Abstract
The suprachiasmatic nucleus (SCN) serves as the central circadian clock in mammals, coordinating daily rhythms in both behavior and physiology. In the SCN, gastrin-releasing peptide (GRP)-producing neurons (GRPNs) are predominantly located in the core region, suggesting their possible involvement in photic entrainment. However, the specific contribution of GRPNs to the regulation of circadian rhythms remains poorly understood. This study utilized a Cre-driver mouse line, Grp-iCre knock-in (KI) mice, in which Cre recombinase is exclusively expressed in GRPNs, allowing the selective manipulation of SCN GRPNs to investigate their characteristics and functional roles in circadian regulation. All experiments were conducted in adult male mice. Anatomical tracing revealed that SCN GRPNs primarily project to the thalamus and hypothalamus, whereas input mapping demonstrated that SCN GRPNs receive most synaptic inputs from within the SCN. Behavioral analyses revealed that neither GRP deficiency nor ablation of SCN GRPNs significantly affected circadian locomotor activity rhythms or photic entrainment. However, chemogenetic stimulation of the SCN GRPNs is sufficient to induce phase shifts in behavioral rhythms. Additionally, calcium imaging with fiber photometry indicated that SCN GRPNs quickly responded to photic stimulation, with increased neural activity following retinal exposure to white light. These findings suggest that SCN GRPNs play a role in photic entrainment, albeit potentially redundant with other neuronal populations such as vasoactive intestinal peptide-producing neurons.
Significance Statement The suprachiasmatic nucleus (SCN) functions as the central circadian clock in mammals, synchronizing internal rhythms with the external light-dark cycle. Among its diverse cell types, gastrin-releasing peptide (GRP)-producing neurons (GRPNs) have been implicated in light-based entrainment, but their specific roles remained unclear. Using targeted genetic tools, we demonstrated that these neurons respond rapidly to retinal light stimulation and, when artificially activated, can induce phase shifts in behavioral rhythms. However, eliminating these neurons does not disrupt circadian behavior or molecular clock rhythms, indicating functional redundancy within the SCN network. Our findings clarify the modulatory—but non-essential—role of GRPNs in light-induced entrainment and underscore the complexity and resilience of circadian circuit organization.
Footnotes
The authors declare no competing financial interests.
This work was supported by JSPS Grant-in-Aid for JSPS Fellows grant number 21 J20226 (RL), Grant-in-Aid for Scientific Research (S) 21H05036 (TS), Grant-in-Aid for Transformative Research Areas (A) 23H04941 (TS), 23H04944 (AH), Grant-in-Aid for Research Activity Start-up grant number 24K23202 (RL); JSPS Fund for the Promotion of Joint International Research grant number 22K21351 (TS, AH) and AMED Grant Number JP21zf0127005 (TS), JP21zf0127003 (AH). Research grant of Japan Foundation for Applied Enzymology (AH), Female Research grant of Naito Foundation (AH), JST CREST Grant Number JPMJCR24T4 (TS).
We thank Dr. Y. Cherasse for preparing virus vectors; Editage for language editing.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
