Working memory performance and neural activity in prefrontal cortex of peripubertal monkeys

Abstract

The dorsolateral prefrontal cortex matures late into adolescence or early adulthood. This pattern of maturation mirrors working memory abilities, which continue to improve into adulthood. However, the nature of the changes that prefrontal neuronal activity undergoes during this process is poorly understood. We investigated behavioral performance and neural activity in working memory tasks around the time of puberty, a developmental event associated with the release of sex hormones and significant neurological change. The developmental stages of male rhesus monkeys were evaluated with a series of morphometric, hormonal, and radiographic measures. Peripubertal monkeys were trained to perform an oculomotor delayed response task and a variation of this task involving a distractor stimulus. We found that the peripubertal monkeys tended to abort a relatively large fraction of trials, and these were associated with low levels of task-related neuronal activity. However, for completed trials, accuracy in the delayed saccade task was high and the appearance of a distractor stimulus did not impact performance significantly. In correct trials delay period activity was robust and was not eliminated by the presentation of a distracting stimulus, whereas in trials that resulted in errors the sustained cue-related activity was significantly weaker. Our results show that in peripubertal monkeys the prefrontal cortex is capable of generating robust persistent activity in the delay periods of working memory tasks, although in general it may be more prone to stochastic failure than in adults.

Keywords: development; eye movement; neurophysiology; persistent activity; principal sulcus.

Fig. 1.

A: structural MRI of 1 adolescent monkey brain. The shaded areas indicate the recording sites in the dorsolateral prefrontal cortex (PFC). Black spots in the image are artifactual “shadows” created by ceramic screws in the skull. AS, arcuate sulcus; PS, principal sulcus. B: successive frames indicate the sequence of events in the oculomotor delayed response (ODR) task. Monkeys were required to remember the stimulus location and to saccade to it after a delay period. B: sequence of events in the ODR with Distractor task. The presentation of the stimulus is the same as in the ODR task, but 1 distractor is shown in the middle of the delay period.

Fig. 2.

Developmental profile. A: body mass for each monkey as a function of time, evaluated in quarterly assays. Data are aligned to the onset of neurophysiological recordings (Q0). Shaded area covers the interval of recordings. B: serum testosterone concentration obtained from each monkey. C: sample radiography for monkey 1752; arrow indicates the epiphyseal plate, which has not fused yet. D: testis size as a function of time. E: femur length as a function of time.

Fig. 3.

A: proportions of possible trial outcomes for the ODR and ODR with Distractor tasks. First 2 bars indicate correct trials in the 2 tasks. Subsequent bars indicate errors due to breaks in fixation during the initial fixation interval; errors during the cue presentation interval; errors during the delay interval; errors during the distractor presentation (in the ODR with Distractor task only); errors during the second delay period, following the distractor; and errors during the saccade interval. Mean values and SE are plotted across monkeys. B: proportions of errors after the cue presentation in the ODR task, separately for each of the monkeys. Types of errors plotted include directional saccade errors, where the monkey's eye movement was away from the cue location; target errors, where the monkey's eye movement was to the cue location but fixation was broken before the minimum time required to obtain a reward; and breaks in fixation during the delay period, prior to the offset of the fixation point, which instructed the animal to make a saccade. C: proportion of correct trials in the ODR and ODR with Distractor tasks, for trials that were completed up to the end of the delay period, shown separately for 4 monkeys. D: proportion of error trials during the delay period of the ODR task. Errors due to a saccade toward the cued location, errors due to a saccade to another location, and premature breaks in fixation at the target location are plotted. E: proportion of error trials during the second delay period (after the distractor) in the ODR with Distractor task. Errors due to a saccade toward the initial cue, errors due to a saccade to the distractor, errors due to a saccade to another location, and premature breaks in fixation at the target location are plotted.

Fig. 4.

Persistent activity in a prefrontal neuron. A: rasters and peristimulus time histograms (PSTHs) of a single neuron during the ODR task. Spike rasters and histograms are arranged according to the spatial location of the cue (i.e., saccade target). Responses during the fixation interval (F), cue presentation (C), and delay period (D) are indicated. Horizontal bars represent the delay period. B: polar plot depicts the average firing rate during the delay period for each cue location; the dashed circle represents the average firing rate during the baseline, fixation period.

Fig. 5.

Rasters and PSTHs (A) and polar plot (B) of a second example neuron recorded during the ODR task. Conventions are the same as in Fig. 4.

Fig. 6.

Population responses of neurons with significantly elevated firing rate during the delay period of the ODR task (n = 263 neurons). A: average PSTH following the best cue location (solid line) or following the diametric location (dotted line). Horizontal line represents baseline fixation discharge rate. Labels indicate fixation (FIX), cue presentation (CUE), and delay (DELAY) periods. Insets: schematic illustrations of the position of the stimulus relative to the receptive field, which differed for each neuron. B: mean Fano factor values of neuronal discharges for the same population of neurons as in A. C: population tuning curves from the cue period and from the delay period.

Fig. 7.

Activity in the ODR with Distractor task. A: rasters and PSTHs of a single neuron during the ODR with Distractor task. Responses during the fixation interval (F), cue presentation (C), first delay period (D1), distractor presentation (Dis), and second delay period (D2) are indicated. Horizontal bars represent the first and second delay periods. B: polar plots depict the average firing rate during the first (top) and second (bottom) delay periods for each cue location; the dashed circle represents the average firing rate during the baseline, fixation period.

Fig. 8.

Population responses of neurons with significant delay activity in the ODR with Distractor task. A: population PSTH (n = 88 neurons) following the best cue location and diametric distractor location (solid line) or following the worst cue location and best distractor location (dotted line). Horizontal line represents baseline fixation discharge rate. B: mean Fano factor values of neuronal discharges during the trial. C: population tuning curves from the cue period, from the first delay, and from the second delay (after distractor presentation). Labels in A and B indicate fixation (FIX), cue presentation (CUE), first delay (DELAY1), distractor presentation (DISTRACT), and second delay (DELAY2) periods. Horizontal dashed lines in A and C represent the baseline firing rate.

Fig. 9.

Neural activity in correct vs. error trials. A: population average firing rate from neurons with at least 2 error trials of any type in the ODR task. Normalized firing rate is shown in correct and error trials in which the cue appeared in the best location (blue traces, n = 43 neurons) and in the diametric location (red traces, n = 40 neurons). Solid and dashed lines indicate correct and error trials, respectively. B: population firing rate from the ODR with Distractor task. Averaged firing rate is shown in correct and error trials in which the cue appeared in the best location (blue traces, n = 10 neurons) and in the diametric location (red traces, n = 11 neurons). C: population firing rate in correct (solid) and error (dashed) trials aborted during the delay period. Error average is for all available trials in which a break in fixation occurred at least 0.5 s after the offset of the cue (n = 47 neurons). D: as in C but with error average for all trials in which an error occurred at least 1 s after the offset of the cue (n = 19 neurons).