862
Effect in CBA Mice of varying Signal Intensity and Age on the Inhibition of the Acoustic Startle Reflex
produced by a Change in Sound Location along the Azimuth
James R. Ison & Paul D. Allen
A litter of “wee, sleekit, cowrin tim’rous
Departments of Brain & Cognitive Sciences and Neurobiology and Anatomy, University of Rochester, Rochester, NY
180
90o
45o
22.5o
Y-10 M-10 O-10
25 wk
C 1 2
-0.3
-0.4
-0.5
5 102040 100 300
ISI (ms)
Fig 1: PPI at 3 age groups,
for separations of 22.5 to
180o across ISI at 60 dB SPL
0.7
0.6
0.5
0.4
0.3
0.2
0.1
-0.0
-0.1
-0.2
-0.3
-0.4
-0.5
Y-50 M-50 O-50
Age Group - ISI
Fig 2: PPI at 45o, 10 ms
ISI above, 50 ms below.
0.4
0.2
-0.0
-0.2
-0.4
-0.6
-0.8
10 ms
40 dB
Y O
60 dB
Y O
78 dB
Y O
60 dB
Y O
Age, Level
78 dB
Y O
100 ms
0.4
0.2
-0.0
-0.2
-0.4
-0.6
-0.8
40 dB
Y O
Fig. 3 show the data for the
single test day : The angular
separation was 45o, the ISI
10 and 100 ms, and levels
were 40, 60 or 78 dB. The
data points are of individual
mice. At ISI = 10 ms PPI was
greater with increasing level
especially in older mice. At
ISI = 100 ms PPI was greater
with increasing level, and
there was no age effect. (All
of these “youngish old” mice
passed the ASR test.)
Experiment 3: This experiment extended the prior study to
include 3 age groups and a range of ISI conditions between 5
and 150 ms, with the level varying across days. (Only the 57
week old mice were new to the experiment.)
101 wk (n = 9)
57 wk (n = 5)
37 wk (n = 9)
0.5 78 dB
0.5 40 dB
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0.0
0.0
45o
-0.1
-0.1
C 5 10 20 40 70 150
C 5 10 20 40 70 150
ISI (ms)
ISI (ms)
The data in Fig 4 show a minimal asymptotic PPI difference
between the age groups at long ISI with a substantial early deficit
in older mice extending out to at least 40 ms, even at 78 dB SPL.
These data also suggest that the positive effect of increased carrier
level continues to increase over longer intervals between the
prepulse and the probe ES for all age groups.
PPI [1- (P/C)]
acuity in the mouse does capture significant features of spatial
acuity in human listeners. However, its small size and reliance on
high frequency hearing necessarily minimize contributions of
interaural timing and phase differences that dominate spatial
acuity in humans. Studies reviewed by Eddins & Hall (2010)
indicate that only ITD/IPD cues lose their effect in the aged, save
for listeners with severe high frequency hearing loss (HFHL).
Similarly, aging C57BL/6J mice with severe HFHL lose spatial
acuity, while aging CBA mice with more modest HFHL (see Fig 6,
below), appear to retain spatial acuity save for deficits at short
lead times.
Finding delayed but near normal
asymptotic PPI in old mice is
unusual. Fig 5 (left) shows PPI
1.0
2 - 4 mo
18 - 19 mo
for a monaural noise offset (Ison
0.8
24 - 26 mo
& Allen, 2003) showing a normal
0.6
growth rate to a lower PPI level
0.4
with age. Perhaps the delay in
the binaural PPI is analogous to
0.2
Noise Offset
delayed cortical AER to binaural
0.0
0 1 2 3 4 5
10 cues in elderly listeners (Ross et
al. 2007).
ISI (ms)
Increasing signal level can have benefits beyond restoring
audibility. Figure 6 (below) shows colony age data for ABR
threshold on the left, and suprathreshold ABR amplitude on the
right (90 dB 12 kHz). Increasing the signal over 20 to 40 dB for
the older mice would repair audibility deficits at threshold, and
may also increase P1 amplitude. Whether it would repair the
deficit at P4 is an interesting question, with neurobiological
implications for understanding spatial acuity deficits in old mice.
