Cognition-enhancing and cognition-impairing doses of psychostimulants exert opposing actions on frontostriatal neural coding of delay in working memory

Abstract

The prefrontal cortex (PFC) and extended frontostriatal circuitry play a critical role in executive cognitive processes that guide goal-directed behavior. Dysregulation of frontostriatal-dependent cognition is implicated in a variety of cognitive/behavioral disorders, including addiction and attention deficit hyperactivity disorder (ADHD). Psychostimulants exert dose-dependent and opposing actions on frontostriatal cognitive function. Specifically, low and clinically-relevant doses improve, while higher doses associated with abuse and addiction impair, frontostriatal-dependent cognitive function. Frontostriatal cognition is supported by the coordinated activity of neurons across this circuit. To date, the neural coding mechanisms that support the diverse cognitive actions of psychostimulants are unclear. This represents a significant deficit in our understanding of the neurobiology of frontostriatal cognition and limits the development of novel treatments for frontostriatal cognitive impairment. The current studies examined the effects of cognition-enhancing and cognition-impairing doses of methylphenidate (MPH) on the spiking activity of dorsomedial PFC (dmPFC) and dorsomedial striatal (dmSTR) neurons in 17 male rats engaged in a working memory task. Across this frontostriatal circuit, we observed opposing actions of low- and high-dose MPH on the population-based representation of delay: low-dose strengthened, while high-dose weakened, representation of this event. MPH elicited a more complex pattern of actions on reward-related signaling, that were highly dose-, region- and neuron-dependent. These observations provide novel insight into the neurophysiological mechanisms that support the cognitive actions of psychostimulants.

Fig. 1. Frontostriatal recordings in working memory-tested rats treated with varying doses of MPH.

A T-maze schematic illustrating key task events, including delay, two distinct auditory tones serving as outcome-related signals on correct versus error trials, and receipt of reward (sugar) and/or pickup. B Bar graph depicts effects of vehicle, 0.5 mg/kg MPH (Low MPH) and 8.0 mg/kg MPH (High MPH) on working memory performance as measured as percent change from baseline (mean ± SEM). Low-dose MPH significantly improved, while high-dose MPH significantly impaired, working memory. C Representative photomicrograph with arrows indicating ventral extent of electrode placement in (left) layer 5 of dmPFC, and (right) dmSTR. D Left, Action potential waveforms of 4 simultaneously discriminated dmSTR MS neurons. Right, Waveforms from these units exhibit separable clusters in 3D-principal component space. **p < 0.01 vs vehicle; fa, anterior forceps of the corpus callosum; dAcg, dorsal anterior cingulate; PL, prelimbic; CC, corpus callosum; LV, lateral ventricle.

Fig. 2. Effects of MPH on delay-related activity.

Left, Exemplar rasters/PETHs for dmPFC (A) and dmSTR (B) neurons strongly tuned to delay. In raster displays, fiducial markers indicate start of delay (left; lighter) and end of delay (right; darker). Line under raster indicates duration of delay. Bar graphs depict changes in firing rate (mean ± SEM) during the delay interval as measured as percent change from baseline activity following vehicle (VEH), 0.5 mg/kg MPH (Low MPH) and 8.0 mg/kg MPH (High MPH) for neurons strongly tuned (Tuned) and not tuned (Untuned) to delay. A Low-dose MPH had no significant effects on neurons tuned to delay, while significantly suppressing the activity of dmPFC neurons not tuned to delay. In contrast, high-dose MPH significantly suppressed the activity of neurons strongly tuned to delay. B Within the dmSTR, neither vehicle nor low-dose MPH significantly affected delay tuned neurons. While vehicle elicited a slight suppression of activity in neurons not tuned to delay, low-dose MPH further suppressed delay-related activity of untuned neurons. In contrast, high-dose MPH robustly increased the delay-related firing activity of neurons regardless of tuning. ++p < 0.01, +++p < 0.001 vs. baseline. *p < 0.05, ***p < 0.001 vs. vehicle.

Fig. 3. Effects of MPH on reward-related activity.

Left, Exemplar rasters/PETHs for dmPFC (A) and dmSTR (B) neurons strongly tuned to reward. In raster displays, fiducial markers indicate start of reward (left; lighter) and end of reward (right; darker). Line under raster indicates duration of reward proximity. Bar graphs depict changes in firing rate (mean ± SEM) during the reward proximity interval as measured by percent change from baseline activity following vehicle (VEH), 0.5 mg/kg MPH (Low MPH) and 8.0 mg/kg MPH (High MPH) for neurons strongly tuned (Tuned) and not tuned (Untuned) to delay. A Following treatment with low-dose MPH there was a trend (p = 0.07) for suppression of activity of dmPFC reward proximity-tuned neurons relative to vehicle, while increasing activity in untuned neurons. High-dose MPH also showed a trend for suppressed activity in strongly tuned neurons relative to vehicle (p = 0.18). B Within the dmSTR, low-dose MPH did not affect the activity of neurons during the reward interval, while high-dose MPH robustly increased firing among both reward-tuned and untuned neurons. +p < 0.05, +++p < 0.001 vs. baseline. ***p < 0.001 vs. vehicle.