Mice hypomorphic forPitx3define a minimal dopamine neuron population sufficient for entraining behavior and metabolism to scheduled feeding

Abstract

Pitx3ak mice lack a functioning retina and nearly all dopamine neurons of the substantia nigra (SN). del Rio-Marten et al (2019) reported that entrainment of circadian rhythms to daily light-dark and feeding schedules is absent in these mice. With food limited to 12h/day, food anticipatory circadian rhythms failed to emerge, and metabolic rhythms failed to synchronize with locomotor and feeding rhythms. The authors propose that retinal innervation of the suprachiasmatic nucleus clock is required for development of cyclic metabolic homeostasis, but methodological issues limit interpretation of the results. Using standardized feeding schedules and procedures for distinguishing free-running from entrained circadian rhythms, we confirm that behavioral and metabolic rhythms in Pitx3ak mice do not entrain to LD cycles, but we find no desynchrony between these rhythms nor a deficit in entrainment to daily feeding schedules. SN dopamine neurons surviving in Pitx3ak mice may define a mininum population sufficient for food entrainment.

Restricting feeding to dark phase fails to entrain circadian activity and energy expenditure oscillations in Pitx3-mutant Aphakia mice

“…Importantly, in that study food anticipatory running wheel activity was observed in animals with food available during the light phase. These studies indicate that entrainment of activity and metabolism can be induced by TRF in the absence of caloric restriction, contrary to that stated by Scarpa et al (2022), in agreement with additional studies showing that temporal restriction of feeding to the scotophase in mice without reducing calorie intake reprograms the regulation of energy metabolism to optimize energy balance (Chaix et al, 2019;Hatori et al, 2012;Johnston et al, 2016;Shamsi et al, 2014).…”

“…In their Matters Arising article, Scarpa et al (2022) call into question most of the conclusions of our previous study (Del Rı ´o-Martı ´n et al, 2019) on the circadian organization of biological cycles of Pitx3 ak mice, arguing that they were drawn primarily from averaging metabolic activity or molecular data. We disagree with that argument, since data from individual mice were taken into consideration and the analyses from which we drew most of our main conclusions were not based solely on averaging data.…”

“…In a previous study (Del Rı ´o-Martı ´n et al, 2019), we found that Aphakia mice, characterized by congenital lack of innervation of the SCN by ipRGC axons due to hypomorphic expression of the transcription factor gene Pitx3 (Pitx3 ak ), exhibit out-of-phase daily cycles of locomotor activity, feeding patterns, energy expenditure, and corticosterone secretion that are resistant to metabolic entrainment by time-restricted feeding (TRF). These results have been challenged by Scarpa et al (2022), who report circadian entrainment of behavioral and metabolic cycles in Pitx3 ak mice. We appreciate the interest of these authors in our study and take good note of their concerns.…”

Type 1 dopamine receptor (D1R)-independent circadian food anticipatory activity in mice

“…Previously, we provided evidence that deletion of D1R in mice nearly eliminated behavioral anticipation but not the body temperature increase associated with a daily meal; we proposed that the circuitry sufficient for FAA involved D1R mediated signaling from the SN into the dorsal striatum [ 21 ]. More recently, we demonstrated that mice with hypomorphic mutations in paired-like homeodomain transcription factor 3 , a transcription factor necessary for survival of 95% of SN dopamine neurons, defines a minimal population of dopamine neurons sufficient for FAA and metabolic entertainment to timed feeding [ 47 ]. To further resolve the circuitry of D1R-expressing neurons and their role promoting FAA, we created a conditional knockout of D1R in Vgat-Cre expressing neurons.…”