Increased Serum Neurofilament Light Chain Concentration Associated With Microglial Morphology Changes in Chronically-Starved Mice

Objective: Anorexia nervosa (AN) is associated with hyperactivity, amenorrhea, and brain atrophy. Weight rehabilitation reversed these symptoms, although the underlying pathophysiological mechanisms are mostly unknown. Serum neurofilament light chain (NfL) levels are widely used as a biomarker of neurodegeneration. Based on neuroimaging studies and increased serum NfL levels, we assume that neurodegeneration is a core neuropathological feature in AN patients. Method: Female mice were given a limited amount of food once a day and had unlimited access to a running wheel until they reached a 25% weight reduction, which was maintained for 2 weeks to mimic chronic starvation. This was followed by 3 weeks of refeeding. Running activity was measured by wheel sensors, while amenorrhea was determined by analyzing vaginal smears. Brain sections were used to investigate brain volumes. NfL levels were determined using a NF-light assay. Behavioral tests such as forced swim and elevated plus maze assessed behavioral changes. Immunohistochemistry was used to quantify the density of microglia, while their morphological analysis was performed using Neurolucida 360. Results: Chronic starvation led to AN-related symptoms of hyperactivity and amenorrhea. The decreased cerebral cortex, hippocampal, and corpus callosum volumes were paralleled by increased NfL levels after chronic starvation. A behavioral association was reduced anxiety-like behavior after chronic starvation. Starvation induced decreased microglial density, increased soma area, and prolonged microglial processes. Discussion: Chronic starvation led to an increase in NfL levels and changed microglial morphology in a mouse model of AN, suggesting that neuronal pathophysiology may contribute to the disease.