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

Neuropsychopharmacology volume 49, pages 837–844 (2024)Cite this article

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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.

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Fig. 1: Frontostriatal recordings in working memory-tested rats treated with varying doses of MPH.
Fig. 2: Effects of MPH on delay-related activity.
Fig. 3: Effects of MPH on reward-related activity.

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Funding

This work was supported by the National Institutes of Health MH09863 (RCS); MH80813, MH116526 (CWB).

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Authors and Affiliations

  1. Department of Psychology, University of Wisconsin-Madison, Madison, WI, 53706, USA

    Robert C. Spencer, Andrea J. Martin & Craig W. Berridge

  2. Department of Cell Biology and Neuroscience, Rowan University, 2 Medical Center Drive, SC220, Stratford, NJ, 08084, USA

    David M. Devilbiss

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RCS and CWB conceived the experiments. RCS and AJM executed the experiments. RCS and AJM, analyzed the data with assistance from DMD. RCS and CWB wrote the manuscript.

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Correspondence to Robert C. Spencer.

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Spencer, R.C., Martin, A.J., Devilbiss, D.M. et al. Cognition-enhancing and cognition-impairing doses of psychostimulants exert opposing actions on frontostriatal neural coding of delay in working memory. Neuropsychopharmacol. 49, 837–844 (2024). https://doi.org/10.1038/s41386-023-01738-6

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