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Medullary Control of REM Sleep

Award Number: R01HL149133
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/17/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Medullary Control of REM Sleep - SUMMARY Rapid eye movement sleep (REMS) is regulated by dynamic interactions between REMS-promoting (REM-on) and REMS-suppressing (REM-off) neurons. Once REMS is entered, the activity in distinct brainstem nuclei gives rise to its distinct phasic features such as rapid eye movements and pontine (P-) waves, defining hallmarks of phasic REMS. Research within the last decade has identified multiple cell populations that control REMS and mapped their connectivity. However, the population-level dynamics underlying REMS initiation and its phasic features remain poorly understood. In the initial grant phase, we showed that inhibitory neurons in the dorsomedial medulla (dmM) strongly promote REMS via their projections to the dorsal and median raphe. In addition, we identified an excitatory subpopulation expressing corticotropin-releasing hormone (CRH) that reliably induces P-waves. These neurons project to the dorsolateral pons, a critical site for P-wave generation in rodents. In preliminary experiments, we performed high- density electrophysiological recordings in dorsal (DR) and median raphe (MR) and in the dorsolateral pons. Performing dynamical systems analysis, we uncovered two key features: First, the population activity in DR/MR exhibits consistent trajectories passing from an NREM attractor to a REM attractor through a specific entry point, and second, the dorsolateral pons shows bistable dynamics that switch between tonic and phasic REMS states. The central objective of this proposal is to understand how distinct populations in the dmM shape downstream midbrain and pontine population dynamics to facilitate transitions to REMS and regulate phasic REMS. This will be accomplished in two aims. First, we will perform high-density recordings combined with opto- and chemogenetic manipulation and viral tracing to reveal how inhibitory dmM inputs and subpopulations within DR and MR shape the population dynamics to initiate REMS. Second, we will investigate how projections from the dmM to the dorsolateral pons regulate P-waves and phasic REM by combining electrophysiological recordings in pons and medulla with optogenetic perturbation. By integrating state-of-the-art systems neuroscience techniques with dynamical systems analysis, our study will uncover how distinct medullary populations regulate the population dynamics in midbrain and pontine areas to regulate REMS induction and its substage architecture. Since disturbances in REMS, particularly in its timing and phasic features, are key symptoms of mood disorders such as major depressive disorder (MDD), our findings will provide critical mechanistic insights and may identify novel therapeutic targets for restoring healthy sleep in depression.


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 = $551,052 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	National Center on Sleep Disorders Research	000	6	6/23/2026	COMPETING CONTINUATION	$551,052
														Subtotal = $551,052

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	National Center on Sleep Disorders Research	000	5	9/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $463,434 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	National Center on Sleep Disorders Research	001	5	9/8/2023	SUPPLEMENT FOR EXPANSION	$65,625
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	National Center on Sleep Disorders Research	000	5	7/24/2023	NON-COMPETING CONTINUATION	$397,809
														Subtotal = $463,434

Issue Date FY: 2022 ( Subtotal = $398,054 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	National Center on Sleep Disorders Research	000	4	6/28/2022	NON-COMPETING CONTINUATION	$398,054
														Subtotal = $398,054

Issue Date FY: 2021 ( Subtotal = $398,293 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	National Center on Sleep Disorders Research	000	3	7/8/2021	NON-COMPETING CONTINUATION	$398,293
														Subtotal = $398,293

Issue Date FY: 2020 ( Subtotal = $397,337 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	National Center on Sleep Disorders Research	000	2	7/16/2020	NON-COMPETING CONTINUATION	$397,337
														Subtotal = $397,337

Issue Date FY: 2019 ( Subtotal = $397,560 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	National Center on Sleep Disorders Research	000	1	8/5/2019	NEW	$397,560
														Subtotal = $397,560

Grand Total All Awards = $2,605,730

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Medullary Control of REM Sleep

Award Number: R01HL149133

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/17/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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