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Sleep-driven reorganization of excitatory and inhibitory synaptic nanoarchitecture

Award Number: R21NS151357
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: 08/27/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Sleep-driven reorganization of excitatory and inhibitory synaptic nanoarchitecture - PROJECT SUMMARY/ABSTRACT Sleep loss is a prevalent problem that is caused by many environmental, social, and health factors. In particular, sleep disruption is common in many neurological conditions, ranging from neurodevelopmental disorders to neurodegenerative disease. However, our understanding of the role of sleep loss in these conditions is limited because sleep function under typical conditions is incompletely understood. Prominent theories posit that sleep plays a crucial role in learning and memory by regulating synaptic plasticity, but the underlying mechanisms are debated. Sleep has been proposed to support learning either by consolidating plastic changes that were induced during prior waking, or by homeostatically downregulating synapses to improve signal-to-noise and restore resources for subsequent learning. Establishing the mechanisms by which sleep supports brain function under typical conditions will advance our fundamental knowledge about the brain and provide insight into the burden of sleep loss, with high relevance to many clinical populations. We and others have shown that sleep regulates synaptic communication between neurons in several brain regions. Moreover, excitatory and inhibitory synaptic transmission are regulated in opposite directions: excitation decreases and inhibition increases over sleep-rich periods. While these physiological changes are robust and replicable across laboratories, we do not yet know what plasticity mechanisms are responsible. In recent years, it has become apparent that nanoscale-level organization of synaptic proteins is a key regulator of synaptic function and plasticity. However, assessing synaptic nanoarchitecture is challenging because conventional light microscopy does not have adequate resolution, and complements of synaptic proteins cannot be simultaneously visualized with electron microscopy. Here, we will use stimulated emission depletion (STED) nanoscopy to determine how sleep and sleep disruption shape synaptic nanoarchitecture of excitatory (Aim 1) and inhibitory (Aim 2) synapses. We will employ cutting-edge approaches that were recently developed and validated in our laboratory to visualize synaptic nanoarchitecture in mouse brain slice. We will determine how sleep alters the alignment and localization of proteins within the active zones and postsynaptic densities of excitatory and inhibitory synapses. We will examine synapses onto GFP-labeled pyramidal and parvalbumin neurons in layers 2/3 of the primary visual cortex, where synaptic transmission has been functionally characterized during sleep. These studies will reveal mechanisms by which sleep modifies synaptic function under typical conditions, laying the groundwork for future studies of how sleep loss impacts the brain in neurological conditions. These innovative high risk/high impact experiments are timely and have great potential to generate key breakthroughs in this important area of neuroscience.


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 = $420,750 )
2026	2026	WEST VIRGINIA UNIVERSITY RESEARCH CORPORATION	886 CHESTNUT RIDGE ROAD	MORGANTOWN	WV	26505	MONONGALIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/27/2026	NEW	$420,750
														Subtotal = $420,750

Grand Total All Awards = $420,750

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Sleep-driven reorganization of excitatory and inhibitory synaptic nanoarchitecture

Award Number: R21NS151357

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: 08/27/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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