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The TTFL and CREB: From cellular- to systems-level clock timing in cortico-limbic circuits

Award Number: R01NS141085
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: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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The TTFL and CREB: From cellular- to systems-level clock timing in cortico-limbic circuits - Project Summary / Abstract The circadian (24hr) timing system influences a vast array of behavioral and neurophysiological processes. Central to this time-keeping process is the circadian pacemaker located within the suprachiasmatic nucleus (SCN). Through both neuronal and hormonal pathways, the SCN sets the phasing of ancillary clock oscillators in a variety of brain regions, including cortico-limbic circuits, and it is the coordinated effects of the SCN and these ancillary forebrain clocks that impart rhythm modulation on complex behavioral states, including mood, memory and executive function. Further, the disruption of clock physiology (at both a cellular and systems level) is a contributing factor in a number of acquired and congenital disorders of the nervous system. Although recent work has provided important clues regarding the profound and far-reaching functional effects of the circadian timing system in the CNS, we still know little about clocks outside of the SCN. Along these lines, within these cortico-limbic circuits, is the circadian timing system cell autonomous (as it is in the SCN); Is it built around the same canonical core clock feedback circuits that form the basis of the core-clock transcriptional feedback loop (TTFL) in the SCN; Is the relationship between the TTFL and ancillary transcriptional circuits similar to, or different from, the relationship in the SCN? Here, we propose to determine the functional significance and mechanistic underpinnings of clock physiology in cortico-limbic circuits, and to assess how these cortico-limbic clocks gate complex behavioral states over the circadian cycle. For these studies, we will utilize a highly innovative combination of approaches, including novel transgenic mouse models, AAV-based genetic interrogation methods, in vitro and in vivo cellular-level longitudinal profiling and novel cellular imaging methods to characterize the relationship between clocks and cognition. In Aim 1, we will test the fidelity and functional properties of the core clock TTFL within cortico-limbic cells and circuits. Mechanisms of TTFL entrainment and rhythm regulation via the CREB/CRE pathway will also be examined. In Aim 2, we propose to use 2-photon in vivo profiling to examine clock timing and entrainment mechanisms within cortico-limbic circuits. In Aim 3 we propose to test the functional relationship between the circadian clock and plasticity- associated signaling pathways and how clock timing could shape the underlying cell biology that gives rise to memory formation. Given the critical role that clock timing plays in human health, new insights into the molecular-, cellular- and systems-level design principles that underlie clock timing through the CNS is absolutely critical for the development of new, efficiently targeted, chronotherapeutic interventions.


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 = $630,925 )
2026	2026	OHIO STATE UNIVERSITY, THE	1960 KENNY RD	COLUMBUS	OH	43210	FRANKLIN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/27/2026	NEW	$630,925
														Subtotal = $630,925

Grand Total All Awards = $630,925

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The TTFL and CREB: From cellular- to systems-level clock timing in cortico-limbic circuits

Award Number: R01NS141085

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: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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