loading
loading
NIH grant 1R21NS151357-01: Sleep-driven reorganization of excitatory and inhibitory synaptic nanoarchitecture
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: Michelle Bridi. Award: $420750.
Start: 2026-08-27T00:00:00.
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.document fetched 2026-09-06 02:47