Acta Oto-Laryngologica
ISSN: 0001-6489 (Print) 1651-2251 (Online) Journal homepage: http://www.tandfonline.com/loi/ioto20
A causal relationship between hearing loss and cognitive impairment So Young Park, Min Jung Kim, Huerxidan Sikandaner, Dong-Kee Kim, Sang Won Yeo & Shi Nae Park To cite this article: So Young Park, Min Jung Kim, Huerxidan Sikandaner, Dong-Kee Kim, Sang Won Yeo & Shi Nae Park (2016): A causal relationship between hearing loss and cognitive impairment, Acta Oto-Laryngologica, DOI: 10.3109/00016489.2015.1130857 To link to this article: http://dx.doi.org/10.3109/00016489.2015.1130857
Published online: 25 Jan 2016.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ioto20 Download by: [University of Florida]
Date: 31 January 2016, At: 18:38
ACTA OTO-LARYNGOLOGICA, 2016 http://dx.doi.org/10.3109/00016489.2015.1130857
RESEARCH ARTICLE
A causal relationship between hearing loss and cognitive impairment So Young Park, Min Jung Kim, Huerxidan Sikandaner, Dong-Kee Kim, Sang Won Yeo and Shi Nae Park
Downloaded by [University of Florida] at 18:38 31 January 2016
Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
ABSTRACT
ARTICLE HISTORY
Conclusion Moderate hearing loss in young mice caused decreases in cognition associated with spatial working and recognition memories in 6 months. These results provide evidence for a causal relationship between hearing loss and cognitive impairment. Objectives Hypothesized mechanisms to connect sensory and cognitive functions include the sensory-deprivation, informationdegradation, and common-cause hypotheses. This study intended to investigate the effect of hearing loss on cognitive function, as estimated by radial arm maze (RAM) and novel object recognition (NOR) tasks in mice through age- and hearing-matched longitudinal work during a 6-month period. Methods Twenty-four male C57BL/6 mice aged 1 month with normal ABR thresholds were used. Twelve mice in the hearing loss (HL) group were exposed to white noise at 110 dB SPL for 60 min every day for 20 days. At post-noise 6 months, all mice underwent RAM and one-trial NOR test. RAM performance measures and NOR discrimination index were compared between two groups. Results At 6 months after noise exposure, all mice in the experimental group had moderate hearing loss. Most of the RAM performances improved gradually within each group across five trials, probably due to learning effect. The HL group showed lower performance scores than the control group in several trial points in the RAM task. The contact time with the novel object was shorter in the HL group than in the control group.
Received 6 October 2015 Revised 25 November 2015 Accepted 30 November 2015 Published online 20 January 2016
Introduction The process of aging is regulated by factors that emerge during later life. The sensory factors such as hearing and vision may be the important determinants between normal and pathological cognitive aging [1]. The relationship between auditory and cognitive functioning in the elderly has been the subject of many studies, yielding conflicting results. Many cross-sectional or longitudinal cohort studies documented that hearing loss is associated with cognitive decline or dementia [2–5]. Hypothesized mechanisms to link between sensory and cognitive functions include the sensory-deprivation [1], information-degradation [6], and common-cause hypotheses [1]. It is challenging to estimate genuine cognitive function in laboratory animals. Therefore, cognitive behavioral tests have focused on working memory that is involved in all forms of cognition. Radial arm maze (RAM) of the most common classical memory tasks is appropriate to animals living in dry habitats. Working memory (WM) for an object within a testing session is distinguishable from reference memory (RM) for the rules of a given task that would typically be acquired with repeated sessions and persist from days to months [7]. A partially baited RAM permits simultaneous measurement of WM and RM errors [8]. In current memory research using rats and mice, another powerful tool that assesses a wide range of cognitive and neuropsychological functions is the one-trial novel object recognition (NOR) task. Rats and mice are innately attracted by novel objects, which indicates the
KEYWORDS
Cognition; dementia; hearing loss; novel object recognition; radial arm maze; reference memory; working memory
representation of a familiar object in memory. This test involves memory of a familiar object in parallel with the detection of a novel object [9]. It is more closely related to conditions under which human recognition memory is measured [10]. The objective of the present study was to investigate the effect of hearing loss on cognitive function, as estimated by RAM and NOR tasks in mice through age- and hearing-matched longitudinal work during a 6-month period.
