Sidikpramana, M. | bioRxiv Science

bioRxiv2022

Mice lacking dopamine production in neurotensin receptor 1 neurons voluntarily undergo time-restricted feeding of high fat diet and resist obesity

The introduction of processed foods high in fat and sugars has caused a dramatic increase in obesity in humans. Diet-induced obesity (DIO) can be modeled in laboratory mice by increasing the fat content of their diet. Previously, it was determined that mice lacking dopamine receptor 1 (Drd1) are completely resistant to DIO and do not eat as much food during the day as control mice. Surprisingly, when Drd1 is restored to the suprachiasmatic nucleus (SCN), which is the central regulator of circadian rhythms, these mice increase day-eating and become obese. The source of dopamine in the SCN is the ventral tegmental area (VTA), but the genetic identity of the dopamine neurons is unknown. Here we create conditional deletion mutants for tyrosine hydroxylase (TH) using neurotensin receptor 1 (Ntsr1) Cre and other Cre drivers and measure feeding and body weight homeostasis on standard and high fat diets. Control mice were susceptible to DIO and overate during the day whereas Ntsr1-Cre conditional knockouts for TH mice did not increase day-eating, nor did they gain much weight on HFD. We used an adeno-associated virus to selectively restore TH to the VTA Ntsr1 neurons and observed an increase in body weight and increased day-eating of HFD. These results implicate VTA Ntsr1 dopamine neurons as promoting out-of-phase feeding behavior on a high fat diet that could be an important contributor to diet-induced obesity.

neuroscience↗

bioRxiv2020

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

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. We were unsuccessful in obtaining conditional deletion of D1R when using transgenically driven D1R-Cre. We then created a conditional deletion of D1R in GABA neurons using Vgat-ires-Cre line, which 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.

neuroscience↗