Abstract
Adult hippocampal neurogenesis (AHN) is important for multiple cognitive functions. We sort to establish a minimal or non-invasive radiation approach to ablate AHN using guinea pigs as an animal model. 125I seeds with different radiation dosages (1.0, 0.8, 0.6, 0.3 mCi) were implanted unilaterally between the scalp and skull above the temporal lobe for 30 and 60 days, with the radiation effect on proliferating cells, immature neurons, and mature neurons in the hippocampal formation determined by assessment of immunolabeled (+) cells for Ki67, doublecortin (DCX), and neuron-specific nuclear antigen (NeuN), as well as Nissl stain cells. Spatially, the ablation effect of radiation occurred across the entire rostrocaudal and largely the dorsoventral dimensions of the hippocampus, evidenced by a loss of DCX+ cells in the subgranular zone (SGZ) of dentate gyrus (DG) in the ipsilateral relative to contralateral hemispheres in reference to the 125I seed implant. Quantitatively, Ki67+ and DCX+ cells at the SGZ in the dorsal hippocampus were reduced in all dosage groups at the two surviving time points, more significant in the ipsilateral than contralateral sides, relative to sham controls. NeuN+ neurons and Nissl-stained cells were reduced in the granule cell layer of DG and the stratum pyramidale of CA1 in the groups with 0.6-mCi radiation for 60 days and 1.0 mCi for 30 and 60 days. Minimal cranial trauma was observed in the groups with 0.3– 1.0-mCi radiation at 60 days. These results suggest that extracranial radiation with 125I seed implantation can be used to deplete HAN in a radioactivity-, duration-, and space-controllable manner, with a “non-invasive” stereotactic ablation achievable by using 125I seeds with relatively low radioactivity dosages.
Highlights
Consistent with literature, Ki67+ cells were found along the subgranular zone (SGZ) of the dentate gyrus (DG), with the immunolabeling appeared as small nuclear profiles and tended to arrange in pairs or small clusters (Supplementary Figures 1A–C)
DCX+ cells were localized to the SGZ morphologically characteristic of immature neurons (Supplementary Figures 1J–L)
As elaborated in the Introduction, 125I seeds are commonly used in brachytherapy of many solid tumors (Schwarz et al, 2012; Wang et al, 2016; Zhang et al, 2016; Hirose et al, 2017; Brun et al, 2018; Vigneault et al, 2018; Zhu et al, 2019; Jia et al, 2020; Li et al, 2020; Watson et al, 2020)
Summary
Adult hippocampal neurogenesis (AHN) is of eminent importance to support learning and memory, regulate emotional behavior, and has been considered as a therapeutic target for neurodegenerative diseases and neuropsychiatric disorders (Aimone et al, 2006; Saxe et al, 2006; Coras et al, 2010; Kang et al, 2016; Anacker and Hen, 2017; Radad et al, 2017; Alam et al, 2018; 125I Seed Radioablation of HANMicheli et al, 2018; Toda and Gage, 2018; Miller and Sahay, 2019; Toda et al, 2019; Berdugo-Vega et al, 2020; Surget and Belzung, 2021). While AHN exists widely in mammals including human (Altman, 1963; Altman and Das, 1965; McDonald and Wojtowicz, 2005; Amrein et al, 2011; Lieberwirth et al, 2016; Kuhn et al, 2018; Gage, 2019; Wan et al, 2019), its specific roles in various cognitive and behavioral functions remain to be refined. Three strategies have been used to ablate AHN, including X-ray radiation, genetic ablation, and mitotic inhibition (Shors et al, 2002; Mizumatsu et al, 2003; Saxe et al, 2006; Wojtowicz, 2006; Ben Abdallah et al, 2013; Yeung et al, 2014; Cho et al, 2015; Tang et al, 2017; Bulin et al, 2018; Youssef et al, 2018; Houben et al, 2019; Kostin et al, 2019; Peng et al, 2019; Rivera et al, 2019). Genetic and pharmacological ablation may be associated with confounding effects derived from cellular changes irrelevant to the blockage of neurogenesis (Saxe et al, 2006; Wojtowicz, 2006)
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