Review article
Acoustic startle modification as a tool for evaluating auditory function of the mouse: Progress, pitfalls, and potential

https://doi.org/10.1016/j.neubiorev.2017.03.009Get rights and content

Highlights

  • Acoustic startle modification and traditional psychoacoustic techniques for behavioral auditory phenotyping are compared.

  • Non-auditory variables and influence of non-auditory inputs to the startle circuit must be taken into account.

  • Acoustic startle modification procedures show low sensitivity compared to operant conditioning techniques.

  • Acoustic startle modification is useful when testing mice with early-onset hearing loss or with learning impairments.

Abstract

Acoustic startle response (ASR) modification procedures, especially prepulse inhibition (PPI), are increasingly used as behavioral measures of auditory processing and sensorimotor gating in rodents due to their perceived ease of implementation and short testing times. In practice, ASR and PPI procedures are extremely variable across animals, experimental setups, and studies, and the interpretation of results is subject to numerous caveats and confounding influences. We review considerations for modification of the ASR using acoustic stimuli, and we compare the sensitivity of PPI procedures to more traditional operant psychoacoustic techniques. We also discuss non-auditory variables that must be considered. We conclude that ASR and PPI measures cannot substitute for traditional operant techniques due to their low sensitivity. Additionally, a substantial amount of pilot testing must be performed to properly optimize an ASR modification experiment, negating any time benefit over operant conditioning. Nevertheless, there are some circumstances where ASR measures may be the only option for assessing auditory behavior, such as when testing mouse strains with early-onset hearing loss or learning impairments.

Introduction

The acoustic startle response (ASR) consists of a rapid contraction of facial and skeletal muscles in mammalian and non-mammalian species in response to an abrupt, intense acoustic stimulus. The magnitude of the ASR can be modulated by a number of background and prestimulus conditions, as well as by fear conditioning, attentional modulation, and behavioral state (Koch, 1999, Li et al., 2009). Commonly used to screen for sensorimotor gating deficits and drug effects in models of neuropsychological disorders (Swerdlow et al., 2001, Swerdlow et al., 2016, Geyer et al., 2002) and to evaluate the effects of genes on sensorimotor behavior (Plappert and Pilz, 2001), ASR modification procedures have gained popularity as behavioral measures of hearing function in rodents due to their perceived ease of implementation. For instance, studies have identified temporal, spatial, and hearing in noise processing deficits in mutant strains (Lauer and May, 2011, Jalabi et al., 2013, Truong et al., 2014, Altschuler et al., 2015, Karcz et al., 2015, Tziridis et al., 2016, Ison et al., 2017), abnormal responsivity after chronic or acute noise exposure (Lauer and May, 2011, Hickox and Liberman, 2014, Salloum et al., 2014; Longenecker et al., 2016), abnormal reactivity to sounds in mouse models of early-onset hereditary hearing loss, fragile X syndrome, and Alzheimer’s disease (Chen and Toth, 2001, McGuire et al., 2015, O’Leary et al., 2017), auditory processing deficits in mild traumatic brain injury (Amanipour et al., 2016), and hormonal effects on auditory processing (Charitidi et al., 2012). Other studies have used ASR modification procedures as behavioral readouts during physiological manipulationand development of neurons in the auditory pathway (Weible et al., 2014a, Weible et al., 2014b, Aizenberg et al., 2015, Moyer et al., 2015).

The most common form of ASR modification is prepulse inhibition (PPI), where a brief sound pulse or a change in an ongoing sound that does not itself elicit an ASR is presented prior to a startle-eliciting stimulus (SES). Under some conditions, the prepulse can actually facilitate the ASR, an effect called prepulse facilitation (PPF) or augmentation. Presumably, any measurement of the ASR involves a combination of facilitating and inhibiting processes.

