Tuesday, July 1, 2025 7/1/2025

CRCNS: Evidence-based modeling of neuromodulatory action on network properties

Award Number: R01DA057767
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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CRCNS: Evidence-based modeling of neuromodulatory action on network properties - PROJECT SUMMARY (See instructions): Overview: The preBotzinger Complex (preBotC) is the neuronal network that drives inspiratory rhythmogenesis whose activity is orchestrated in response to changes in homeostasis and is critical for maintaining and adapting breathing to the demands of the organism. Respiratory networks are constantly modulated by numerous neuromodulators through altering properties of neurons, synapses and networks. Understanding action of neuromodulation on respiratory networks is critical to understanding control of breathing. While there is extensive experimental effort on studying network effects of neuromodulation, the mechanisms underlying neuromodulatory action on respiratory network properties cannot be easily understood just by experimental work alone. Despite the well-established utility of computational approaches to studying the neural control of breathing, a knowledge gap exists for a computational understanding of the detailed mechanisms underlying how different neuromodulators interact to impact respiratory rhythmogenesis. The overall objective of this proposal is to uncover the mechanism by which the temporal order of neuromodulation with opposing actions (i.e., inhibitory and excitatory) differentially impact respiratory network dynamics. Our preliminary data suggest that such temporal sequencing can induce bifurcations and bistability in network states. We hypothesize that temporal order of opposing neuromodulators yields different changes in intrinsic and synaptic properties of a network which together produce qualitatively different network behaviors when the order is reversed. We will combine electrophysiological experiments and computational modeling across the levels of molecules (glutamates), neurons and networks to test this hypothesis via a focus on respiration, with three Specific Aims: (1) Identify how changes in inhibitory neuromodulation (e.g., opioids) impacts synaptic dynamics and properties in glutamatergic synapse. (2) Dissect the mechanisms by which excitatory neuromodulation (e.g., norepinephrine) regulates respiratory network dynamics through changes in both intrinsic and synaptic properties. (3) Examine the synaptic and intrinsic mechanisms by which temporal order of opposing neuromodulators produces different network states. We will explore and identify relevant bifurcations induced by temporal order of neuromodulators using dynamical systems theory.


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 = $357,884 )
2025	2025	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Drug Use and Addiction Research Programs	000	5	4/25/2025	NON-COMPETING CONTINUATION	$357,884
														Subtotal = $357,884

Issue Date FY: 2024 ( Subtotal = $357,884 )
2024	2024	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Drug Use and Addiction Research Programs	002	4	4/23/2024	NON-COMPETING CONTINUATION	$357,884
2024	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Drug Use and Addiction Research Programs	000	2	4/1/2024	NON-COMPETING CONTINUATION	-$19,624
2024	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Drug Use and Addiction Research Programs	001	3	4/1/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$19,624
														Subtotal = $357,884

Issue Date FY: 2023 ( Subtotal = $430,360 )
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Drug Use and Addiction Research Programs	001	2	8/11/2023	NON-COMPETING CONTINUATION	-$320,637
2023	2023	BRANDEIS UNIVERSITY	415 SOUTH ST	WALTHAM	MA	02453	MIDDLESEX	USA	Drug Use and Addiction Research Programs	002	3	8/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$390,809
2023	2023	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Drug Use and Addiction Research Programs	000	2	4/19/2023	NON-COMPETING CONTINUATION	$360,188
														Subtotal = $430,360

Issue Date FY: 2022 ( Subtotal = $334,132 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Drug Use and Addiction Research Programs	000	1	6/7/2022	NEW	$334,132
														Subtotal = $334,132

Grand Total All Awards = $1,480,260

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CRCNS: Evidence-based modeling of neuromodulatory action on network properties

Award Number: R01DA057767

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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