Maternal separation alters the reward system of activity-based anorexia rats

Maternal separation (MS) is a known chronic stressor in the postnatal period and when associated with another paradigm like the activity-based anorexia (ABA) rat model, causes different effects in the two sexes. In ABA females, the separation leads to increased hyperactivity and anxiety reduction, whereas, in males, the separation induces decreased locomotor activity without similar reduction of anxiety-like behaviors as observed in females. To understand the mechanisms altered by MS in synergy with the induction of the anorexic-like phenotype, we considered the reward system, which involves neurons synthesizing dopamine (DA) in the ventral tegmental area (VTA), substantia nigra pars compacta, and serotoninergic neurons in the dorsal raphe nucleus. Moreover, we analyzed the orexin circuit in the lateral hypothalamic area (LHA), which affects DA synthesis in the VTA and is also known to regulate food consumption and locomotor activity. Rats of both sexes were exposed to the two paradigms (MS and ABA), leading to four experimental groups for each sex: non-separated control (CON), non-separated ABA groups (ABA), MS control (MSCON), and MS plus ABA groups (MSABA). Immunohistochemistry analysis was performed to determine quantitative differences in the number of cells expressing DA, orexin, and serotonin (5-HT) among the experimental groups. The results showed that, in the DA system, the effect of MS was more evident in females than in males, with a substantial increase in DA cells in the VTA of MSABA. However, the analysis of the orexin system revealed a similar cellular increment in the LHA in the non-separated ABA groups of both sexes. Regarding 5-HT, there was an opposite effect in males and females of the MSABA groups, with only females showing a greater density of 5-HT cells. The changes in the reward system could partially explain the behavioral data: the hyperactivity, weight loss, and decreased anxiety levels of the MSABA females could be linked to an increase in DA and 5-HT cells, whereas in males, MS could mitigate the behavioral effects of the ABA protocol affecting the anxiety levels and locomotor activity through a lack of increased activation of the reward system.