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  • br Acknowledgements br Introduction High


    Introduction High-intensity noise exposure has long been known to induce damage in the peripheral and central auditory system, often resulting in auditory pathologies such as hearing loss, tinnitus and hyperacusis (Syka, 2002; Roberts et al., 2010). Within the inner ear, structures including the cochlear hair cells, stria vascularis, and auditory nerve fiber terminals are all vulnerable to noise-induced damage (Henderson et al., 2006; Salvi et al., 2000a). Additionally, intense noise exposure impacts central auditory structures of the 5-Hydroxy-CTP sale leading to changes in spontaneous firing rates, neural synchrony, tonotopic map reorganization, neural degeneration, and axonal sprouting (Salvi et al., 2000b; Norena and Eggermont, 2003; Michler and Illing, 2002; Baizer et al., 2015; Roberts et al., 2010; Illing et al., 2005). Although the effects of intense noise exposure on the peripheral and central auditory pathway have been the focus of most research, its effects on non-classical auditory structures in the brain are less well understood. The ascending non-classical auditory pathway supplies information to a widely distributed network in the brain including structures of the limbic system such as the hippocampus (Moller, 2007; Moller and Rollins, 2002). The hippocampus is one of the few regions within the brain in which neurogenesis occurs during adulthood (Altman, 1962; Bayer et al., 1982; Eriksson et al., 1998; Gould et al., 1999), and mounting evidence suggests that the production and integration of new neurons into the circuitry of the adult hippocampus contributes to this structure's role in spatial navigation, learning and memory (for review see: Deng et al., 2010). Recently, a number of studies have identified the hippocampus as particularly vulnerable to intense noise exposure and hearing loss (Goble et al., 2009; Saljo et al., 2002; Kraus et al., 2010; Kovesdi et al., 2011; Kwon et al., 2011; Kamnaksh et al., 2012; Newman et al., 2015; Wang et al., 2018). For example, rats acutely exposed to a loud tone demonstrated dramatic alterations in hippocampal place cell activity (Goble et al., 2009). Furthermore, intense noise exposure and noise-induced hearing loss alters hippocampal gene expression, down-regulates cell proliferation and neurogenesis, induces cell death, and results in hippocampal-dependent cognitive deficits in animal models (Saljo et al., 2002; Kraus et al., 2010; Kovesdi et al., 2011; Kwon et al., 2011; Kamnaksh et al., 2012; Newman et al., 2015; Cheng et al., 2011; Cui et al., 2009; Sajja et al., 2012; Liu et al., 2016). Previously, we demonstrated that a single high-intensity unilateral noise exposure that resulted in permanent hearing loss suppressed cell proliferation and neurogenesis in the hippocampus out to 10 weeks post-exposure (Kraus et al., 2010); however, the mechanisms responsible for these changes are poorly understood. One possibility is that the long-term reduction in hippocampal neurogenesis following intense noise exposure and hearing loss is related to a persistent level of stress. Chronic stress and elevated stress hormone levels have long been known to suppress hippocampal neurogenesis (Cameron and Gould, 1994; Alahmed and Herbert, 2008; Brummelte and Galea, 2010). Thus, the noise-induced reduction in hippocampal neurogenesis could be due to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis that controls the release of stress-related hormones from the hypothalamus, pituitary, and adrenal glands. Importantly, the hippocampus contains one of the highest concentrations of stress hormone responsive receptors in the brain, the glucocorticoid (GR) and mineralocorticoid receptors (MR), which underlies the important role of the hippocampus in providing negative feedback regulation on HPA axis activity (Felt et al., 1984; Van Eekelen et al., 1988; Morimoto et al., 1996; Sapolsky et al., 1984). Given that intense noise can activate the HPA axis acutely (Samson et al., 2007, De Boer et al., 1989), it is conceivable that noise-induced hearing loss could also act as a chronic stressor (Garnefski and Kraaij, 2012; Kraus and Canlon, 2012; Gomaa et al., 2014) and alter basal and/or reactive corticosterone levels or the expression of GRs and MRs in the hippocampus. To test this hypothesis, we monitored basal and reactive blood plasma levels of the stress hormone corticosterone in rats for 10 weeks following intense noise exposure and assessed the expression of GR and MR in the hippocampus using immunohistochemical techniques.