P301S Mutant Human Tau Transgenic Mice Manifest Early Symptoms of Human Tauopathies with Dementia and Altered Sensorimotor Gating methods
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Sensorimotor gating
The prepulse inhibition (PPI) test is widely used to measure deficits in information-processing abilities or sensorimotor gating in schizophrenia patients, and it can be employed in both human and animal experiments. PPI is defined as the degree (%) by which the motor acoustic startle response is reduced when the startle-eliciting stimulus is preceded by a brief, low-intensity, non-eliciting stimulus. Tauopathy model mice had lower startle amplitudes than wild type mice at both 110 dB and 120 dB, and this was statistically significant at 120 dB ( ). Especially, the %PPI, an index of sensorimotor gating, was significantly greater in tauopathy model mice ( ). The reduced PPI values at 120 dB rather than those at 110 dB might be a ceiling effect caused by the strong intensity of the startle stimulus.
Decreased sociability/object recognition memory in tauopathy model mice
During the social interaction test in a one-chamber novel environment, no statistical significance was observed in the time spent and the number of contacts, duration of active contacts, mean of duration/contact ratio, and distance traveled between the two groups of mice ( ).
Open field test
Locomotor activity was measured using the open field test, which was performed with 14-week-old male mice. Each mouse was placed in the center of the open field apparatus (40 × 40 × 30 cm; Accuscan Instruments, Columbus, OH, USA). Total distance traveled (in cm), vertical activity (rearing measured by counting the number of photobeam interruptions), time spent in the center, beam-break counts for stereotyped behaviors, and number of fecal boli were recorded. Data were collected for 120 min.
Light/dark transition test
Light/dark transition test was performed as previously described. The apparatus used consisted of a cage (21 × 42 × 25 cm) divided into two chambers of equal size by a partition containing a door (O'Hara & Co.). One chamber was brightly illuminated (390 lux), whereas the other was dark (2 lux). Mice were placed into the dark side and allowed to move freely between the two chambers with the door open for 10 min. The total number of transitions between chambers, time spent in each side, first latency to enter the light side, and distance traveled were recorded automatically using Image LD software (see 'Image and data analysis').
Elevated plus-maze test
Elevated plus-maze test was performed as previously described. The elevated plus-maze (O'Hara & Co.) consisted of two open arms (25 × 5 cm) and two enclosed arms of the same size, with 15-cm high transparent walls. The arms and central square were made of white plastic plates and were elevated to a height of 55 cm above the floor. To minimize the likelihood of animals falling from the apparatus, 3-mm high plastic ledges were provided for the open arms. Arms of the same type were arranged at opposite sides to each other. Each mouse was placed in the central square of the maze (5 × 5 cm), facing one of the closed arms. Mouse behavior was recorded during a 10-min test period. The numbers of entries into, and the time spent in open and enclosed arms, were recorded. The illumination level was 100 lux at the center of the maze. For data analysis, we used the following four measures:...
Porsolt forced swim test
The Porsolt forced swim test apparatus consisted of four Plexiglas cylinders (20 cm high × 10 cm diameter). A nontransparent panel separated the cylinders to prevent the mice from seeing each other (O'Hara & Co.). The cylinders were filled with water (23°C) up to a height of 7.5 cm. Mice were placed into the cylinders, and their behavior was recorded over a 10-min test period (Day 1). Retention tests were administered 24 hours after training (Day 2). Data acquisition and analysis were performed automatically using Image PS software (see 'Image and data analysis').
Social interaction test in a novel environment (one-chamber social interaction test)
In the social interaction test, two mice of identical genotypes that were previously housed in different cages were placed in a box together (40 × 40 × 30 cm) and allowed to explore freely for 10 min. Social behavior was monitored with a CCD camera connected to a computer. Analysis was performed automatically using Image SI software (see 'Image and data analysis'). The total number of contacts, total duration of active contacts, total contact duration, mean duration per contact, and total distance traveled were measured. Active contact was defined as follows. Images were captured at 1 frame per second, and distance traveled between two successive frames was calculated for each mouse. If the two mice contacted each other and the distance traveled by either mouse was longer than 2 cm, the behavior was considered as 'active contact'. Genotypic mismatch was f...
Startle response/Prepulse inhibition (PPI) test
An acoustic startle reflex measurement system was used (O'Hara & Co.). A test session was begun by placing a 16-week-old mouse in a Plexiglas cylinder, where it was left undisturbed for 10 min. The duration of white noise, used as the startle stimulus, was 40 ms for all trial types. The startle response was recorded for 140 ms (measuring response every 1 ms) starting with the onset of the prepulse stimulus. The background noise level in each chamber was 70 dB. The peak startle amplitude recorded during the 140-ms sampling window was used as dependent variable. A test session consisted of 6 trial types (i.e., two types for startle stimulus-only trials, and four types for PPI trials). Intensity of the acoustic startle stimulus was 110 or 120 dB. The prepulse sound was presented 100 ms before the startle stimulus, and its intensity was 74 or 78 dB. Four combinations of prepulse and start...