Materials and methods Animals, ABR, and noise exposure Twenty-four male C57BL/6 mice aged 1 month were obtained from Orient Bio (Sungnam, Korea). They were kept in the colony (4 mice/cage, 23 C, 50% relative humidity, 12-h lightdark cycle) and fed with regular rodent chow and distilled water ad libitum. All animal procedures followed the national ethical guidelines and relevant laws. The experimental protocol was approved by the Animal Care and Use Committee of the Catholic University of Korea College of Medicine. Mice were anesthetized with intraperitoneal injection of a mixture of zolazepam-tiletamine (5 mg/kg) and xylazine (5 mg/kg). For hearing screening, auditory brainstem responses (ABRs) to click (0.1 ms, 19.3/s) and tone bursts (8/16/32 kHz, 1.5 ms, 21.1/s) were recorded in a sound-attenuated chamber using SmartEP fitted with high-frequency transducers 9911-20-0035 and high-frequency software version 2.33 (Intelligent Hearing
CONTACT Shi Nae Park, MD, PhD [email protected] Department of Otorhinolaryngology-Head and Neck Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Korea ß 2016 Taylor & Francis
2
S. Y. PARK ET AL.
Downloaded by [University of Florida] at 18:38 31 January 2016
systems, Miami, FL). Test stimuli were delivered to the ear canal through a miniature insert earphone from 90 to 10 dB SPL in 5 dB steps. Electrical potentials in the first 12 ms after the stimuli were sampled via subdermal stainless steel needle electrodes at the vertex (active) and pinna (reference) with 0.1– 3 kHz bandpass filtering, and averaged for 256 sweeps. Thresholds were defined as the lowest stimulus intensity where the typical wave V was still identified. Mice were divided into two groups: the control and hearing loss (HL) groups (n ¼ 12, each group). The control mice remained naive and the mice in the HL group were exposed to continuous white noise at 110 dB SPL for 60 min every day during a 20-day period by the same method as described in our previous article [11]. Immediately after noise and at post-noise 6 months, ABR thresholds were re-checked in all mice before the behavioral tests. RAM and NOR tasks At post-noise 6 months, all mice underwent spatial learning and memory assessment in an unconfined, partially-bated, 8arm radial maze, which is composed of 25 cm central platform and transparent plexiglas arms of 25/5/5 cm length/height/ width. At the end of each arm food cups were deposited. The maze was always oriented in space in the same way with a fixed food reward scheme. Several extra-maze cues were provided. Before the RAM task, mice were deprived of food until their body weight was reduced to 65% of the original weight. Radial maze learning was performed in the order of 2 day acclimatization (all arms unbaited, 5 min), 3 day habituation (all arms baited, 10 min), and 5 day trials (4 arms baited, 10 min, one trial per day). Trials were terminated when the mice had eaten all foods or 10 min had passed. The indicators of the radial maze performances were (1) total trial time (TT) to accomplish the task, (2) the number of WM error (WME): re-entry into an arm, either baited or unbaited, (3) the number of RM error (RME): the first entry into unbaited arm or entry into baited arm without food intake, and (4) the correct entry ratio (CER): correct entries with food intake divided by total entries. Object recognition was performed using ‘two sample objects in one environment’ according to the protocol as described in the earlier literature [12]. Briefly, mice were exposed to two identical sample objects in the apparatus for 10 min. During the intermission, one sample object was replaced by a novel object. After a 1-h interval, mice were re-exposed to one familiar and one novel object for 5 min. Directed contact was defined as any contact with the object using mouth, nose, or paw. The performance measure was the discrimination index, that is, novel object (NO) contact time (T) minus familiar object (FO) contact time (T) divided by total contact time with both objects [100 (TNO TFO)/(TNO + TFO)]. Total contact time indicated the baseline motor activity. All test sessions were recorded using high resolution video equipment for data scoring.
