Kimberly D. Derderian

Mammalian circadian rhythms are primarily entrained by light, but nonphotic cues can also reorganize behavioral timing through mechanisms that remain poorly understood. Nocturnal foot shocks delivered to rodents while they forage away from the safety of their nesting area have been shown to entrain circadian behavioral rhythms and shift foraging and feeding to the daytime. To identify the neural circuits underlying this nonphotic fear entrainment, we optogenetically stimulated tachykinin 1-expressing neurons in the parabrachial nucleus (Tac1 ^PBN ) during the subjective night while the animals foraged outside of their nest, which recapitulated the total activity-rest phase switch in circadian behaviors induced by foot shocks. Furthermore, selective stimulation of Tac1 ^PBN projections to the central amygdala (CeA) produced a significant but reduced phase shift compared to direct stimulation of Tac1 ^PBN cell bodies. When Bmal1 , a core clock gene, was conditionally deleted from the CeA, mice failed to fearentrain, implicating the CeA molecular clock as a necessary component for fear entrainment. Together, these experiments demonstrate that activation of a defined neuronal population outside of the suprachiasmatic nucleus (SCN) can reorganize circadian behavior by engaging a non-SCN circadian oscillator network that requires an intact CeA molecular clock.

Dysfunction in sodium channels and their ankyrin scaffolding partners have both been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). In particular, the genes SCN2A, which encodes the sodium channel Na_V1.2, and ANK2, which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in Scn2a impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how Na_V1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding Na_V1.2 to the dendritic membrane of mouse neocortical neurons, and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a^+/- conditions. Thus, these results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can be etiological to neurodevelopmental disorder pathophysiology.