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The prepulse inhibition (PPI) test is widely used to measure deficits in information-processing abilities or sensorimotor gating in schizophrenia patients, and it can be employed in both human and animal experiments. PPI is defined as the degree (%) by which the motor acoustic startle response is reduced when the startle-eliciting stimulus is preceded by a brief, low-intensity, non-eliciting stimulus. Tauopathy model mice had lower startle amplitudes than wild type mice at both 110 dB and 120 dB, and this was statistically significant at 120 dB ( ). Especially, the %PPI, an index of sensorimotor gating, was significantly greater in tauopathy model mice ( ). The reduced PPI values at 120 dB rather than those at 110 dB might be a ceiling effect caused by the strong intensity of the startle stimulus.
During the social interaction test in a one-chamber novel environment, no statistical significance was observed in the time spent and the number of contacts, duration of active contacts, mean of duration/contact ratio, and distance traveled between the two groups of mice ( ).
Locomotor activity was measured using the open field test, which was performed with 14-week-old male mice. Each mouse was placed in the center of the open field apparatus (40 × 40 × 30 cm; Accuscan Instruments, Columbus, OH, USA). Total distance traveled (in cm), vertical activity (rearing measured by counting the number of photobeam interruptions), time spent in the center, beam-break counts for stereotyped behaviors, and number of fecal boli were recorded. Data were collected for 120 min.
Light/dark transition test was performed as previously described. The apparatus used consisted of a cage (21 × 42 × 25 cm) divided into two chambers of equal size by a partition containing a door (O'Hara & Co.). One chamber was brightly illuminated (390 lux), whereas the other was dark (2 lux). Mice were placed into the dark side and allowed to move freely between the two chambers with the door open for 10 min. The total number of transitions between chambers, time spent in each side, first latency to enter the light side, and distance traveled were recorded automatically using Image LD software (see 'Image and data analysis').
Elevated plus-maze test was performed as previously described. The elevated plus-maze (O'Hara & Co.) consisted of two open arms (25 × 5 cm) and two enclosed arms of the same size, with 15-cm high transparent walls. The arms and central square were made of white plastic plates and were elevated to a height of 55 cm above the floor. To minimize the likelihood of animals falling from the apparatus, 3-mm high plastic ledges were provided for the open arms. Arms of the same type were arranged at opposite sides to each other. Each mouse was placed in the central square of the maze (5 × 5 cm), facing one of the closed arms. Mouse behavior was recorded during a 10-min test period. The numbers of entries into, and the time spent in open and enclosed arms, were recorded. The illumination level was 100 lux at the center of the maze. For data analysis, we used the following four measures: the percentage of entries into the open arms, time spent in the open arms (sec), number of total entries, and total distance traveled (cm). Data acquisition and analysis were performed automatically using Image EP software (see 'Image and data analysis'). Three wild type mice and a tauop...
The Porsolt forced swim test apparatus consisted of four Plexiglas cylinders (20 cm high × 10 cm diameter). A nontransparent panel separated the cylinders to prevent the mice from seeing each other (O'Hara & Co.). The cylinders were filled with water (23°C) up to a height of 7.5 cm. Mice were placed into the cylinders, and their behavior was recorded over a 10-min test period (Day 1). Retention tests were administered 24 hours after training (Day 2). Data acquisition and analysis were performed automatically using Image PS software (see 'Image and data analysis').
In the social interaction test, two mice of identical genotypes that were previously housed in different cages were placed in a box together (40 × 40 × 30 cm) and allowed to explore freely for 10 min. Social behavior was monitored with a CCD camera connected to a computer. Analysis was performed automatically using Image SI software (see 'Image and data analysis'). The total number of contacts, total duration of active contacts, total contact duration, mean duration per contact, and total distance traveled were measured. Active contact was defined as follows. Images were captured at 1 frame per second, and distance traveled between two successive frames was calculated for each mouse. If the two mice contacted each other and the distance traveled by either mouse was longer than 2 cm, the behavior was considered as 'active contact'. Genotypic mismatch was found in one pair (one tauopathy model pair), and they could not be analyzed.
An acoustic startle reflex measurement system was used (O'Hara & Co.). A test session was begun by placing a 16-week-old mouse in a Plexiglas cylinder, where it was left undisturbed for 10 min. The duration of white noise, used as the startle stimulus, was 40 ms for all trial types. The startle response was recorded for 140 ms (measuring response every 1 ms) starting with the onset of the prepulse stimulus. The background noise level in each chamber was 70 dB. The peak startle amplitude recorded during the 140-ms sampling window was used as dependent variable. A test session consisted of 6 trial types (i.e., two types for startle stimulus-only trials, and four types for PPI trials). Intensity of the acoustic startle stimulus was 110 or 120 dB. The prepulse sound was presented 100 ms before the startle stimulus, and its intensity was 74 or 78 dB. Four combinations of prepulse and startle stimuli were employed (74-110 dB, 78-110 dB, 74-120 dB, and 78-120 dB). Six blocks of the 6 trial types were presented in a pseudorandom order such that each trial type was presented once within a block. The average inter-trial interval was 15 sec (range, 10-20 sec)....
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