0.05. For RAM analysis, repeated measures ANOVA was performed at five levels to determine any interaction between group and trial: the within-subjects factor was trial; the between-subjects factor was group; and the dependent variables were TT, WME, RME, and CER, respectively. In addition, the dependent variables were compared between the control and HL groups at each trial point using t-test after Shapiro–Wilk’s test for normal distribution. Otherwise, the Mann–Whitney test was applied. ABR thresholds and the discrimination indices of NOR task were compared between the groups in the same way.
Results Before the experiment, all mice had ABR thresholds less than 20 dB SPL at test stimuli on both ears. At post-noise 6 months, ABR thresholds at click, 8 kHz, 16 kHz, and 32 kHz tones were 21.8 1.01 (mean SEM), 16.8 0.76, 18.6 1.19, and 18.2 1.22 dB SPL in the control group, and 47.5 1.69, 47.1 1.79, 48.8 1.25, and 49.2 2.03 dB SPL in the HL group (p50.001) (Figure 1). In the RAM task, WME and RME decreased gradually (p ¼ 0.029 and 0.004), and CER increased gradually (p ¼ 0.004) through five trials within each group. TT also appeared to decrease, but there was no statistical significance (p ¼ 0.122). Significant interaction was not found between group and trial. The hearing loss group exhibited significantly lower performance scores than the control group at several trial points: TT in trials 1 (p ¼ 0.048) and 5 (p ¼ 0.028); WME in trials 1 (p ¼ 0.018) and 5 (p ¼ 0.035); CER in trial 5 (p ¼ 0.032) (Figure 2). NOR discrimination index of the hearing loss group (1.5 6%, mean SEM) was significantly lower than that of the control group (19.8 4.5%) (p ¼ 0.024). Total contact times, representing the baseline motor activity, were not different between the control (58.4 7.5 s) and HL groups (51.1 5.4 s) (Figure 3).
Discussion In this study, we compared RAM/NOR-based cognitive functions between normal and hearing-impaired young mice to investigate the relationship between hearing and cognition.
Data analyses Statistical analysis was done using IBM SPSS 18.0 software (IBM Corp., Armonk, NY) at a two-tailed significance level of
Figure 1. ABR thresholds at click, 8 kHz, 16 kHz, and 32 kHz tone bursts. *p50.001 vs control group. Error bars indicate SEM.
Downloaded by [University of Florida] at 18:38 31 January 2016
ACTA OTO-LARYNGOLOGICA
3
Figure 2. The effect of hearing impairment on radial maze learning. (A) Total trial time (TT), (B) the number of working memory error (WME), (C) the number of reference memory error (RME), and (D) the correct entry ratio (CER). *p50.05 vs the control. Error bars indicate SEM.
Figure 3. The effect of hearing impairment on novel object recognition performance. (A) Total contact time and (B) discrimination index. Error bars indicate SEM.
Many studies have documented evidence for the relationship, but the causality is not clear. Is hearing loss a causal factor for cognitive impairment or only comorbidity associated with aging? The sensory-deprivation and information-degradation hypotheses consider cognitive decline as the byproduct of devoting cognitive resources to effortful sensory perception. Increased perceptual load and consequential decrease in cognitive reserves lead to cognitive decline [1,13]. Cognitive changes by information degradation are potentially reversible, whereas those by sensory deprivation may be permanent.
