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

Abstract

Circadian rhythms are entrained by light and influenced by non-photic stimuli, such as feeding. The activity preceding scheduled mealtimes, food anticipatory activity (FAA), is elicited in rodents fed a limited amount at scheduled times. FAA is thought to be the output of an unidentified food entrained oscillator. Previous studies, using gene deletion and receptor pharmacology, implicated dopamine type receptor 1 (D1R) signaling in the dorsal striatum as necessary for FAA in mice. To further understand the role of D1R in promoting FAA, we utilized the Cre-lox system to create cell type-specific deletions of D1R, conditionally deleting D1R in GABA neurons using Vgat-ires-Cre line. This conditional deletion mutant had attenuated FAA, but the amount was higher than expected based on prior results using a constitutive knockout of D1R, D1R KODrago. This result prompted us to re-test the original D1R KODrago line, which expressed less FAA than controls, but only moderately so. To determine if genetic drift had diminished the effect of D1R deletion on FAA, we re-established the D1R KODrago knockout line from cryopreserved samples. The reestablished D1R KODrago-cryo had a clear impairment of FAA compared to controls, but still developed increased activity preceding mealtime across the 4 weeks of timed feeding. Finally, we tested a different deletion allele of D1R created by the Knockout Mouse Project. This line of D1R KOKOMP mice had a significant impairment in the acquisition of FAA, but eventually reached similar levels of premeal activity compared to controls after 4 weeks of timed feeding. Taken together, our results suggest that D1R signaling promotes FAA, but other dopamine receptors likely contribute to FAA given that mice lacking the D1 receptor still retain some FAA.

Dopamine systems and biological rhythms: Let’s get a move on

“…Daily pharmacological activation of Drd1 neurons via systemic injection is sufficient to entrain circadian activity rhythms even without manipulating feeding ( Gallardo et al, 2014 ). Taken together, these results indicated that Drd1 is required for stable entrainment of circadian activity (but not body temperature entrainment) to scheduled feeding ( Gallardo et al, 2014 ; Assali et al, 2021 ). However, in a followup study, the defect in FAA in three different strains of Drd1 KO mice was much less than initially reported, suggesting that other DA receptors also promote FAA ( Assali et al, 2021 ).…”

“…Taken together, these results indicated that Drd1 is required for stable entrainment of circadian activity (but not body temperature entrainment) to scheduled feeding ( Gallardo et al, 2014 ; Assali et al, 2021 ). However, in a followup study, the defect in FAA in three different strains of Drd1 KO mice was much less than initially reported, suggesting that other DA receptors also promote FAA ( Assali et al, 2021 ). A potentially interesting result was obtained in transgenic mice overexpressing Drd2, as these mice had normal FAA during a short temporal restriction (i.e., severe calorie restriction) but were impaired under longer time windows of feeding (4 vs. 8 h) ( LeSauter et al, 2020 ).…”

Mice hypomorphic for Pitx3 show robust entrainment of circadian behavioral and metabolic rhythms to scheduled feeding

“…Several lines of evidence point to an important role for dopamine signaling in the dorsal striatum for induction or expression of food-anticipatory circadian activity rhythms, but which and how many of the dopamine neurons are necessary for this rhythm are not known (Assali et al, 2021;Gallardo et al, 2014a;Liu et 2012;Michalik et al, 2015;Smit et al, 2013). Pitx3 ak mice develop only a small fraction of the normal complement of SN dopamine neurons responsible for dopamine signaling in the dorsal striatum, and therefore we were fully expecting to see a significant deficit in food-anticipatory rhythms.…”

Effects of Chemogenetic Inhibition of D1 or D2 Receptor-Containing Neurons of the Substantia Nigra and Striatum in Mice With Tourette Syndrome

“…In our study, after inhibiting or activating D1R-containing neurons in the dSTR, the stereotyped behavior of TS or vehicle-treated mice was significantly decreased or increased, respectively. Since D1R is mainly expressed on GABAergic projection neurons but not inhibitory interneurons in the dSTR ( Figure 9C ; Avila-Luna et al, 2019 ; Assali et al, 2021 ), chemogenetic inhibition of D1R-containing neurons in the dSTR may inhibit the direct pathway, thus alleviating the stereotyped behavior of the TS model. Although chemogenetically activating D1R-containing neurons might have enhance the direct pathway, it only induced stereotyped behavior in vehicle-treated mice, but did not deteriorate the stereotyped behavior of TS mice.…”

“…In addition, D2Rs are distributed on GABAergic projecting neurons of the indirect pathway and inhibitory interneurons in the dSTR ( Alcantara et al, 2003 ; Maurice et al, 2004 ; Zhang et al, 2009 ; Jijon-Lorenzo et al, 2018 ; Brandenburg et al, 2020 ; Lewis et al, 2020 ). However, D1R is only expressed on GABAergic projecting neurons of the direct pathway in the dSTR ( Avila-Luna et al, 2019 ; Assali et al, 2021 ), which is closely related to the regulation of dyskinesia in patients with Parkinson’s disease ( Calabrese et al, 2020 ). Therefore, we wondered whether manipulating D1R- or D2R-containing neurons in the SNpc or dSTR by chemogenetic strategies affected behavioral stereotypies in normal and TS mice.…”