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Local circadian regulation of synaptic function and sleep/wake behavior

Award Number: R01NS144151
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: 05/02/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Local circadian regulation of synaptic function and sleep/wake behavior - PROJECT SUMMARY The earth's 24 hour light/dark cycle imposes predictable environmental variability to the nervous system. To synchronize internal cellular and organismal states with this daily geophysical oscillation, a multi-scaled circadian clock orchestrates global behaviors such as sleep/wake as well as circuit-specific behaviors like associative learning. Disruption of circadian rhythms and sleep loss are endemic in technological cultures and have been directly linked to sleep disorders, neurodegenerative and neuropsychiatric disorders. Since behavioral plasticity is rooted in the ability of synapses to adjust their computations, a crucial goal is to define how circadian rhythms regulate synaptic function to modulate behavior with the time of day. On the molecular level, circadian timing is rooted in a transcriptional-translational feedback loop present in all cells driven by the transcription factor BMAL1. In this collaborative proposal, we, a circadian biologist and synapse neuroscientist, capitalize on our recent discovery that BMAL1 is rhythmically localized to synapses in a manner dependent on its phosphorylation at Ser42 (pBMAL1S42). pBMAL1S42 regulates the timing of the key synaptic kinase CaMKIIα. We have engineered phosphorylation-incompetent Bmal1S42A mice, that strongly support roles for pBMAL1S42 in orchestrating synaptic vesicle (SV) dynamics, hippocampal memory, and sleep/wake. We have found that pBMAL1S42 is potentiated by serotonin, a crucial neuromodulator of SV dynamics, synaptic plasticity, and sleep/wake behavior. Based on these preliminary data, we hypothesize that synaptic BMAL1 – whose phosphorylation is regulated by serotonin – regulates CaMKIIα, SV dynamics, and sleep need in a phosphorylation-dependent manner. In Aim1, we will dissect the structure-function relationship between BMAL1 and CaMKIIα and define how BMAL1 modulates the biochemistry and biophysics of CaMKIIα to regulate presynaptic function. The goal of Aim 2 is to define the mechanisms by which serotonin potentiates pBMAL1S42 in brain to regulate SV dynamics. In Aim 3, we will define how pBMAL1S42 coordinates SV dynamics and serotonin signaling to consolidate wakefulness at the right time of day. Together, these experiments will expand our fundamental knowledge about the mechanisms by which the circadian clock facilitates behavioral plasticity by orchestrating foundational processes of neurotransmission and computation. Our proposal will provide new insights into the complex relationships between circadian rhythms and the nervous system and should have generalizable applicability to disorders like Alzheimer's disease and schizophrenia, which commonly share defects in serotonin signaling, circadian rhythms, and synaptic function.


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 = $711,952 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/5/2026	NEW	$711,952
														Subtotal = $711,952

Grand Total All Awards = $711,952

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Local circadian regulation of synaptic function and sleep/wake behavior

Award Number: R01NS144151

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: 05/02/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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