Another potential mechanism of the sensory-deprivation hypothesis is deafferentation and atrophy in the auditory area, which could also affect cognitive functions [13]. The common-cause hypothesis, in contrast, proposes a third factor; namely, a shared pathology in the aging brain such as loss of the integrity of brain physiology or widespread neural degeneration [1]. To disentangle those hypotheses and rule out the common-cause hypothesis, age-matched longitudinal work would be needed. This is the first study in which the ageand hearing-matched longitudinal research has been
Downloaded by [University of Florida] at 18:38 31 January 2016
4
S. Y. PARK ET AL.
conducted on cognitive function. The auditory system can be permanently impaired by noise in this mouse model [11]. Additional advantages in using young inbred mice are a short life span and few demographic confounding factors. At 6 months after noise exposure, all mice in the HL group showed moderate hearing loss in the range of 40–55 dB SPL at the test stimuli. In the RAM task, WM, RM, and CER showed gradual improvement within each group across five trials, probably due to the learning effect. Overall trends of task learning were more or less similar between the normal and HL groups, without significant interaction between group and trial. However, mice in the HL group performed poorly compared with the control mice in the first and last trials of TT and WME, and in the last trial of CER. The NOR task revealed a remarkable difference between the groups. With the similar motor activity between the groups as assessed by total contact time, the HL group demonstrated a much lower discrimination index than the control group, which indicates a shorter contact time with the novel object; that is, decreased recognition memory. The novelty-preference paradigm has become a powerful tool in current memory research using rats or mice, since it is very versatile and has some advantages over maze learning tasks. The NOR task does not require food deprivation, spatial learning, reinforcing stimuli, or multiple learning trials [10]. We have yielded noticeable results through two different behavioral tests for different types of working memory: the RAM task for spatial memory and the NOR task for recognition memory, although little is known about how mice discriminate familiarity and novelty [9]. Our data have shown that hearing loss can be an independent causal factor of developing cognitive impairment, irrespective of age. Cognitive impairment generally refers to a wide clinical spectrum from mild cognitive decline to full dementia [5]. In old subjects, both hearing impairment and brain aging may contribute to overall cognitive status. We suggest that the combination of hearing loss and pathological brain aging, and, furthermore, the weight of each morbidity may determine the degree of cognitive impairment in an individual. In conclusion, moderate hearing loss in young mice caused decreases in cognition associated with spatial working and recognition memories in 6 months. These results provide evidence for a causal relationship between hearing loss and cognitive impairment, and will help to support the sensorydeprivation hypothesis. Further studies on long-term changes of cognition related with hearing loss are needed, along with morphological assessment of the brain and cochlea.
Acknowledgments This work was supported in part by grants from the Basic Science Research Program of the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (NRF-20100004744 & NRF-2013R1A1A2011870).
Declaration of interest The authors report no conFicts of interest. The authors alone are responsible for the content and writing of the paper.
References 1. Lindenberger U, Baltes PB. Sensory functioning and intelligence in old age: a strong connection. Psychol Aging 1994;9: 339–55. 2. Lin FR. Hearing loss and cognition among older adults in the United States. J Gerontol A Biol Sci Med Sci 2011;66:1131–6. 3. Lin FR, Yaffe K, Xia J, Xue QL, Harris TB, Purchase-Helzner E, et al. Hearing loss and cognitive decline in older adults. JAMA Intern Med 2013;173:293–9. 4. Sugawara N, Sasaki A, Yasui-Furukori N, Kakehata S, Umeda T, Namba A, et al. Hearing impairment and cognitive function among a community-dwelling population in Japan. Ann Gen Psychiatry 2011;10:27. 5. Gurgel RK, Ward PD, Schwartz S, Norton MC, Foster NL, Tschanz JT. Relationship of hearing loss and dementia: a prospective, population-based study. Otol Neurotol 2014;35:775–81. 6. Pichora-Fuller MK. Cognitive aging and auditory information processing. Int J Audiol 2003;42(Suppl 2):2S26–32. 7. Dudchenko PA. An overview of the tasks used to test working memory in rodents. Neurosci Biobehav Rev 2004;28:699– 709. 8. Crusio WE, Schwegler H. Learning spatial orientation tasks in the radial-maze and structural variation in the hippocampus in inbred mice. Behav Brain Funct 2005;1:3. 9. Ennaceur A. One-trial object recognition in rats and mice: methodological and theoretical issues. Behav Brain Res 2010;215:244–54. 10. Dere E, Huston JP, De Souza Silva MA. The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents. Neurosci Biobehav Rev 2007;31:673–704. 11. Park SN, Back SA, Park KH, Seo JH, Noh HI, Akil O, et al. Comparison of functional and morphologic characteristics of mice models of noise-induced hearing loss. Auris Nasus Larynx 2013;40:11–17. 12. Bevins RA, Besheer J. Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study ‘recognition memory’. Nat Protoc 2006;1:1306–11. 13. Wayne RV, Johnsrude IS. A review of causal mechanisms underlying the link between age-related hearing loss and cognitive decline. Ageing Res Rev 2015;23:154–66.
