Transcript No Slide Title

Colony-Wide Analysis of Mouse Auditory Brainstem Responses (II): Maturational, Gender and Aging Effects in C57Bl/6J and CBA/CaJ Mice
Paul Allen1, John Housel2, Jason Moore1, William O'Neill1,2, Peter Rivoli1, James Ison1
of Brain & Cognitive Sciences, University of Rochester;2 Dept of Neurobiology & Anatomy, University of Rochester School of Medicine and Dentistry; Rochester, NY
CBA/CaJ
ABR Thresholds from 1 to 30 Months of Age
Subjects and Methods
175
80
80
70
50
40
30
20
10
70
60
50
40
30
20
10
SEM
3 kHz Female
3 kHz Male
6 kHz Female
6 kHz Male
48 kHz Female
48 kHz Male
SEM
3
6
12
24
32
7-14
23-27
1 2 3 4 5-6
28-34
23-27
Male
Female
6.0×10 -6
20
10
SEM
3
6
30
12
• No systematic sex differences
24
32
0
-1.5×10 -6
-3.0×10 -6
2
3
4
5
6
1.5×10 -6
• Subtle changes in ABR waveform with age
0
-1.5×10 -6
-3.0×10 -6
-4.5×10 -6
1
2
3
4
5
6
3
5
7
Age (Months)
8
10
12
1
4.5×10 -6
3
5
7
Age (Months)
8
10
12
2-4 mo
6.0×10 -6
7.0×10 -06
Male
Female
4.0×10 -6
6.0×10 -06
Reduction in P1 amplitude (shown for 12kHz, 90 dB)
2.0×10 -6
5.0×10
-06
4.0×10
-06
Early: 2-4 mo
Middle: 4-6 mo
Late: 6-8 mo
-2.0×10 -6
1
2
3
4
5
6
1.5×10 -6
8
Male
Female
4.0×10 -6
ABR waveforms change with hearing-loss
2.0×10 -6
0
-2.0×10 -6
1
2
3
4
5
6
6-8 mo
6.0×10 -6
7
8
Male
Female
4.0×10 -6
-1.0×10 -06
2.0×10 -6
-2.0×10 -06
0
(Note that waveforms have been aligned on P1)
2.0×10 -06
-2.3×10 -13
Change in appearance of P1a/N1 complex
3.0×10 -6
7
4-6 mo
1.0×10 -06
8
Male
Female
6.0×10 -6
2
12 kHz, 90 dB SPL
23-25 mo
7.5×10 -6
-6
7
SEM
0
2
3.0×10 -06
3.0×10 -6
0
10
SEM
1
C57
12 kHz, 90 dB SPL
(Note that wave forms are aligned on P1)
Male
Female
4.5×10 -6
30
Changes in ABR Waveforms with Hearing-loss
8
11-13 mo
6.0×10 -6
2.0×10 -6
7
40
0
48
6.0×10 -6
1
50
20
10
-4.5×10 -6
7.5×10 -6
60
20
Frequency (Hz)
• Lengthening of Inter-peak intervals
1.5×10 -6
Young: 2-4 mo
Middle-aged: 11-13 mo
Old: 23-25 mo
-6
40
12 mo
0
28-34
32 kHz Female
32 kHz Male
50
70
0
3.0×10 -6
-2.0×10
1 mo
3 mo
6 mo
8 mo
30
• Reduction in P1 amplitudes (as seen for 12kHz, 90dB SPL)
2-4 mo
7.5×10 -6
4.5×10 -6
ABR (V)
15-22
Age (Months)
40
Changes in ABR Waveforms with Age
6.0×10 -6
4.0×10
7-14
50
60
80
Inter-peak intervals remain stable (except P2, P4)
Females have slightly larger ABR peaks (Head size?)
0
-1.5×10 -6
-4.5×10 -6
1
2
3
4
5
6
7
8
1
2
Time (msec)
3
4
5
6
7
8
-2.0×10 -6
• No sex effect on ABR waveforms
-3.0×10 -06
1
2
8-14 mo
15-22 mo
23-27 mo
5
6
7
1
8
2
3
4
5
6
7
8
Changes in Superthreshold ABR with Hearing-loss
28-34 mo
Level (dB SPL)
ABR Ratio Plots
5-7 mo
4
Time (ms)
Aging-related Changes in Superthreshold ABR
2 mo
3
2 mo
ABR Ratio Plots
3 mo
5 mo
7 mo
8 mo
Level (dB SPL)
-3.0×10 -6
-4.0×10 -6
Male
N
Difference in Ratio
25
Male - Female
0
0
4
8
12
16
20
24
28
32
36
Age (mo)
120
Difference in Ratio
Male - Female
35 M - 35 F
11 M - 10 F
41 M - 22 F
22 M - 17 F
16 M - 20 F
SEM
5
ABR Ratio vs Age
40
90dB SPL
20
ABR RMS Ratio
60
4
3 kHz
6 kHz
12 kHz
24 kHz
32 kHz
48 kHz
• Superthreshold S/N ratio plots show substantial decline with age in first
year of life, despite negligible threshold changes
Central neural aging?
