Changes in Circadian Rhythm in Chronically-Starved Mice Are Associated With Glial Cell Density Reduction in the Suprachiasmatic Nucleus.

Abstract

Objective: Anorexia nervosa (AN) is an eating disorder characterized by severe weight loss and associated with hyperactivity and circadian rhythm disruption. However, the cellular basis of circadian rhythm disruption is poorly understood. Glial cells in the suprachiasmatic nucleus (SCN), the principal circadian pacemaker, are involved in regulating circadian rhythms. We hypothesize that the circadian rhythm disruption in AN patients is associated with glial cell changes in the SCN.

Method: In the starvation-induced hyperactivity mouse model, mice had free access to a running wheel and received a restricted amount of food once a day, until a 25% body weight loss was reached and maintained their weight loss for two weeks. This was followed by a refeeding phase. Different daily periods of running wheel activity were defined, such as food anticipatory activity up to 4 h before feeding. Circadian rhythmicity was analyzed using the cosinor method. Gene expression was evaluated using real-time polymerase chain reaction. Immunohistochemistry was used to quantify astrocytes, microglia, and oligodendrocytes.

Results: Starvation induced changes in circadian rhythm, as indicated by changes in cosinor-based characteristics. Refeeding reversed these effects. Additionally, there was an increase in cryptochrome circadian regulator 1 expression and a decrease in the density of astrocytes and oligodendrocytes in the SCN after chronic starvation.

Discussion: Starvation-induced alterations in circadian rhythms are associated with molecular, and cellular changes in the hypothalamus. Reduced astrocytes and oligodendrocytes in the SCN in a mouse model of AN suggest that glial pathophysiology may play a role in circadian rhythm disruption.