ISSN: 0001-6489 (Print) 1651-2251 (Online) Journal homepage: http://www.tandfonline.com/loi/ioto20
A causal relationship between hearing loss and cognitive impairment So Young Park, Min Jung Kim, Huerxidan Sikandaner, Dong-Kee Kim, Sang Won Yeo & Shi Nae Park To cite this article: So Young Park, Min Jung Kim, Huerxidan Sikandaner, Dong-Kee Kim, Sang Won Yeo & Shi Nae Park (2016): A causal relationship between hearing loss and cognitive impairment, Acta Oto-Laryngologica, DOI: 10.3109/00016489.2015.1130857 To link to this article: http://dx.doi.org/10.3109/00016489.2015.1130857
Published online: 25 Jan 2016.
Submit your article to this journal
Article views: 33
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ioto20 Download by: [University of Florida]
Date: 31 January 2016, At: 18:38
ACTA OTO-LARYNGOLOGICA, 2016 http://dx.doi.org/10.3109/00016489.2015.1130857
RESEARCH ARTICLE
A causal relationship between hearing loss and cognitive impairment So Young Park, Min Jung Kim, Huerxidan Sikandaner, Dong-Kee Kim, Sang Won Yeo and Shi Nae Park
Downloaded by [University of Florida] at 18:38 31 January 2016
Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
ABSTRACT
ARTICLE HISTORY
Conclusion Moderate hearing loss in young mice caused decreases in cognition associated with spatial working and recognition memories in 6 months. These results provide evidence for a causal relationship between hearing loss and cognitive impairment. Objectives Hypothesized mechanisms to connect sensory and cognitive functions include the sensory-deprivation, informationdegradation, and common-cause hypotheses. This study intended to investigate the effect of hearing loss on cognitive function, as estimated by radial arm maze (RAM) and novel object recognition (NOR) tasks in mice through age- and hearing-matched longitudinal work during a 6-month period. Methods Twenty-four male C57BL/6 mice aged 1 month with normal ABR thresholds were used. Twelve mice in the hearing loss (HL) group were exposed to white noise at 110 dB SPL for 60 min every day for 20 days. At post-noise 6 months, all mice underwent RAM and one-trial NOR test. RAM performance measures and NOR discrimination index were compared between two groups. Results At 6 months after noise exposure, all mice in the experimental group had moderate hearing loss. Most of the RAM performances improved gradually within each group across five trials, probably due to learning effect. The HL group showed lower performance scores than the control group in several trial points in the RAM task. The contact time with the novel object was shorter in the HL group than in the control group.
