Elsevier

Hearing Research

Volume 395, 15 September 2020, 108022
Hearing Research

Research Paper
Blast-induced hearing loss suppresses hippocampal neurogenesis and disrupts long term spatial memory

https://doi.org/10.1016/j.heares.2020.108022Get rights and content

Highlights

  • Hearing loss and blast wave exposure are risk factors for cognitive impairment.

  • Hippocampal neurogenesis suppressed in blast-exposed rats with hearing loss.

  • Blast-exposed rats learned a spatial navigation task (memory acquisition) normally.

  • Blast-exposed rats exhibited spatial memory retention deficits (long term memory).

  • Long term memory deficits linked to decreased hippocampal neurogenesis.

Abstract

Acoustic information transduced by cochlear hair cells is continuously relayed from the auditory pathway to other sensory, motor, emotional and cognitive centers in the central nervous system. Human epidemiological studies have suggested that hearing loss is a risk factor for dementia and cognitive decline, but the mechanisms contributing to these memory and cognitive impairments are poorly understood. To explore these issues in a controlled experimental setting, we exposed adult rats to a series of intense blast wave exposures that significantly reduced the neural output of the cochlea. Several weeks later, we used the Morris Water Maze test, a hippocampal-dependent memory task, to assess the ability of Blast Wave and Control rats to learn a spatial navigation task (memory acquisition) and to remember what they had learned (spatial memory retention) several weeks earlier. The elevated plus maze and open field arena were used to test for anxiety-like behaviors. Afterwards, hippocampal cell proliferation and neurogenesis were evaluated using bromodeoxyuridine (BrdU), doublecortin (DCX), and Neuronal Nuclei (NeuN) immunolabeling. The Blast Wave and Control rats learned the spatial navigation task equally well and showed no differences on tests of anxiety. However, the Blast Wave rats performed significantly worse on the spatial memory retention task, i.e., remembering where they had been two weeks earlier. Deficits on the spatial memory retention task were associated with significant decreases in hippocampal cell proliferation and neurogenesis. Our blast wave results are consistent with other experimental manipulations that link spatial memory retention deficits (long term memory) with decreased cell proliferation and neurogenesis in the hippocampus. These results add to the growing body of knowledge linking blast-induced cochlear hearing loss with the cognitive deficits often seen in combat personnel and provide mechanistic insights into these extra auditory disorders that could lead to therapeutic interventions.

Introduction

Exposure to intense noise has long been known to damage the sensory hair cells and neurons in the cochlea resulting in permanent hearing loss (Hamernik et al., 1984; Lin et al., 2011b). Although the primary site of damage is in the cochlea, there is growing recognition that noise-induced hearing loss causes structural and functional changes in the central auditory pathway (Baizer et al., 2015; Calford et al., 1993; Feng et al., 2012; Michler and Illing, 2002; Morest and Bohne, 1983; Robertson et al., 2013). These noise-induced disturbances in the central auditory system are believed to contribute to debilitating disorders such as tinnitus and hyperacusis (Eggermont, 2015; Mohan et al., 2018; Xu et al., 2016). The auditory system, however, does not function in isolation, but is part of a much larger neural connectome in which information is exchanged with other sensory, motor, emotional and cognitive centers in the brain (Chen et al., 2015; Kraus and Canlon, 2012; Lesicko et al., 2016; McIntosh and Gonzalez-Lima, 1998; Pascual et al., 2015; Xu et al., 2016; Yang et al., 2018). When viewed in this broader context, it may come as no surprise to learn that hearing loss is a risk factor for dementia and cognitive decline (Lin et al., 2011a; Liu and Lee, 2019). The link between hearing loss and cognitive decline is reinforced by intervention studies showing that hearing remediation with a cochlear implant leads to a significant improvement in cognitive function (Mosnier et al., 2015).

The hippocampus, which plays a critical role in memory and cognitive processing (Munoz-Lopez et al., 2010; Sweatt, 2004), is one of two regions in the adult brain where neurogenesis occurs (Altman and Das, 1965; Shors et al., 2001). Recent evidence suggests that neurogenesis in the granule cell layer of dentate gyrus plays a pivotal role in pattern separation and spatial navigation (Clelland et al., 2009; Goodman et al., 2010; Winocur et al., 2006). New granule cells in the dentate gyrus are integrated into hippocampal-cortical networks involved in the retrieval of remote spatial memories (Goodman et al., 2010). Granule cell neurons are spatially tuned and possess stable place fields (Jung and McNaughton, 1993).

