title: Amphetamine Exerts Dose-Dependent Changes in Prefrontal Cortex Attractor Dynamics during Working Memory.
abstract: Modulation of neural activity by monoamine neurotransmitters is thought to play an essential role in shaping computational neurodynamics in the neocortex, especially in prefrontal regions. Computational theories propose that monoamines may exert bidirectional (concentration-dependent) effects on cognition by altering prefrontal cortical attractor dynamics according to an inverted U-shaped function. To date, this hypothesis has not been addressed directly, in part because of the absence of appropriate statistical methods required to assess attractor-like behavior in vivo. The present study used a combination of advanced multivariate statistical, time series analysis, and machine learning methods to assess dynamic changes in network activity from multiple single-unit recordings from the medial prefrontal cortex (mPFC) of rats while the animals performed a foraging task guided by working memory after pretreatment with different doses of d-amphetamine (AMPH), which increases monoamine efflux in the mPFC. A dose-dependent, bidirectional effect of AMPH on neural dynamics in the mPFC was observed. Specifically, a 1.0 mg/kg dose of AMPH accentuated separation between task-epoch-specific population states and convergence toward these states. In contrast, a 3.3 mg/kg dose diminished separation and convergence toward task-epoch-specific population states, which was paralleled by deficits in cognitive performance. These results support the computationally derived hypothesis that moderate increases in monoamine efflux would enhance attractor stability, whereas high frontal monoamine levels would severely diminish it. Furthermore, they are consistent with the proposed inverted U-shaped and concentration-dependent modulation of cortical efficiency by monoamines.
authors.affiliation: Department of Psychology, Stark Neuroscience Institute, Institute for Mathematical Modeling and Computational Sciences, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana 46202, clapish@iupui.edu.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Lapish
authors.affiliation: Faculty of Science and Technology, Bournemouth University, Poole, BH12 5BB, United Kingdom, Department of Theoretical Neuroscience, Bernstein Center for Computational Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, D-68159 Mannheim, Germany, and.
authors.forename: Emili
authors.initials: E
authors.lastname: Balaguer-Ballester
authors.affiliation: Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3.
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Seamans
authors.affiliation: Department of Psychiatry, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z3.
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Phillips
authors.affiliation: Department of Theoretical Neuroscience, Bernstein Center for Computational Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, D-68159 Mannheim, Germany, and School of Computing and Mathematics, Faculty of Science and Environment, Plymouth University, Plymouth, PL4 8AA, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Durstewitz
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001185:Artificial Intelligence; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects*; D015999:Multivariate Analysis; D009474:Neurons / Q000187:drug effects; D017711:Nonlinear Dynamics; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D020318:Rats, Long-Evans; D013997:Time Factors
chemical_list: D000697:Central Nervous System Stimulants; D000661:Amphetamine
keywords: dopamine; multiple single-unit recordings; neural computation; neural dynamics; neuromodulation; prefrontal cortex