Received 6 October 2015 Revised 25 November 2015 Accepted 30 November 2015 Published online 20 January 2016
Introduction The process of aging is regulated by factors that emerge during later life. The sensory factors such as hearing and vision may be the important determinants between normal and pathological cognitive aging [1]. The relationship between auditory and cognitive functioning in the elderly has been the subject of many studies, yielding conflicting results. Many cross-sectional or longitudinal cohort studies documented that hearing loss is associated with cognitive decline or dementia [2–5]. Hypothesized mechanisms to link between sensory and cognitive functions include the sensory-deprivation [1], information-degradation [6], and common-cause hypotheses [1]. It is challenging to estimate genuine cognitive function in laboratory animals. Therefore, cognitive behavioral tests have focused on working memory that is involved in all forms of cognition. Radial arm maze (RAM) of the most common classical memory tasks is appropriate to animals living in dry habitats. Working memory (WM) for an object within a testing session is distinguishable from reference memory (RM) for the rules of a given task that would typically be acquired with repeated sessions and persist from days to months [7]. A partially baited RAM permits simultaneous measurement of WM and RM errors [8]. In current memory research using rats and mice, another powerful tool that assesses a wide range of cognitive and neuropsychological functions is the one-trial novel object recognition (NOR) task. Rats and mice are innately attracted by novel objects, which indicates the
KEYWORDS
Cognition; dementia; hearing loss; novel object recognition; radial arm maze; reference memory; working memory
representation of a familiar object in memory. This test involves memory of a familiar object in parallel with the detection of a novel object [9]. It is more closely related to conditions under which human recognition memory is measured [10]. The objective of the present study was to investigate the effect of hearing loss on cognitive function, as estimated by RAM and NOR tasks in mice through age- and hearing-matched longitudinal work during a 6-month period.
Materials and methods Animals, ABR, and noise exposure Twenty-four male C57BL/6 mice aged 1 month were obtained from Orient Bio (Sungnam, Korea). They were kept in the colony (4 mice/cage, 23 C, 50% relative humidity, 12-h lightdark cycle) and fed with regular rodent chow and distilled water ad libitum. All animal procedures followed the national ethical guidelines and relevant laws. The experimental protocol was approved by the Animal Care and Use Committee of the Catholic University of Korea College of Medicine. Mice were anesthetized with intraperitoneal injection of a mixture of zolazepam-tiletamine (5 mg/kg) and xylazine (5 mg/kg). For hearing screening, auditory brainstem responses (ABRs) to click (0.1 ms, 19.3/s) and tone bursts (8/16/32 kHz, 1.5 ms, 21.1/s) were recorded in a sound-attenuated chamber using SmartEP fitted with high-frequency transducers 9911-20-0035 and high-frequency software version 2.33 (Intelligent Hearing
CONTACT Shi Nae Park, MD, PhD [email protected] Department of Otorhinolaryngology-Head and Neck Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Korea ß 2016 Taylor & Francis
