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Shaping of offline cortical reactivations of recent experiences by pre-existing ensembles and inhibitory microcircuits

Award Number: F31MH146366
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/01/2027
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Shaping of offline cortical reactivations of recent experiences by pre-existing ensembles and inhibitory microcircuits - SUMMARY/ABSTRACT The main goal of this proposal is to elucidate how the brain reshapes neural representations during offline replay of past experience, a neurophysiological signature of memory consolidation1. Replay is associated with the incidence of a transient high-frequency oscillation in the hippocampus called a sharp-wave ripple (SWR)2. Causal evidence suggests that despite constituting a very small proportion of time in an animal’s life, SWR-associated replay plays an outsized role in supporting memory consolidation21-24. Exactly how replay contributes to learning is an active area of investigation. An emerging explanation is that replay may not only rehearse experience-evoked neural activity patterns but also re-organize and optimize neural representations65. Psychologists have long appreciated that memory consolidation is an active rather than passive process; new experiences are not copied onto a blank slate, but rather integrated with learned priors80. Accordingly, replayed patterns of neural activity are not carbon copies of representations evoked by prior experience, but instead predict future adaptive plasticity5,60,65,82. In this proposal, I will investigate a potential role for local neocortical microcircuits in reshaping representations during offline replay. Traditionally, SWRs and associated replay have been studied by recording from the hippocampus alone, but more recent work suggests that changes in the activity of cortical circuits can precede and predict content of SWR-aligned spiking in the hippocampus3-4. Thus, SWR-preceding cortical activity is well-positioned to play a privileged role in shaping brain-wide processing during offline replay, but its function is still unclear. Based on recent work from our lab and new preliminary data, we hypothesize that pre-SWR cortical activity maps new experiences onto pre-existing activity patterns shaped by stable recurrent connectivity5. In this proposal, I will investigate this hypothesis from two perspectives: neural representations (Aim 1) and local circuit mechanisms (Aim 2). In Aim 1, I will use two- photon calcium imaging to record the activity of thousands of excitatory neurons with simultaneous hippocampal electrophysiology to investigate how the structure of visual cortex population activity shifts during hippocampal SWRs. In Aim 2, I will investigate whether dendrite-targeting interneurons gate pre-SWR changes in cortical population activity using new pipeline for alignment of in-vivo two-photon calcium imaging to ex-vivo spatial transcriptomics. Taken together, these directions will enhance our understanding of memory consolidation by shining new light on how the neocortex reprocesses experiences during spontaneous offline replay. In the long term, this work may have clinical relevance as reductions in biomarkers for offline learning, including SWRs, precede major cognitive impairments in memory disorders such as Alzheimer’s disease83-84. Enhancing our understanding of the fundamental building blocks of offline memory consolidation may therefore enable new, mechanistically guided treatments for memory disorders that affect a growing number of Americans.


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 = $43,325 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	1	8/17/2026	NEW	$43,325
														Subtotal = $43,325

Grand Total All Awards = $43,325

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Shaping of offline cortical reactivations of recent experiences by pre-existing ensembles and inhibitory microcircuits

Award Number: F31MH146366

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/01/2027

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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