3 kHz
6 kHz
12 kHz
24 kHz
32 kHz
48 kHz
7
6
ABR Ratio vs Age
3
2
19 M -17 F
8
90dB SPL
ABR RMS Ratio
6
Female
Male
5
4
3
2
1M-8F
3M-7F
0M-8F
Superthreshold S/N ratios show progressive high frequency hearing loss in
parallel with the elevated ABR thresholds. The 90 dB S/N data show a
progressive decline with age for all frequencies
1
0
0
1
2
3
4
Superthreshold ABR is assessed via signal to noise
5
6
7
8
9
10
11
SEM
1
12
1 2 3 4 5-6
Age (mo)
7-14
15-22
23-27
Age (mo)
0.6
Pre-Response RMS: 4.4125e-07
Response RMS: 3.1721e-08
Ratio: 13.9103
5.0×10 -6
RMS windows: Pre-response = 0.75-1.5 ms, Evoked Response = 1.5-10 ms
0.5
Male Advantage
0.3
2.5×10 -6
ABR (V)
3 kHz
6 kHz
12 kHz
24 kHz
32 kHz
48 kHz
SEM
0.4
Difference in Ratio
0
Male - Female
-2.5×10 -6
filtered
raw
-5.0×10 -6
ABR RMS Ratio
S/N ratio calculated from the RMS of 2kHz high-pass filtered waveforms
28-34
0.2
0.1
-0.0
-0.3
-0.4
Female Advantage
-0.5
0
1
2
3
4
5
6
Time (ms)
7
8
9
10
Artifact of changes in head size, or dielectric properties of cranium?
-0.6
1 2 3 4 5-6
7-14
15-22
Age (mo)
23-27
28-34
0
1
2
3
4
5
6
7
8
Age (mo)
• Possible weak female advantage seen in S/N color plots up to 22
months
• S/N ratios for 90 dB highlight the progressive decline into old age and
lack of systematic sex differences with age and frequency
0.5
Difference in Ratio
Male - Female
9
3 kHz
6 kHz
12 kHz
24 kHz
32 kHz
48 kHz
0.6
-0.1
-0.2
0
ABR RMS Ratio difference
N
9M-9F
Age distribution of C57 mice
100
Animals undergoing drug treatment etc. are excluded
27 M - 21 F
Level (dB SPL)
50
Level (dB SPL)
75
80
C57Bl/6 (N=99, 39 Males and 60 Females)
SEM
• Progressive loss, equal across frequency,
beyond 14 mo of age
60
70
Left: “Classic” frequency across age
Right: Age effect across frequency
1) Initial slow loss for all frequencies,
then delayed abrupt loss, higher first
2) Old females are slightly more
sensitive to low frequencies
3 kHz Female
3 kHz Male
6 kHz Female
6 kHz Male
48 kHz Female
48 kHz Male
90
16 kHz Female
16 kHz Male
24 kHz Female
24 kHz Male
80
70
100
12 kHz Female
12 kHz Male
Age distribution of CBA mice
100
For methods see presentation 437
CBA/CaJ (N=259, 145 Males and 114 Females)
20
90
80
40
30
100
90
Female
Routinely measured in conjunction with behavioral,
electrophysiological or histological experiments
S/N calculated for a subset of mice (using TDT System II apparatus)
15-22
Age (Months)
Frequency (Hz)
CBA
12 kHz 90 dB SPL
32 kHz Female
32 kHz Male
50
100
0
1 2 3 4 5-6
48
60
10
0
0
• No threshold loss (and possible
maturational gain?) up to 14 mo of age
12 kHz Female
12 kHz Male
24 kHz Female
24 kHz Male
ABR threshold (dB SPL)
60
90
7-14 mo
15-22 mo
23-27 mo
28-34 mo
Level (dB SPL)
Level (dB SPL)
70
1 mo
125
Auditory brainstem response (ABR)
Multiple ABRs were accepted for an animal only if there
was a minimum of 60 days between recordings
80
150
CBA/CaJ: (710 recordings, 388 from Males, 322 from Females)
C57Bl/6: (484 recordings, 244 from Males, 240 from Females)
90
ABR threshold (dB SPL)
CBA/CaJ and C57BL/6J mice provide useful models for
contrasting rapid degenerative vs. slow age-related
hearing loss. The descriptions of ABR hearing measures
in these mice are mostly obtained in small groups (save
for Li and Borg, 1991), and concerned with thresholds
(save for Hunter and Willott, 1987). Our colony at the
University of Rochester provides these mice to
investigators focused on age-related changes in complex
auditory processing. Both threshold and superthreshold
ABR measures are taken on many mice at ages that meet
the special needs of particular protocols. Here we
describe ABR measures collected over 6 years, in a total
of 570 CBA mice (267F, 303M) and 353 C57 (161F,
192M), most born in the vivarium from Jackson Lab
breeding stock. The youngest mice for which records are
available were 27 days of age while the oldest mice were
1046 days of age for the CBA (n = 2) and 787 days of age
for the C57 (n=2). The data we present are grouped in
age bins providing sufficiently large samples of males and
females to minimize potential cohort and procedural
differences across time.
C57Bl/6J
ABR Thresholds: 1 to 12 Months of Age
ABR threshold (dB SPL)
Introduction
Voltage
433
1Department
ABR threshold (dB SPL)
ARO 2005
Male Advantage
0.4
0.3
0.2
0.1
SEM
-0.0
-0.1
2
3
-0.3
-0.4
-0.5
-0.6
4
5
Age (mo)
-0.2
6
7
8
Possible female advantage is seen in S/N ratios above threshold, and is
consistent with threshold data
The initial age-related gradual hearing loss across frequencies is consistent
with, e.g., Hequembourg & Liberman, (2001), but the data favoring female
over male inconsistent with Willott & Bross (2004) or Henry (2002).
Female Advantage
Supported by NIA Grant #AG09524 and The Schmitt Program on Integrative Brain Research