Age-Related Learning And Working Memory Impairment in The Common Marmoset Part 2
Jan 11, 2024
Software
Cognitive tasks were programmed using Animal Behavior Environment Test (ABET) Cognition software (Lafayette Instrument Company) that controlled all aspects of the task including the number and order of trials, timing, stimuli selection and display location, and delivery of liquid rewards.
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The software also recorded several measures of task performance including trial number, correct and incorrect responses, the location on the screen of the correct choice and the chosen location, and response latency.
Stimuli for all tasks included simple shapes and black and white clipart images, 3.5 3.5 cm displayed on a black background (see Figs. 2E, 3A for examples of stimuli).
Statistical analyses
Data were analyzed using MATLAB (MathWorks). Kolmogorov–Smirnov tests determined that the data were not normally distributed, and so nonparametric statistical analyses were used throughout the study.
Therefore, correlations were assessed using Spearman's rank-order correlations, Scheirer Ray Hare tests were used to assess two-factor interactions across time, and Friedman's tests with Nemenyi post hoc tests, or Wilcoxon signed-rank tests, were used to identify within-factor differences.
Performance was compared with chance using x2 Goodness of Fit Tests. Chance levels were determined via a Monte Carlo simulation and p, 0.05 was considered significant.
Cognitive testing
Touch training
Marmosets were naive to cognitive testing at the beginning of the study. Therefore, they were first trained to touch the screen to earn fluid rewards. The touch training process had three stages. The goals of the first stage were to habituate marmosets to the touch screen station, encourage physical engagement with the screen and the reward sink, and associate touching the screen and reward delivery.
To do this, a sweet substance (Marshmallow Fluff) was applied on the screen, in small quantities, at each of the nine locations accessible through the mask. When the training session started, blue square target stimuli appeared in each of the nine locations, under the Fluff. When the marmosets touched the screen to obtain the Fluff a touch was detected and 0.2 ml of reward was dispensed into the sink below the screen. The marmoset's behavior was remotely observed via Ethernet-enabled cameras (RLK16-410B8, Reolink).
Animals were observed to identify when they learned that touching the screen caused a reward to be dispensed. Their behavior changed as they learned this association. Early in training the monkeys only consumed rewards when they noticed accumulation in the sink. When the association had been made, however, the monkey's behavior changed, and immediately following each screen touch, they consumed the reward from the sink before touching the screen again. Once this association was established, the second stage of touch training began.
The goals of the second stage were to characterize marmoset responses to each of the nine possible stimulus display locations and to train the marmosets that only locations with stimuli have the potential to yield rewards when selected. Initially, all nine locations had targets. As training continued throughout approximately five daily training sessions, the number of target stimuli presented on the screen on each trial decreased in a stepwise manner from nine targets to one.
During this stage, Fluff was no longer applied to the screen, and correct target selections were rewarded with 0.2 ml of reward. Each target stimulus was placed in a randomly selected location. Once marmosets reliably touched the one randomly positioned target, the third and final stage of touch training commenced. The goal of the third stage was to maintain robust engagement with the task while reducing the volume of reward earned for each response.
On each trial of this third stage, one stimulus was displayed on the screen in a randomly chosen location. Reward volumes were decreased from 0.2 ml per response to a final volume of 0.05 ml per response, in a stepwise manner over approximately four daily training sessions.
DRST (Fig. 3A)
The Delayed Recognition Span Task (DRST) measures working memory capacity. Each trial of the DRST was initiated by the marmoset touching a blue square stimulus in the center of the screen. Then, a single black and white stimulus, drawn randomly from a set of 400 images, was displayed on the screen in one of nine possible locations, also selected randomly.
When the marmoset touched this first stimulus, a small liquid reward was dispensed. Following a 2-s delay, during which the screen was blank, two alternative forced choices were presented with the original stimulus appearing in its original location, and a second, novel stimulus appearing in a different pseudo-randomly selected location.
If the marmoset selected the novel object, a correct response was logged, a liquid reward was dispensed, and another 2-s delay ensued. Following the delay, the first two stimuli appeared in their original locations, and a third, novel stimulus, also appeared, in a pseudo-randomly chosen location. The marmoset was again rewarded for choosing the novel stimulus. Novel stimuli were added after subsequent delays until the trial was terminated in one of three ways: (1) the marmoset made nine correct selections in a row; (2) the marmoset failed to make a selection within 12-s (i.e., omitted); (3) the marmoset made an incorrect response (i.e., selected a non-novel stimulus).
In the case of an omission or incorrect response, no reward was dispensed and a 5-s time-out period began before the start of a new trial. For each trial, the number of stimuli correctly selected before the trial terminated was recorded as the Final Span Length (FSL). Reward volumes were increased with increased trial difficulty to encourage continued task engagement.
