GABAergic network from AVP neurons to VIP neurons in the suprachiasmatic nucleus sets the activity/rest time of the circadian behavior rhythm

The central circadian clock of the suprachiasmatic nucleus (SCN) is a network composed of multiple types of γ-aminobutyric acid (GABA)-ergic neurons and glial cells. However, the precise role of GABAergic transmission in the SCN remains unclear. In this study, we investigated the GABAergic regulation from arginine vasopressin (AVP)-producing neurons in the SCN shell to vasoactive intestinal polypeptide (VIP)-producing neurons in the SCN core. Blocking GABA release from AVP neurons by a vesicular GABA transporter ( Vgat ) gene deletion lengthened the activity time (the interval between the onset and offset of locomotor activity) and shortened the duration of high Ca ²⁺ activity in VIP neurons to match the behavioral rest time. Conversely, eliminating functional GABA _A receptors (GABA _A R) in VIP neurons by in vivo genome editing reduced locomotor activity level and the activity time, and lengthened the high Ca ²⁺ duration in VIP neurons. Optogenetic activation of AVP neurons in vivo increased Ca ²⁺ in VIP neurons during the night. A similar Ca ²⁺ response of VIP neurons to AVP neuronal activation was also observed in SCN slices and was inhibited by a GABA _A R antagonist, gabazine. Importantly, gabazine application alone raised the baseline Ca ²⁺ in VIP neurons, suggesting a tonic depression of these neurons by GABA. Moreover, AVP neuronal activation decreased Ca ²⁺ in non-AVP neurons located between AVP- and VIP-rich regions in the SCN. These results suggest that GABA from AVP neurons disinhibits VIP neurons indirectly by suppressing other intermediate GABA neurons to set the behavior activity/rest time precisely.