Research reportEffects of age-related hearing loss on startle reflex and prepulse inhibition in mice on pure and mixed C57BL and 129 genetic background
Introduction
The startle reflex is a transient motor response to an unexpected intense stimulus (e.g., auditory, tactile or visual). The startle reflex is observed in all mammals including humans, and is thought to be a primitive preservative behavior directed at protecting the individual from external threats [1], [2]. In spite of its relative simplicity, the startle reflex shows several forms of behavioral plasticity, including habituation, sensitization, prepulse inhibition and modification by prior associative learning (e.g., fear potentiated startle). These features of startle reflex made it an important research tool for studying not only sensory processes but also complex brain functions such as cognition, emotions and movement control. For instance, prepulse inhibition of acoustic startle reflex (PPI) refers to the inhibition of the startle reflex response (ASR) by presentation of a barely detectable stimulus (prepulse) immediately prior to the acoustic startling pulse. PPI phenomenon is considered as an operational measure of sensorimotor gating, which reflects a basic inhibitory process that regulates sensory input to the brain and allows the early stage of information processing to occur without disruption (for review, see [3]). Reduced sensorimotor gating is observed in patients with schizophrenia, obsessive compulsive disorder and Huntington's disease [4], while exaggerated acoustic startle is prominent symptom of post-traumatic stress disorder [5], [6], [7]. Hence, the possibility to measure ASR and PPI in animals provides an attractive way of investigating neural mechanisms of behavioral traits relevant to complex brain disorders.
Studies using inbred strains of mice have demonstrated that ASR and auditory PPI are polygenic traits and that genetic background is an important determinant for responses to drugs in PPI paradigms [8], [9], [10], [11], [12], [13], [14]. Genetic factors are also known to influence profoundly the ability of mammals to hear, in this respect the mouse represent a good model for human deafness [15], [16]. Previous studies have shown that more than 10 strains undergo genetically determined progressive hearing loss that begins between 2 and 3 months of age, and varies in severity with further aging depending of the mouse strains and the tone frequencies [17], [18], [19], [20]. Such deterioration of the hearing sensitivity can have profound consequences on the mouse performances in ASR paradigms. Indeed, numerous studies have shown that the age-related hearing loss (AHL) is accompanied in C57BL/6J (C57) mice by complex changes in ASR and auditory PPI elicited by pure tones [21], [22], [23], [24]. More specifically, PPI levels were found to be reduced for high frequency (e.g., >20 kHz) and increased for low and middle frequency prepulses (e.g., 4–12 kHz) in 5 months compared to 1-month-old mice [21], [23]. Beside their utility in hearing research, ASR paradigms are increasingly used in mice for evaluation of pharmacological and genetic manipulations [11]. However, most of the studies rely primarily on the use of white-noise bursts instead of pure tone. Hence, to date little is known about the impact of AHL phenotype on behavioral performances of mice in such paradigms.
In the present study, we sought to address several questions: firstly, whether a 129 substrain such as 129S2/SvPas (129) mice, which is frequently used as donor of the embryonic stem cell for targeted mutagenesis studies [25], develops hearing impairments with age? Secondly, do hybrid mice derived from 129 and C57 mice matting exhibit AHL phenotype as their progenitors? Because of the impoverished performance of 129 mice on number of behavioral tasks, the behavioral phenotype of genetic manipulations are most often examined on mixed 129 × C57 genetic background [25]. However, it is unknown whether mice on mixed 129S2/SvPasxC57BL/6J (129 × C57) background develop a progressive hearing impairment with age. Thirdly, whether changes in auditory sensitivity could affect ASR and PPI levels elicited by white-noise bursts? For that purpose, auditory brainstem responses (ABR), ASR and PPI were studied in C57, 129 mice and their hybrids. In order to determine the temporal development of AHL phenotype and its possible consequences on ASR and PPI, mice were analyzed at various time points: 6, 28, 41 and 94 weeks of age.
Section snippets
Animals
Male mice of the following strains, C57BL/6J (C57), 129S2/SvPassIco (129) and C57BL/6JX129/SvPasIco F1 hybrid (hybrid) mice were studied. Males and females C57 and 129 mice were initially purchased from Charles Rivers labs (France) and bred in house to generate C57, 129 and F1 hybrid mice. Animals were housed in groups of four or five in individually ventilated cages (M.I.C.E. cages, Charles Rivers) with water and food ad libitum. Mice were maintained on 12-h light:12-h dark cycle (light on at
Auditory thresholds from ABR recordings
Fig. 1A illustrates the ABR thresholds of 6 weeks old 129, C57 and hybrid mice. The hybrid mice had the lowest ABR threshold from 30 kHz and up, as between 3 and 5 kHz (p < 0.03, Fisher PLSD test). C57 mice displayed significantly a higher ABR threshold than 129 mice especially for the high frequencies ranging between 40 and 50 kHz (p < 0.02, Fisher PLSD test). It was not possible to compare 60 kHz because the maximum output of our stimulation set up without distortion was around 90 dB (SPL). When the
Discussion
The present study compared the developmental course of the AHL and its consequences on the expression of ASR and auditory PPI in 129, C57 and hybrid mice. Both parental strains showed a gradual impairment of hearing between 6 and 94 weeks, by contrast, the hybrids exhibited only minor changes. The ABR threshold modifications exhibited by the hybrid mice are relatively comparable to that of CBA/CaJ or CAST/Ei mice, which retain a good hearing throughout most of their life [26]. As compared to
Acknowledgements
This work was supported by the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Sante et de la Recherche Médicale (INSERM) and the Université de Louis Pasteur de Strasbourg (ULP). The authors want to thank Prof. Pierre Chambon for his support.
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