchnic firing frequencies associated with variations in sympathetic tone. Three Specific Aims are proposed to fill this gap in our understanding of the stress response pathway. The Aims will test the overall hypothesis that variations in presynaptic splanchnic input are translated by different receptor-coupled pathways in chromaffin cells to dynamically regulate the amount of hormone output. Aim 1 builds on recent preliminary data that shows, for the first time, a role for any synaptotagmin (Syt) at the splanchnic-chromaffin cell synapse. Planned studies, using in situ slice electrophysiology, will define the role of Ca2+ sensing at this synapse, and evaluate the idea that synaptic facilitation, regulated by Syt7, amplifies hormone discharge from chromaffin cells when splanchnic fibers discharge at high frequencies. Aim 2 is motivated by preliminary data that shows Phospholipase C-epsilon (PLC) is required for transducing PACAP stimulation into Ca2+ signals in chromaffin cells that cause exocytosis. PACAP is thought to underlie chromaffin cell secretion during stress. This has prompted us to posit that with increased splanchnic firing frequencies that produce facilitation, PLC activity in chromaffin cells must be “turned on” to sustain increases in hormone output. Aim 3 builds on data which shows that PACAP stimulates exocytosis in chromaffin cells, but does so while paradoxically restricting the release of peptide hormones packaged within a chromaffin granule. Relevant for the differential release of biogenic amines and hormone peptides, we will characterize the properties of PACAP-stimulated fusion pores and investigate mechanisms by which they are constrained. We expect these studies will provide a coherent molecular and physiological framework for understanding how presynaptic activity, postsynaptic receptor- coupled signaling pathways, and exocytosis are mechanistically linked to regulate the stress response.


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 = $370,154 )
2025	2025	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	4/10/2025	NON-COMPETING CONTINUATION	$370,154
														Subtotal = $370,154

Issue Date FY: 2024 ( Subtotal = $359,051 )
2024	2024	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	2/19/2024	NON-COMPETING CONTINUATION	$333,140
2024	2024	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	4/25/2024	NON-COMPETING CONTINUATION	$25,911
														Subtotal = $359,051

Issue Date FY: 2023 ( Subtotal = $370,159 )
2023	2023	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	2/16/2023	NON-COMPETING CONTINUATION	$370,159
														Subtotal = $370,159

Issue Date FY: 2022 ( Subtotal = $365,961 )
2022	2022	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	4/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$365,961
2022	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON STREET	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	8/25/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	4/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	6/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $365,961

Issue Date FY: 2021 ( Subtotal = $359,438 )
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	3/3/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$304,711
2021	2021	REGENTS OF THE UNIVERSITY OF MICHIGAN	503 THOMPSON ST	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	3/31/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$54,727
														Subtotal = $359,438

Grand Total All Awards = $1,824,763

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Pre and post-synaptic pathways underlying the stress response in the adrenal medulla

Award Number: R01NS122534

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: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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