Dietary protein restriction alters food-related behaviour and the activity of the mesolimbic pathway

Evolution has provided species with adaptive behavioural mechanisms that guarantee tight dietary protein regulation. However, little is known about how the brain encodes protein need. Here, we elucidate the contribution of the brain reward system in maintaining balanced protein status, examine whether protein need alters food-related motivation and whether protein appetite is innate or learned.

We assessed c-fos expressing neurons in the dorsal striatum and nucleus accumbens (NAc) in protein restricted (5% protein diet) and non-restricted (20% protein) rats, after consumption of protein and carbohydrate-containing solutions.

After, in two separate cohorts, we expressed the calcium indicator, GCaMP6s, in ventral tegmental area (VTA), or the dopamine sensor, dLight1.2, in the NAc core, and used fibre photometry to measure neural activity or dopamine release during nutrients intake.

Additionally, we investigated temporal dynamics of protein consumption when rats first experienced nutrients. Finally, we used a progressive ratio task with protein-rich and nutritionally balanced pellets.

Consumption of protein increased the density of c-Fos positive cells in the NAc core and shell of both protein-restricted and non-restricted rats.

In photometry experiments, protein consumption, relative to carbohydrate, was associated with elevated VTA activation in protein-restricted rats only. Conversely, carbohydrate consumption was associated with increased dopamine release in the NAc core of nonrestricted rats only.

We found that protein was preferred over carbohydrate within the first 5 minutes of exposure to nutrients. Finally, breakpoint for casein pellets was increased in protein-restricted rats, relative to non-restricted controls, whereas there was no difference between groups when nutritionally balanced pellets were used.

Altogether, these results indicate an involvement of VTA and NAc in modulating protein appetite. Additionally, protein need elevates the motivation for protein food, and protein appetite does not require previous learning about nutrients to develop. These findings, beyond contributing to the literature, may have positive repercussions for human health.