Olfactory, cognitive, and psychiatric disorders are known sequelae of the COVID-19 infection (Chippa et al., 2023; Delgado-Alonso et al., 2022; Silva Andrade et al., 2021), and olfactory impairment in patients with COVID-19 has been associated with the development of anxiety and depression (Liu et al., 2022; Speth et al., 2020). The sense of smell has several effects on daily life, including dietary deviance, emotional modulation, and social and spontaneous behavior. Olfaction is first perceived by olfactory neurons in the olfactory epithelium. Then, the information is transmitted via the olfactory bulb (OB) to the cerebral cortex, hippocampus, amygdala, and other brain regions that play important roles in emotion (Marin et al., 2023; Soudry et al., 2011).

Olfactory bulbectomy (OBX) causes persistent anosmia and leads to abnormalities such as depression-like behaviors and memory deficits, as well as neurochemical changes such as decreased brain monoamines (Takahashi et al., 2016, 2018a, 2020b), decreased neurogenesis (Nakagawasai et al., 2020a, 2020b; Odaira et al., 2019; Takahashi et al., 2017, 2020a, 2022b), and enhanced neuroinflammation in the hippocampus (Takahashi et al., 2018a). However, OBX is accompanied by permanent anosmia and circulatory damage in the brain (Kelly et al., 1997), which can cause retrograde neurodegeneration in several brain regions (Jancsár and Leonard, 1983; Song and Leonard, 2005). Therefore, an OBX model that adds organic damage is inappropriate for basic research on the relationship between olfactory dysfunction and depression, as it may lead to clinical discrepancies. Nasal administration of zinc sulfate (ZnSO4) can cause reversible lesions of the olfactory epithelium and transient anosmia in mice (Ahn et al., 2018) and induce abnormal behaviors, including depression and memory deficits (Chen et al., 2019; Liu et al., 2020b, 2020c; Takahashi et al., 2021b, 2023c). Hence, ZnSO4-treated mice are appropriate for exploring how noninvasive olfactory dysfunction contributes to the development of psychiatric disorders.

Reduction in neurogenesis of the adult hippocampal dentate gyrus (DG) has been associated with depression in both rodents and humans (Castrén et al., 2007; Duman and Monteggia, 2006; Scorza et al., 2005), and chronic administration of antidepressants may promote hippocampal neurogenesis (Santarelli et al., 2003). Moreover, depression is closely related to neuroinflammation and microglia activation (Yirmiya et al., 2015) and is characterized by elevated inflammatory cytokine levels in the brain (Milior et al., 2016). Elevated inflammatory cytokines induce apoptosis and decrease neurogenesis in the hippocampus, which results in depression-like behavior in mice exposed to chronic mild stress (Liu et al., 2020a). These findings suggest that neuroinflammation contributes to depression by reducing neurogenesis in the hippocampal DG (Takahashi et al., 2023b; Troubat et al., 2021; Wu and Zhang, 2023).

Microglia play a dual role by acquiring distinct physiological properties, consisting of inflammatory (M1) and anti-inflammatory (M2) phenotypes (Maezawa et al., 2018). Type M1 microglia produce inflammatory cytokines and a high expression of inducible nitric oxide synthase (iNOS), while type M2 microglia produce anti-inflammatory cytokines as well as arginase-1 (Orihuela et al., 2016). Minocycline (Mino), an inhibitor of microglial activity, exhibits anti-inflammatory and antidepressant effects by suppressing polarization of type M1 microglia, and its efficacy in patients with depression has been reported in clinical trials (Kobayashi et al., 2013; Miyaoka et al., 2012; Murrough et al., 2018; Rosenblat and McIntyre, 2018; Savitz et al., 2018); however, its efficacy has not been studied in ZnSO4-treated mice.

In this study, we investigated the pathogenesis of depression-like behavior observed in mice models of olfactory dysfunction underlying neuroinflammation.