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Neocortical-hippocampal coordination and plasticity in sleep-dependent memory storage

Award Number: R21NS143254
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: 03/04/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Neocortical-hippocampal coordination and plasticity in sleep-dependent memory storage - Project summary: Turning fleeting life experiences into long-lasting memories is a fundamental function of the brain and critical for survival. Across animal species, this process, which is linked to plastic changes at synapses between neurons, has been shown to require transition into a sleeping brain state. However, very little is known about 1) how and where this plasticity is brought about by state-specific brain activity, and 2) how sleep states facilitate de novo memory consolidation. The Aton laboratory has recently made inroads to addressing these gaps by studying contextual fear memory (CFM) in mice, a simple form of memory consolidation in which learning occurs in a single training trial (contextual fear conditioning; CFC), and consolidation occurs subsequently in a sleep-dependent manner. We have recently found that CFC selectively drives long-term transcriptional changes in the hippocampal dentate gyrus (DG), and that post-CFC sleep is essential for reactivation of “engram” neurons in DG – i.e. the population of neurons that encode CFC context during fear learning. Brief post-CFC sleep deprivation (SD), which disrupts CFM consolidation, prevents DG engram neuron reactivation in the first few hours following CFC. While sleep-associated coordination of activity between thalamocortical circuits and the hippocampus is thought to be critical for memory storage, the precise synaptic and circuit-level mechanisms affected by corticohippocampal communication during sleep remain unclear. Here, we propose to investigate the precise sleep-dependent processes that are associated with and necessary for successful CFM consolidation, with a focus on sleep regulation of corticohippocampal information transfer from entorhinal cortex (EC) to DG. These studies will use recently developed genetic tools for targeted recombination in activated populations (TRAP), which will allow selective visualization and manipulation of context encoding engram neurons in the EC and DG, as well as the connections between them. We will first quantify sleep-dependent reactivation of engram neurons in these two structures, in the hours immediately following CFC. We will then use state-targeted optogenetic manipulations to disrupt EC engram neurons’ input (or all EC input) to DG during bouts of post-CFC non-rapid eye movement (NREM) sleep, REM sleep, or wake. We will test how these state- specific disruptions of EC input affect reactivation of DG engram neurons, overall hippocampal network activity, and CFM consolidation. Finally, in collaboration with the Soiza-Reilly lab at the University of Buenos Aires, we will use nanoscale array tomography (AT) to quantify changes in synaptic density, size, and protein content resulting from CFC and post-CFC sleep vs. SD. These studies will separately characterize synapses formed between EC and DG engram neurons vs. corticohippocampal synapses where one or both partners are non- engram neurons. These studies will test the hypothesis that post-CFC sleep is required for the selective strengthening of excitatory synapses between EC and DG engram neurons. These studies will provide a highly detailed mechanistic understanding of sleep-dependent memory storage in corticohippocampal circuits.


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 = $419,920 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/4/2026	NEW	$419,920
														Subtotal = $419,920

Grand Total All Awards = $419,920

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Neocortical-hippocampal coordination and plasticity in sleep-dependent memory storage

Award Number: R21NS143254

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: 03/04/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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