Research report
Factors governing prepulse inhibition and prepulse facilitation of the acoustic startle response in mice

https://doi.org/10.1016/j.bbr.2003.10.025Get rights and content

Abstract

The influence of prepulses on the acoustic startle response (ASR) was measured in three inbred mouse strains, C57BL/6J, 129/SvHsd, and AKR/OlaHsd, and one hybrid strain produced by crossing wild mice and NMRI mice. Prepulse inhibition (PPI), i.e. reduction of ASR by prepulses, was maximal when the interval between prepulses and startle stimuli was in the range of 37.5–100 ms. Prepulse facilitation (PPF), i.e. increase of ASR by prepulses, was maximal when the prepulse preceded the startle stimulus by 12.5 ms. PPI increased with increasing prepulse SPL, PPF first increased then decreased when prepulse SPL was increased. Percent PPI was independent from startle stimulus SPL. All strains showed a long-term increase of PPI when tested for several days; one strain (129) also showed an increase of PPF over days. The present results clearly show that PPI and PPF are independent processes, which add to yield the final response change. PPF and the observed long-term changes of PPI and PPF are stronger expressed in mice than have been observed in rats under similar conditions. Since there were significant differences between the strains of mice with respect to PPI and PPF, genetically different strains of mice are a promising tool to study these two processes.

Introduction

Intense acoustic stimuli elicit the startle response, a coordinated contraction of muscles from the eyelids to the extremities. Small changes in the sensory environment prior to the startle stimulus, called prepulses, can modify the magnitude of the acoustic startle response (ASR). In rats, inhibition of the ASR by a prepulse, referred to as prepulse inhibition (PPI), is most reliably observed when an acoustic, non-startling prepulse precedes the startle stimulus by 10–500 ms [14], [15]. Because impaired PPI is found in humans in some neuropsychiatric disorders, including schizophrenia [32], there is great interest in the mechanisms mediating PPI.

In contrast to PPI, prepulse facilitation (PPF) is an increase in startle amplitude. PPF has been observed in rats [13], [19], [29] and mice [6], [36] when prepulses are given just before the startle stimulus (0–10 ms interpulse-interval (IPI)).

PPI has been primarily studied in rats to date [23], [32]. However, the mouse has increasingly gained importance during the last decade for studying the genetic basis of PPI. For example, inbred mouse strains differing in PPI ([1], [3], reviewed in [12], [28]) can be used to study genetically based differences. In particular, mouse strains with impaired PPI can potentially serve as an animal model for schizophrenia, with the advantage that no drugs are required to induce this impairment [26].

In most studies on PPI in mice, the stimulus parameters established for rats are used. However, if PPI evoked at an IPI of 100 ms (which produces about the strongest PPI in rats) is compared in different strains of mice, it is unclear whether observed effects are really due to differences in PPI strength, or to strain differences concerning the influence of the IPI on PPI strength. Accordingly, Varty et al. [35] pointed out that occurring differences in the pharmacological effect on PPI between rats and mice may be due to not testing mice under the optimal startle and PPI conditions. One first aim of the present study was therefore to extend the parametric investigation of Varty et al. [35] and to further optimize the paradigms for PPI and also additionally for PPF in the mouse on a sound basis of parametric studies.

There is a hint that PPI and PPF are independent processes: the effect of a prepulse on the startle response depends on the level of the prepulse in a different manner in PPI and PPF (e.g. [29]). In the present study, we wanted to further inspect this presumable independence of PPI and PPF. For this purpose we first varied characteristics of the prepulse and the startle stimulus to test whether these parameters differently influence PPI and PPF. Second, we studied the effect of experience on the two processes. There is an ongoing debate about whether repeated testing changes the amount of PPI over sessions [4], [10], [25], [29]. Concerning PPF, nothing is known about the effect of experience. Third, to examine whether PPI and PPF are genetically differently influenced, we tested genetically different strains of mice.

Section snippets

Experiment I: variation of startle stimulus SPL and prepulse SPL

In rats and mice, PPI increases when the sound pressure of the prepulse is increased ([5], e.g. [6], [16], [21], [27], [35]). In contrast, the level of the startle stimulus has no influence on the amount of PPI [30]. As the latter was only shown in rats and not in mice until now, we tested the influence of startle SPL on PPI in the first experiment with different prepulse levels. We tested three different inbred strains of mice (C57, 129, and AKR) and a hybrid strain obtained by the crossing

Experiment II: variation of interpulse-interval and prepulse SPL

The results of the previous experiment showed that the amount of PPI does not depend on startle stimulus intensity, but does vary as a function of prepulse intensity. A second parameter known to influence the amount of PPI is the IPI duration, as studies in rats [13], [14], [17], [31] and mice ([5], [6], [35] and our pretest in Experiment I) have shown. Therefore, in the following experiment, both prepulse parameters, prepulse intensity and IPI, were varied systematically. In our focus of

Experiment III: effect of repetitive presentation of prepulses over several test days

In the literature, PPI is usually considered to be a hard-wired phenomenon, not influenced by experience (reviewed in [9], [38]). Possible effects of experience on PPI were only shown by Reijmers and Peeters [29] where PPI in rats progressively increased over several days of testing. To inspect this phenomenon in more detail, we tested the magnitude of PPI strength over 5 consecutive test days. In addition, we again used different IPIs to evoke both processes, PPI and PPF. Naı̈ve mice of the

General discussion

The present study shows that PPI and PPF depend on: (1) the IPI between prepulse and startle stimulus, (2) prepulse intensity, (3) long-term experience, and (4) mouse strain. PPI did not depend on startle stimulus intensity, which confirms earlier observations in rats [30].

It is well known in rats that IPI duration determines the amount of PPI or PPF in rats. In rats, maximum PPI is elicited with prepulses about 50–100 ms before the startle stimulus. In the present study, maximum PPI was found

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