Local circadian regulation of synaptic function and sleep/wake behavior

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. Project Number: 1R01NS144151-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Jonathan Lipton (+1 co-PI) | Institution: BOSTON CHILDREN'S HOSPITAL, BOSTON, MA | Award Amount: $711,952 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 ICN-P (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11365473