Specifically, marmosets earned 0.05 ml of reward for correct responses when one stimulus was on the screen, 0.1 ml of reward for correct responses when two, three, or four stimuli were on the screen, and 0.2 ml of reward for correct responses when five, six, seven, eight, or nine stimuli were on the screen. The number of objects on the screen is referred to below as trial difficulty levels (TDLs).
Each marmoset was tested 2–5 d per week, and each testing session was terminated after 3 h, or after the marmoset had earned 20 ml of reward, whichever came first.
Reaction Time Task (Fig. 7A)
The Reaction Time Task (RTT) measures the time required for the marmoset to reach out and touch the screen. It was used to distinguish age-related changes in noncognitive motor speed from age-related changes in the performance of the working memory task (DRST). Each trial of the RTT was initiated by the marmoset touching a green square stimulus in the center of the screen.
Then, a target appeared in one of nine locations chosen pseudo-randomly. When the marmoset touched the target, they earned a 0.1-ml liquid reward, and the amount of time elapsed between target onset and selection by the marmoset was recorded as the reaction time on that trial.
Marmosets were given one practice session to learn the task, and then data were collected from ten subsequent test sessions. Each of the 10 test sessions was concluded when marmosets had performed 108 trials or 1 h had elapsed since the beginning of the testing session.
Progressive Ratio Task (PRT; Fig. 7B)
The Progressive Ratio Task (PRT) measures motivation. It was used to distinguish age-related changes in noncognitive motivation from age-related changes in DRST performance. Each trial of the PRT began with the presentation of a stimulus in the middle of the screen.
Marmosets were rewarded for touching the stimulus under a progressive-ratio schedule of reinforcement where response requirements increased during a testing session.
The initial response requirement was one touch to earn a reward. Once the monkey satisfied a response requirement, the stimulus was removed from the screen, the reward was dispensed, and then the stimulus was replaced on the screen. The response requirement increased by one until eight response requirements were completed, and subsequently doubled after every eight response requirements were completed thereafter.
The specific response requirements used were: (increment = 1) 1, 2, 3, 4, 5, 6, 7, 8; (increment = 2) 10, 12, 14, 16, 18, 20, 22, 24; (increment = 4) 28, 32, 36, 40, 44, 48, 52, 56; etc. Test sessions were concluded when 1 h had elapsed or the marmoset reached a response requirement of 120 touches. Marmosets were given one practice session to learn the task, and then data were collected from three subsequent test sessions.
Results
DRST
To assess whether marmosets demonstrate age-related working memory impairment, we implemented a touch screen version of the Delayed Recognition Span Task in a cohort of animals across a broad age range.
In this task, marmosets initiated a trial and were then rewarded for touching a single visual stimulus (an "object") appearing on the screen. Following a brief delay, during which the screen was blank, marmosets were rewarded for identifying the novel object in a two-alternative forced choice. If correct, a brief delay was followed by the appearance of three objects; the two that had been seen earlier in the trial, and one novel.
After each correct answer, a reward was delivered, and an additional object was added to the array. When a marmoset chose a non-novel object, the trial ended without reward, and the trial sequence began anew.
The primary measure used to assess DRST performance was Final Span Length (FSL). As in prior work (Herndon et al., 1997; Moss et al., 1997; Killiany et al., 2000; Moore et al., 2017), this measure quantifies the animal's working memory ability and is defined as the number of stimuli the marmoset correctly reported as novel on each trial.
The raw data learning curves for each animal, plotted as a function of FSL over time, were smoothed using a Gaussian-weighted moving average over a 2000-trial window (Fig. 3B), and a Monte Carlo simulation was used to model chance performance.
We analyzed performance during three distinct Phases along each marmoset's learning curve, designated as "Novice," "Learner," and "Expert." The Novice Phase was defined as the trials on which performance did not deviate from that expected by chance and began with the first trial ever performed. The end of the Novice Phase was determined using Kolmogorov–Smirnov Goodness of Fit Tests to identify the initial point where 100 successive experimentally measured FSL distributions differed significantly from a null distribution drawn from the Monte Carlo simulations.
The Learner Phase began immediately after the Novice Phase and ended on the trial before the 90th percentile of performance. The Expert Phase encompassed trials with performance between the 90th and 100th percentiles, inclusive.
These Phases were distinct from one another, with no trials falling into multiple categories. To validate these Phase definitions, we tested whether, as expected, average performance increased significantly across the three Phases and found that it did (Fig. 3C; nonparametric Friedman's test: x2 (2) = 30, p = 3.1 107 ); pairwise post hoc Nemenyi tests: Novice vs Learner: p = 0.017; Novice vs Expert: p = 1.4 107; Learner vs Expert: p = 0.017).
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