In this review, we discuss the various ways to modify the ASR, including the caveats and interactions of non-auditory factors that should be taken into account whether studying auditory processing or the general neurophysiological underpinnings of sensorimotor gating using acoustic stimuli. We also review comparisons between ASR modification behavioral measures and perceptual measures obtained using traditional operant conditioning techniques. It should be understood that ASR modification may not be a measure of auditory perception, per se. Perception infers the active reception of a signal by an organism and is shaped by attention, experience, motivation, and expectation. An animal is not required to attend to or make decisions about a stimulus in ASR modification tasks, and in fact ASR modification works even in sleeping infants (Hoffman et al., 1985). We do not review the growing literature that uses a gap-PPI paradigm to attempt to measure tinnitus in rodent models. The reader is referred to previous accounts (Hayes et al., 2014, Lobarinas et al., 2013, Galazyuk and Hébert, 2015, Brozoski and Bauer, 2015) for discussions of gap-PPI tinnitus screening.

Section snippets

Acoustic startle circuits

The primary ASR circuit and its known modulatory inputs are summarized in Fig. 1. It should be noted that there is some debate about the involvement of various nuclei in the primary ASR pathway, as well as which nuclei are important for producing long- or short-latency effects. Our intent is not to provide an exhaustive review, but rather to highlight the major findings. The reader is referred to Koch and Schnitzler (1997), Koch (1999), Fendt et al. (2001), and Li et al. (2009) for a thorough

Typical acoustic startle modification experiments

Basic ASR modification procedures have been reviewed in detail elsewhere (Hoffman and Ison, 1980, Ison and Hoffman, 1983, Ison, 2001, Carlson and Willott, 2001). The most commonly used form of ASR modification tests is the PPI using brief tones pulses or noise-bursts presented approximately 100 ms prior to an SES (Fig. 2A, B). This type of test is performed in quiet or in background noise. The SES is typically a brief, loud broadband noise with a rapid onset and offset, but tones have also been

Strain, sex, age, and developmental effects

Differences in ASR and ASR modification have been reported to vary with strain, age, development, and sex. Possible interactions of these factors must be considered when designing and interpreting ASR modification experiments. The effects of these factors on modification of the ASR also provide interesting opportunities for investigation.

Non-associative and associative learning effects

PPI studies require that responses need to be recorded in a relatively large number of trials (usually more than 100 trials, often a number of sessions with 100 trials each are combined in data collection). Such an extended testing requires taking into account the experience-dependent changes of the ASR and PPI over time, e.g., by presenting the different prepulses in random sequence in blocks including all conditions and repeating these blocks. The potential effects of learning should be

Other considerations

There are several other important factors to consider when designing and interpreting ASR and PPI experiments, such as whether the sound is presented to one or both ears, housing environment, and handling and husbandry effects. On one hand, manipulation of these factors may provide important information about auditory processing. On the other hand, lack of control or reporting of these factors may introduce unintended effects into a study.

Essentials for a well designed PPI experiment

For conducting an acoustic PPI experiment, a number of factors have to be taken into account (for an extended review of technical issues with a focus on tinnitus assessment, see Longenecker and Galazyuk, 2012). Many of these factors can be found in published protocols (e.g., Geyer and Swerdlow, 1998, Valsamis and Schmid, 2011), but most available protocols do not address all of the important parameters to consider when assessment of auditory function is the primary goal of the experiment. The

Comparison between acoustic startle modification and operant conditioning

It is often argued that PPI procedures provide for a time-efficient testing since no prior training is required. Young and Fechter (1983) used a prepulse inhibition paradigm to estimate the audiogram of young adult Long-Evans rats. Short prepulse tones at a range of intensities were presented 100 ms prior to a 115 dB startle-eliciting noise burst. This interstimulus interval was selected as the optimal interval for eliciting PPI based on previous studies and pilot experiments in the authors’

Why use PPI?

In light of the issues raised in the previous sections, the reader might wonder why PPI should be used at all as a measure of auditory behavior. It is perhaps incorrect to consider PPI a measure of perception, per se. The term perception implies a conscious behavioral response to a sound or changes in sound. Typical PPI experiments are thought to reflect mainly pre-attentive processes, and conventional PPI using a discrete prepulse burst and also noise offset PPI do not even require the

Acknowledgments

Funding: This work was supported by grants from the National Institute for Deafness and Other Communication DisordersDC012352, DC009353, and DC00521; the David M. Rubenstein Fund for Hearing Research; and the Deutsche Forschungsgemeinschaft EXC 1077 “Hearing4all.” We thank Michael Koch for his comments on a previous version of the manuscript.

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