Establishment of a novel model of depression caused by olfactory dysfunction through intranasal administration of 3-methylindole

3-Methylindole (3-MI) administered intranasally establishes a non-invasive, ethically sound depression model. • Targets the olfactory pathway to replicate core pathological features of depression. • Novel depression model based on the “olfactory dysfunction-neuroinflammation-hippocampal injury” cascade. Olfactory dysfunction has been closely linked to depression. However, the olfactory bulbectomy (OBX) model, a commonly employed animal model of depression, presents significant limitations, including poor alignment with clinical etiology and an elevated risk of mortality. In this study, we introduced an innovative, non-invasive model of depression by inducing olfactory dysfunction via the intranasal administration of a thermosensitive poloxamer gel containing 3-methylindole (3-MI) loaded in hydroxypropyl-β-cyclodextrin (HP-β-CD). This method specifically targets the olfactory pathway, thereby enhancing the model's safety and reliability. Through behavioral assessments, histopathological examination, transmission electron microscopy (TEM), immunohistochemistry, and neurotransmitter analyses, we found that the intranasal administration of the 3-MI gel significantly impaired olfactory sensitivity, damaged the olfactory epithelium, and induced inflammation and oxidative stress within the olfactory bulb. These alterations resulted in depressive-like behaviors, mitochondrial dysfunction, and apoptosis in the hippocampus, as well as reduced neurotransmitter release and metabolism in brain tissues. Treatment with mecobalamin or fluoxetine effectively alleviated olfactory dysfunction and depressive symptoms, respectively. Mecobalamin restored olfactory function and ameliorated depressive pathologies. Importantly, fluoxetine substantiated the model's predictive validity by reversing depressive and neurochemical deficits, although its efficacy in improving olfactory function was limited. Compared with the OBX and chronic unpredictable mild stress (CUMS) models, the intranasal 3-MI gel administration approach avoids both invasive surgery and prolonged stress exposure, aligning with animal welfare principles through minimized distress. These findings affirm the dual utility of this approach as both an effective and ethically optimized method for modeling depression. Schematic illustration of 3-MI/HP-β-CD-ATG for nose-to-brain delivery, inducing depression via olfactory dysfunction. Download: Download high-res image (331KB) Download: Download full-size image