Amphetamine increases timing variability by degrading prefrontal temporal encoding

Area of Science:

• Neuroscience
• Psychopharmacology
• Computational Neuroscience

Background:

• Amphetamine is a widely abused psychostimulant known to elevate synaptic catecholamine levels and impair executive functions.
• The precise impact of acute amphetamine on prefrontal cortex (PFC) circuits, crucial for executive control, remains incompletely understood.
• Interval timing, a key executive function requiring precise temporal estimation, relies on rodent PFC ensembles.

Purpose of the Study:

• To investigate how acute amphetamine administration affects interval timing behavior and PFC neuronal ensemble activity in mice.
• To test the hypothesis that amphetamine disrupts interval timing by degrading temporal encoding within the PFC.
• To explore potential neurophysiological markers for amphetamine use and inform PFC-targeted treatments.

Main Methods:

• Conducted a meta-analysis of 15 prior rodent studies to quantify amphetamine's effects on interval timing performance.
• Utilized multielectrode arrays to record neuronal ensemble activity in the dorsomedial prefrontal cortex (dmPFC) of mice during an interval timing task.
• Administered D-amphetamine (1.5 mg/kg, intraperitoneally) and analyzed its effects on behavior, neuronal ramping, inter-neuronal communication, and low-frequency oscillations.

Main Results:

• Meta-analysis revealed a large effect size of amphetamine on interval timing variability and a medium effect size on central tendencies.
• In vivo recordings showed amphetamine increased trial-to-trial variability in PFC neuronal ramping during interval timing.
• Amphetamine also attenuated interactions between ramping neurons and dampened low-frequency oscillations in the dmPFC.

Conclusions:

• Amphetamine alters prefrontal temporal processing by increasing the variability of neural representations of time.
• These findings elucidate amphetamine's effects on PFC activity, offering insights into neurophysiological markers and therapeutic targets.
• The study highlights the disruption of temporal encoding in the PFC as a key mechanism underlying amphetamine's behavioral effects.