80
ABR threshold (dB ABR)
o
PPI Scores (Median)
0.4
0.3
0.2
0.1
-0.0
-0.1
-0.2
PPI Scores (Median)
PPI (1 - [P/C)]
described in detail in Allen and Ison (2010, in press). Below is a
photograph of the apparatus, showing the mouse in the test cage,
the overhead speaker for startle stimuli (the ES), and two prepulse
(PP) speakers on the azimuth at the level of the mouse. A single
trial is comprised of 15 to 25 s in which a noise is on one side,
then switches to the other
(the PP), the ES following
from 1 ms to 300 ms later.
An accelerometer under
the cage detects the
reflex flinch, its output
integrated for 100 ms
after the ES quantifies
ASR amplitude.
Separate angles are presented across days, while ISI, Carrier
Level or Spectrum may be varied between or within days. Each
stimulus condition is repeated 11 times. Trials are on average 20
seconds apart, the test session lasts about 50 minutes.
PPI (1 - [P/C)]
Methods The adaptation of RMA to study spatial acuity is
“audibility decrement” hypothesis: a spatial deficit in the old will
be remedied by increasing the carrier level. Prior data in young
humans and animal models (including mice, Allen & Ison, 2010)
show that spatial acuity improves with increasing signal level at
and above threshold (e.g., Sabin et al. 1995; Woods et al.
2006) Mice were 35 and 100 weeks old (n = 10,10) .
PPI [1-(P/C)]
Allen et al. (2003). There was a total of 42 mice: 25 weeks old,
N=12, 4M,8F; 56 weeks old, N = 25, 9M,4F; and 115 weeks old, n
= 18, 11 M, 7F. Very old mice, like old humans, (Ford et al. 1995)
have a reduced ASR: only 7 of these mice passed an ASR test,
that the ASR is at least twice that of background activity. Overall
the ASR of old mice shares a modest correlation with the ABR
(R2=0.29), and we regard these successful mice as the equivalent
of the “golden ear” human. The mice were tested at angular
separations of 180o, 90o, 45o, 22.5o, and 7.5o (this had no effect
and is not presented).
As seen in Fig 1, left, the
0.4
older mice were less
0.3
sensitive to shifts in
0.2
location of the noise, but
0.1
the major effect of age
-0.0
as well as decreasing
-0.1
angular separation was
115
wk
-0.2
to slow the growth of
C 1 2 5 102040 100 300 PPI across ISI: thus the
effect of age was most
0.4
prominent at a small ISI,
0.3
as shown at 45o, below.
0.2
0.7
0.1
0.6
0.5
-0.0
0.4
0.3
-0.1
0.2
56
wk
0.1
-0.2
-0.0
-0.1
C 1 2 5 102040 100 300
-0.2
Discussion: These data and others indicate that spatial
PPI [1-(P/C)]
function in mice can complement electrophysiological and
molecular research focused on the auditory brainstem. It may also
provide an interpretative context in which neurobiological research
can contribute to our understanding of auditory function in humans,
including age-related hearing loss (Ison et al. 2010). Here we
study spatial acuity in the mouse, not a commonly used animal
model for this sensory ability: in contrast to humans its small head
restricts the relevant acoustic signal to level changes in the high
frequency spectrum (as shown in middle-aged C57BL/6J mice by
Heffner et al. 2001, in CBA by Allen & Ison 2010), and its “cowrin
and tim’rous nature” (Burns, 1786) is hard to adapt to classic
behavioral psychophysics (Birch et al. 1968). Its unique benefit is
that it supports genetic analyses of auditory function. Fortunately,
as Burns had described, it has a strong startle reflex and thus it is
an ideal subject for Reflex Modification Audiometry (RMA: Young &
Fechter, 1983). We examined both the timing and asymptotic
strength of startle reflex inhibition provided by shifts in sound
location at different carrier levels, to detect any changes in spatial
acuity with advancing age. We also present colony-wide agerelated changes in ABR thresholds and suprathreshold values that
may possibly contribute to these behavioral effects.
Experiment 2: This experiment tested a prediction of the
PPI [1-(P/C)]
Experiment 1: This analysis is an extension of a report by
PPI (1 - [P/C)]
Introduction The behavioural study of complex auditory
beasties” (Burns, 1786)
115 weeks of age
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Test Frequency (kHz)
48
ABR Amplitude (micro-V)
ARO 2010
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Latency (msec)
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Support from NIH (AG09524, DC05409) and the Schmitt Foundation
for Integrative Brain Research JIson@bcs.rochester.edu