Iron is the most abundant transition metal in the brain and is essential for brain development and neuronal function; however, its abnormal accumulation is also implicated in various neurological disorders. The olfactory bulb (OB), an early target in neurodegenerative diseases, acts as a gateway for environmental toxins and contains diverse neuronal populations with distinct roles. This study explored the cell-specific vulnerability to iron in the OB using a mouse model of intranasal administration of ferric ammonium citrate (FAC). Olfactory function was assessed through olfactory discrimination tests, while iron levels in OB tissues, cerebrospinal fluid (CSF), and serum were quantified using inductively coupled plasma mass spectrometry (ICP-MS), immunohistochemical staining, and iron assays. Transcriptomic changes and immune responses were assessed using RNA sequencing and immune cell infiltration analysis. Results showed that intranasal FAC administration impaired olfactory function, accompanied by iron deposition in the olfactory mucosa and OB, as well as damage to olfactory sensory neurons. Notably, these effects occurred without elevations in CSF or serum iron levels. OB iron accumulation activated multiple immune cells, including microglia and astrocytes, but did not trigger ferroptosis. Spatial transcriptomic sequencing of healthy adult mouse OBs revealed significant cellular heterogeneity, with an abundance of neuroglia and neurons. Among neurons, GABAergic neurons were the most prevalent, followed by glutamatergic and dopaminergic neurons, while cholinergic and serotonergic neurons were sparsely distributed. Under iron-stressed conditions, oligodendrocytes, dopaminergic neurons, and glutamatergic neurons exhibited significant damage, while GABAergic neurons remained unaffected. These findings highlight the selective vulnerability of neuronal and glial populations to iron-induced stress, offering novel insights into the loss of specific cell types in the OB during iron dysregulation.
铁是大脑中最丰富的过渡金属，对大脑发育和神经元功能至关重要。然而，铁沉积与多种神经系统疾病相关。嗅球作为环境毒素的入口，在神经退行性疾病中早期受到影响。嗅球内包含具有不同特征和功能的多种神经元群体。在该研究中，我们通过建立经鼻给铁的小鼠模型，探讨了嗅球中特定细胞对铁的脆弱性。采用嗅觉辨别实验评估小鼠嗅觉功能；通过电感耦合等离子体-质谱法、Perl's-DAB/免疫组化双重染色及铁测定试剂盒评估了小鼠嗅球、脑脊液和血清中的铁水平。此外，还对小鼠嗅球进行了RNA测序和免疫浸润分析，以解析嗅球的转录谱和免疫反应。结果显示，经鼻给铁导致小鼠嗅觉功能障碍、嗅粘膜中的铁沉积、嗅感受神经元损伤和嗅球铁沉积，而脑脊液和血液中的铁水平并未增加。嗅球中的铁沉积激活了多种免疫细胞，包括小胶质细胞和星形胶质细胞，但未引发铁死亡。通过健康成年小鼠嗅球的空间转录组数据鉴定神经元和胶质细胞的表达。在小鼠嗅球中观察到了细胞异质性，其中富含神经胶质细胞与不同类型的神经元；在这些神经元中，GABA能神经元表达最丰富，其次是谷氨酸能神经元，再然后是多巴胺能神经元，而胆碱能和5-羟色胺能神经元几乎不表达。在给铁小鼠中观察到少突胶质细胞、多巴胺能及谷氨酸能神经元的损伤，而GABA 能神经元不受影响。这些结果为理解在铁沉积条件下特定神经元和少突胶质细胞的丧失提供了新的视角。.
Keywords: Ferroptosis; Immune response; Intranasal administration; Iron; Olfactory bulb.