People with anorexia are excessively preoccupied with weight gain and severely limit their food intake, exercise excessively and thus experience significant weight loss. “Anorexia has the highest mortality rate of any psychiatric illness,” says lead author Dr. Yong Xu, professor of pediatrics, nutrition, and molecular and cellular biology at Baylor. Anorexia is more common in women than in men, but this difference in prevalence remains poorly understood. This team not only identifies abnormal activity in a brain circuit associated with anorexia, but also shows that the genetic and pharmacological restoration of the activity of the brain circuit in question reduces the symptoms of the condition.
“The condition has no approved treatment and the underlying cause remains poorly understood,” adds the author. In this study, we identify, in an animal model of anorexia, alterations in the cerebral circuit which seem to be involved in this TCA.
The in vivo study: lhe team has been working on TCAs for years and has already shown that the dysfunction of dopaminergic and serotonergic neurons, which regulate eating, is associated with anorexia. However, how these 2 groups of neurons in the brain contribute to anorexia remained poorly understood. This animal study reveals that:
- under normal conditions, dopaminergic neurons communicate with serotonergic neurons, and this interaction regulates feeding;
- the strength of the signal transmitted along the cerebral dopamine-serotonin circuit determines the importance of food intake;
- when the dopaminergic neurons emit a low frequency signal, for example between 2 and 10 Hertz, the result is the inhibition of the serotonergic neurons and an overfeeding behavior;
- when the dopaminergic neurons fire at a higher frequency between 10 and 30 Hertz, the serotonergic neurons are activated, which induces the cessation of feeding.
The dopamine-serotonin circuit in the development or persistence of anorexia: in mice, this brain circuit appears super-activated in the event of a lack of appetite and excessive exercise. Finally, the DRD1 dopamine receptor has been identified as a key mediator of the hyperactivity of this circuit. The inactivation of the DRD1 gene makes it possible to partially restore normal feeding behavior in the animal;
What implications? This work suggests that targeting and inhibiting the DRD1 receptor could contribute to reducing the hyperactivity of the circuit and therefore anorexic behaviors. Moreover, the team shows that a drug that interferes with the activity of the DRD1 receptor can – again in mice – effectively prevent anorexia and weight loss.
These first very promising results will give rise to future clinical trials.