Early-stage olfactory bulbectomy induces hyperlocomotion with increased astrocyte and microglial density in the prefrontal cortex of male rats.

Abstract

Major depressive disorder (MDD) severely affects people's productivity and quality of life. Olfactory bulbectomy (OBX) yields reproducible behavioral changes resembling agitated depression. Since most studies examine models after the depressive phenotype is fully established, this work examines mood disorder and glial structure during the early period following OBX, aiming to identify initial circuit adaptations that precede the MDD development. Male Wistar rats were assigned to OBX or SHAM groups. Experiments were conducted exclusively in male animals to reduce hormonal variability, which may limit generalizability. One week after surgery, exploratory behavior was assessed using the open-field test. Subsequently, brain samples of prefrontal cortex (Cg1), hippocampus (CA1), and basolateral amygdala were collected. Immunohistochemical stains were performed to evidence astrocytes (GFAP) and microglia (Iba-1), followed by cell counts and morphometric analyses. OBX rats showed increased total and peripheral distance traveled, with no differences in center distance, rearing, or grooming. Region-specific analyses revealed a significant increase in astrocytes and microglia in the PFC, with no significant changes in Sholl- derived morphological parameters. In the CA1, a significant increase in the length of fourth-order microglial branching was observed. Finally, no significant changes were observed in the BLA across any analyzed parameter. These results show a phenotype that resembles agitated depression and demonstrates differential region-specific glial susceptibility. The PFC is the area that shows the first changes in cell number, without morphological changes, suggesting small adaptations that can later give rise to the manifestations described above by our working group.