2
S. Y. PARK ET AL.
Downloaded by [University of Florida] at 18:38 31 January 2016
systems, Miami, FL). Test stimuli were delivered to the ear canal through a miniature insert earphone from 90 to 10 dB SPL in 5 dB steps. Electrical potentials in the first 12 ms after the stimuli were sampled via subdermal stainless steel needle electrodes at the vertex (active) and pinna (reference) with 0.1– 3 kHz bandpass filtering, and averaged for 256 sweeps. Thresholds were defined as the lowest stimulus intensity where the typical wave V was still identified. Mice were divided into two groups: the control and hearing loss (HL) groups (n ¼ 12, each group). The control mice remained naive and the mice in the HL group were exposed to continuous white noise at 110 dB SPL for 60 min every day during a 20-day period by the same method as described in our previous article [11]. Immediately after noise and at post-noise 6 months, ABR thresholds were re-checked in all mice before the behavioral tests. RAM and NOR tasks At post-noise 6 months, all mice underwent spatial learning and memory assessment in an unconfined, partially-bated, 8arm radial maze, which is composed of 25 cm central platform and transparent plexiglas arms of 25/5/5 cm length/height/ width. At the end of each arm food cups were deposited. The maze was always oriented in space in the same way with a fixed food reward scheme. Several extra-maze cues were provided. Before the RAM task, mice were deprived of food until their body weight was reduced to 65% of the original weight. Radial maze learning was performed in the order of 2 day acclimatization (all arms unbaited, 5 min), 3 day habituation (all arms baited, 10 min), and 5 day trials (4 arms baited, 10 min, one trial per day). Trials were terminated when the mice had eaten all foods or 10 min had passed. The indicators of the radial maze performances were (1) total trial time (TT) to accomplish the task, (2) the number of WM error (WME): re-entry into an arm, either baited or unbaited, (3) the number of RM error (RME): the first entry into unbaited arm or entry into baited arm without food intake, and (4) the correct entry ratio (CER): correct entries with food intake divided by total entries. Object recognition was performed using ‘two sample objects in one environment’ according to the protocol as described in the earlier literature [12]. Briefly, mice were exposed to two identical sample objects in the apparatus for 10 min. During the intermission, one sample object was replaced by a novel object. After a 1-h interval, mice were re-exposed to one familiar and one novel object for 5 min. Directed contact was defined as any contact with the object using mouth, nose, or paw. The performance measure was the discrimination index, that is, novel object (NO) contact time (T) minus familiar object (FO) contact time (T) divided by total contact time with both objects [100 (TNO TFO)/(TNO + TFO)]. Total contact time indicated the baseline motor activity. All test sessions were recorded using high resolution video equipment for data scoring.
0.05. For RAM analysis, repeated measures ANOVA was performed at five levels to determine any interaction between group and trial: the within-subjects factor was trial; the between-subjects factor was group; and the dependent variables were TT, WME, RME, and CER, respectively. In addition, the dependent variables were compared between the control and HL groups at each trial point using t-test after Shapiro–Wilk’s test for normal distribution. Otherwise, the Mann–Whitney test was applied. ABR thresholds and the discrimination indices of NOR task were compared between the groups in the same way.
Results Before the experiment, all mice had ABR thresholds less than 20 dB SPL at test stimuli on both ears. At post-noise 6 months, ABR thresholds at click, 8 kHz, 16 kHz, and 32 kHz tones were 21.8 1.01 (mean SEM), 16.8 0.76, 18.6 1.19, and 18.2 1.22 dB SPL in the control group, and 47.5 1.69, 47.1 1.79, 48.8 1.25, and 49.2 2.03 dB SPL in the HL group (p50.001) (Figure 1). In the RAM task, WME and RME decreased gradually (p ¼ 0.029 and 0.004), and CER increased gradually (p ¼ 0.004) through five trials within each group. TT also appeared to decrease, but there was no statistical significance (p ¼ 0.122). Significant interaction was not found between group and trial. The hearing loss group exhibited significantly lower performance scores than the control group at several trial points: TT in trials 1 (p ¼ 0.048) and 5 (p ¼ 0.028); WME in trials 1 (p ¼ 0.018) and 5 (p ¼ 0.035); CER in trial 5 (p ¼ 0.032) (Figure 2). NOR discrimination index of the hearing loss group (1.5 6%, mean SEM) was significantly lower than that of the control group (19.8 4.5%) (p ¼ 0.024). Total contact times, representing the baseline motor activity, were not different between the control (58.4 7.5 s) and HL groups (51.1 5.4 s) (Figure 3).
Discussion In this study, we compared RAM/NOR-based cognitive functions between normal and hearing-impaired young mice to investigate the relationship between hearing and cognition.
Data analyses Statistical analysis was done using IBM SPSS 18.0 software (IBM Corp., Armonk, NY) at a two-tailed significance level of
Figure 1. ABR thresholds at click, 8 kHz, 16 kHz, and 32 kHz tone bursts. *p50.001 vs control group. Error bars indicate SEM.
