Seasonal affective disorder (SAD) is a major depressive disorder that reoccurs in the fall and winter when day-lengths get short. It is well accepted that day-length is encoded by the principal circadian clock located in the suprachiasmatic nucleus (SCN), but very little is known about day-length encoding in diurnal mammals. The present study utilized the grass rat, Arvicanthis niloticus, to investigate how the circadian system responds to photoperiodic changes in a diurnal mammal that shows day-length dependent mood changes. The animals were initially housed in equatorial day-length (12hr, EP) followed by either long (16hr, LP) or short (8hr, SP) photoperiods. The LP animals showed an expansion of the peak phase of the PER1 and PER2 rhythm in the SCN as well as an extended behavioral active phase. In contrast, the SP animals did not show any compression of their active phase nor a change in the peak duration of PER1 or PER2 expression, compared to those in EP. The results suggest that the circadian system in the diurnal grass rats is less responsive when day-lengths get short compared to when they get longer. The depression-like behaviors were assessed using sweet solution preference (SSP) and forced swimming test (FST). Animals in the SP group showed decreased SSP and increased immobility time in FST as compared to the EP group, suggesting a depressive phenotype. The present study serves as the first step toward exploring the role the circadian system plays in SAD using a diurnal rodent model.
Daily changes in light and food availability are major time-cues influencing circadian timing 1 . Little is known, however, about the circuits integrating these time-cues to drive a coherent circadian output 1 – 3 . Here, we investigated whether retinal inputs modulate the entrainment to non-photic cues, such as time-restricted feeding. Photic information is relayed to the suprachiasmatic nucleus (SCN), which houses the central circadian pacemaker, and the intergeniculate leaflet (IGL) through intrinsically-photosensitive retinal ganglion cells (ipRGCs) 4 . Adult mice lacking ipRGCs since early-postnatal stages displayed impaired entrainment to time-restricted feeding, whereas ablating ipRGCs at later stages had no effect. Early-postnatal ipRGC innervation influences neuropeptide Y (NPY)-expressing IGL neurons, guiding the functional IGL NPY -SCN circuit assembly. Moreover, silencing the IGL NPY neurons in adult animals mimicked the deficits induced by early-postnatal ipRGC ablation, and acute inhibition of IGL NPY terminals in the SCN decreased food-anticipatory activity. Thus, early-postnatal ipRGC innervation tunes the IGL NPY -SCN circuit to allow entrainment to time-restricted feeding.
Retinal ganglion cells (RGCs) relay visual information from the eye to the brain. RGCs are the first cell type generated during retinal neurogenesis. Loss of function of the transcription factor Atoh7, expressed in multipotent early neurogenic retinal progenitors leads to a selective and essentially complete loss of RGCs. Therefore, Atoh7 is considered essential for conferring competence on progenitors to generate RGCs. Despite the importance of Atoh7 in RGC specification, we find that inhibiting apoptosis in Atoh7-deficient mice by loss of function of Bax only modestly reduces RGC numbers. Single-cell RNA sequencing of Atoh7;Bax-deficient retinas shows that RGC differentiation is delayed but that the gene expression profile of RGC precursors is grossly normal. Atoh7;Bax-deficient RGCs eventually mature, fire action potentials, and incorporate into retinal circuitry but exhibit severe axonal guidance defects. This study reveals an essential role for Atoh7 in RGC survival and demonstrates Atoh7-dependent and Atoh7-independent mechanisms for RGC specification.
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