Information from neurons in the dentate gyrus is relayed to the CA1 area of the dorsal hippocampus (Fontana et al., 2006; Gehrmann et al., 1991; McNaughton et al., 1989). Spatially-tuned pyramidal place cells in the dorsal hippocampus (Fenton et al., 2000; Hufner et al., 2011; Ravassard et al., 2013; Tamura et al., 1992a, 1992b) receive inputs from grid cells in the entorhinal cortex (Moser et al., 2014). This hippocampal-entorhinal circuit has been implicated in memory-guided behaviors (Aronov et al., 2017). The spatial tuning of hippocampal place cells is not static, but can be altered by intense noise exposures that cause temporary hearing loss (Goble et al., 2009; Szczepaniak and Moller, 1996). These results suggest that the functional properties of hippocampal place cells might be permanently altered by hearing loss which could disrupt the formation or consolidation of long-term memory traces relevant to spatial recognition memory.

We previously reported that severe unilateral noise-induced hearing loss significantly reduced cell proliferation and neurogenesis in the hippocampus (Kraus et al., 2010). Subsequently, others reported that bilateral noise-induced hearing loss also suppresses cell proliferation and neurogenesis in the hippocampus (Liu et al., 2018; Shukla et al., 2019). Additionally, when their subjects were tested on the Morris Water Maze (MWM), rats and mice with noise-induced hearing loss had significantly more difficulty learning the spatial navigation task (memory acquisition) and as well as remembering the task (memory consolidation). These deficits were correlated with decreased cell proliferation and neurogenesis.

Combat personnel exposed to blast waves not only suffer from hearing loss (Helfer et al., 2011), but also memory deficits (Cooper et al., 2016; Gilbertson et al., 2001; McDermott et al., 2016). Among noise-exposed combat personnel, lower memory scores were correlated with a decline in hippocampal volume (Tischler et al., 2006). However, it is unclear if the memory deficits were due to noise-induced hearing loss or other comorbid factors. To overcome these limitations, we exposed rats to a series of 185 dB peak SPL blasts which we previously have shown causes a severe hair cell loss in the basal third and a moderate hair cell lesion (<30% loss) in the apex of the cochlea (<20 kHz) plus a 35% reduction in hippocampal neurogenesis (Newman et al., 2015). This intensity was used because it is similar to those experienced by military personnel operating howitzers, rocket launchers and some rifles (Garinther, 1979; Jokel et al., 2019), but below the intensity that causes the tympanic membrane to rupture in rats. Afterwards, we tested for memory deficits, anxiety and changes in hippocampal cell proliferation and neurogenesis. Among the rats with blast-induced hearing loss, there was a significant reduction of cell proliferation and neurogenesis and a significant deficit in spatial memory consolidation. However, the blast-induced hearing loss did not impair short-term spatial memory acquisition or induce anxiety.

Section snippets

Methods

The experimental time line for conducting different components of the study are schematized in Fig. 1. Bromodeoxyuridine (BrdU) was administered for 12 consecutive days prior to the blast wave exposure or sham exposure; the goal was to determine if the blast wave exposure would affect the long-term survival of new cells generated just prior to the exposure. Forty-five days after the blast wave exposure, the rats were trained for 6-days on the MWM task to assess their ability to learn a spatial

Hearing impairment

To confirm that the intense blast exposure caused a severe hearing loss similar to that observed in our earlier report (Newman et al., 2015), the CAP was evaluated in three rats in the Blast Wave group and compared to the CAP obtained from three rats in the Control group approximately 11-weeks post-exposure. The CAP input/output functions at 6, 8, 12, 16, 24 and 40 kHz are shown in Fig. 2A–F. The horizontal dashed line at 3 μV was operational defined as the CAP threshold. In Controls, the

Discussion

The 185 dB peak SPL blast wave exposure employed in this study caused a massive decrease in CAP amplitudes that reduced the neural input to the central auditory pathway. The pathophysiological changes in the rat cochlea were associated with a persistent reduction in hippocampal cell proliferation and neurogenesis. Despite the substantial decrease in cell proliferation and neurogenesis in the hippocampus, the Blast Wave rats were able to learn where the hidden platform was located in the MWM

Author statement

Research Data Related to this Submission

There are no linked research data sets for this submission. The following reason is given:

Data will be made available on request.

Acknowledgements

Research supported in part by grants from the United States of America National Institutes of Health (R01DC011808 and R01DC014452). We gratefully acknowledgement the technical assistance of Kimberly Dahar and Robert Dingman.

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