NALCN IN THE SUPRACHIASMATIC NUCLEUS LINKS INTRINSIC EXCITABILITY TO CIRCUIT-LEVEL COORDINATION OF CIRCADIAN RHYTHMS

Coherent daily rhythms emerge when intrinsically oscillating neurons couple through cell-type–specific circuit mechanisms. In mammals, the suprachiasmatic nucleus (SCN) of the hypothalamus functions as the central circadian pacemaker, where thousands of individual neuronal oscillators must synchronize to generate daily rhythms in physiology and behavior. While transcriptional–translational feedback loops establish intrinsic molecular oscillations, the ionic mechanisms that couple individual oscillators to circuit-level synchronization remain poorly defined. We tested the role of the sodium leak channel NaLCN, a subthreshold conductance previously implicated in SCN activity. Using viral-mediated deletion of NaLCN in the SCN of NaLCN ^fl/fl mice, we found that loss of NaLCN abolishes circadian locomotor rhythms in constant darkness. Cell-type–specific deletion further revealed that NaLCN is required in dorsal SCN AVP neurons, but not in ventral SCN VIP neurons. These results indicate NaLCN in SCN AVP neurons is required to coordinate circadian behaviors. To evaluate the role of NaLCN in circadian gene expression, we imaged the core circadian gene, PERIOD2 (PER2). We found that the robust dorsal-to-ventral wave of PER2 expression in controls was lost when NaLCN was deleted from SCN neurons or SCN AVP neurons. To assess the role of NaLCN in electrical firing, we recorded from SCN neurons using multielectrode arrays. Preliminary results indicate that circadian firing in SCN neurons requires NaLCN. Together, these findings identify NaLCN as an ionic mechanism linking intrinsic neuronal oscillators to circuit-level coordination within the SCN, revealing how subthreshold excitability supports circadian output at the behavioral level. Supported by NIH R01NS12116.