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

/ 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. Project Number: 1R01NS141085-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: KARL OBRIETAN (+1 co-PI) | Institution: OHIO STATE UNIVERSITY, Columbus, OH | Award Amount: $630,925 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 ICN-N (92)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11311541