Downloaded by [University of Florida] at 18:38 31 January 2016
ACTA OTO-LARYNGOLOGICA
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Figure 2. The effect of hearing impairment on radial maze learning. (A) Total trial time (TT), (B) the number of working memory error (WME), (C) the number of reference memory error (RME), and (D) the correct entry ratio (CER). *p50.05 vs the control. Error bars indicate SEM.
Figure 3. The effect of hearing impairment on novel object recognition performance. (A) Total contact time and (B) discrimination index. Error bars indicate SEM.
Many studies have documented evidence for the relationship, but the causality is not clear. Is hearing loss a causal factor for cognitive impairment or only comorbidity associated with aging? The sensory-deprivation and information-degradation hypotheses consider cognitive decline as the byproduct of devoting cognitive resources to effortful sensory perception. Increased perceptual load and consequential decrease in cognitive reserves lead to cognitive decline [1,13]. Cognitive changes by information degradation are potentially reversible, whereas those by sensory deprivation may be permanent.
Another potential mechanism of the sensory-deprivation hypothesis is deafferentation and atrophy in the auditory area, which could also affect cognitive functions [13]. The common-cause hypothesis, in contrast, proposes a third factor; namely, a shared pathology in the aging brain such as loss of the integrity of brain physiology or widespread neural degeneration [1]. To disentangle those hypotheses and rule out the common-cause hypothesis, age-matched longitudinal work would be needed. This is the first study in which the ageand hearing-matched longitudinal research has been
Downloaded by [University of Florida] at 18:38 31 January 2016
4
S. Y. PARK ET AL.
conducted on cognitive function. The auditory system can be permanently impaired by noise in this mouse model [11]. Additional advantages in using young inbred mice are a short life span and few demographic confounding factors. At 6 months after noise exposure, all mice in the HL group showed moderate hearing loss in the range of 40–55 dB SPL at the test stimuli. In the RAM task, WM, RM, and CER showed gradual improvement within each group across five trials, probably due to the learning effect. Overall trends of task learning were more or less similar between the normal and HL groups, without significant interaction between group and trial. However, mice in the HL group performed poorly compared with the control mice in the first and last trials of TT and WME, and in the last trial of CER. The NOR task revealed a remarkable difference between the groups. With the similar motor activity between the groups as assessed by total contact time, the HL group demonstrated a much lower discrimination index than the control group, which indicates a shorter contact time with the novel object; that is, decreased recognition memory. The novelty-preference paradigm has become a powerful tool in current memory research using rats or mice, since it is very versatile and has some advantages over maze learning tasks. The NOR task does not require food deprivation, spatial learning, reinforcing stimuli, or multiple learning trials [10]. We have yielded noticeable results through two different behavioral tests for different types of working memory: the RAM task for spatial memory and the NOR task for recognition memory, although little is known about how mice discriminate familiarity and novelty [9]. Our data have shown that hearing loss can be an independent causal factor of developing cognitive impairment, irrespective of age. Cognitive impairment generally refers to a wide clinical spectrum from mild cognitive decline to full dementia [5]. In old subjects, both hearing impairment and brain aging may contribute to overall cognitive status. We suggest that the combination of hearing loss and pathological brain aging, and, furthermore, the weight of each morbidity may determine the degree of cognitive impairment in an individual. In conclusion, moderate hearing loss in young mice caused decreases in cognition associated with spatial working and recognition memories in 6 months. These results provide evidence for a causal relationship between hearing loss and cognitive impairment, and will help to support the sensorydeprivation hypothesis. Further studies on long-term changes of cognition related with hearing loss are needed, along with morphological assessment of the brain and cochlea.
Acknowledgments This work was supported in part by grants from the Basic Science Research Program of the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (NRF-20100004744 & NRF-2013R1A1A2011870).
Declaration of interest The authors report no conFicts of interest. The authors alone are responsible for the content and writing of the paper.
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