Inactivation of the Medial-Prefrontal Cortex Impairs Interval Timing Precision, but Not Timing Accuracy or Scalar Timing in a Peak-Interval Procedure in Rats

Abstract

Motor sequence learning, planning and execution of goal-directed behaviors, and decision making rely on accurate time estimation and production of durations in the seconds-to-minutes range. The pathways involved in planning and execution of goal-directed behaviors include cortico-striato-thalamo-cortical circuitry modulated by dopaminergic inputs. A critical feature of interval timing is its scalar property, by which the precision of timing is proportional to the timed duration. We examined the role of medial prefrontal cortex (mPFC) in timing by evaluating the effect of its reversible inactivation on timing accuracy, timing precision and scalar timing. Rats were trained to time two durations in a peak-interval (PI) procedure. Reversible mPFC inactivation using GABA agonist muscimol resulted in decreased timing precision, with no effect on timing accuracy and scalar timing. These results are partly at odds with studies suggesting that ramping prefrontal activity is crucial to timing but closely match simulations with the Striatal Beat Frequency (SBF) model proposing that timing is coded by the coincidental activation of striatal neurons by cortical inputs. Computer simulations indicate that in SBF, gradual inactivation of cortical inputs results in a gradual decrease in timing precision with preservation of timing accuracy and scalar timing. Further studies are needed to differentiate between timing models based on coincidence detection and timing models based on ramping mPFC activity, and clarify whether mPFC is specifically involved in timing, or more generally involved in attention, working memory, or response selection/inhibition.

Interval timing is disrupted in female 5xFAD mice: An indication of altered memory processes

“…This constitutes an important test since scalar variability (proportionality of timing imprecision to target intervals) is a psychophysical signature of interval timing in healthy samples (Buhusi & Meck, ). Given that it allows for within‐group comparisons, the use of a dual‐peak procedure (Buhusi, Reyes, Gathers, Oprisan, & Buhusi, ) in future studies would be the ideal procedure to investigate this specific question.…”

Time-Encoding Migrates from Prefrontal Cortex to Dorsal Striatum During Learning of a Self-Timed Response Duration Task

“…Smith and collaborators also showed that the mPFC disengages from the task during habit formation 35 . However, these results are at odds with several results showing the critical role of the mPFC in timing 15,23,24,36 . Particularly, results from different tasks show that this region's inactivation impaired the timing precision but not accuracy 23,24 .…”

“…Reports of the spiking activity of neurons involved in keeping track of time implicate regions like medial prefrontal cortex 5,8,[13][14][15] , motor cortex 10,16,17 , striatum 2,5,8,10,[18][19][20] , hippocampus 6,7 , thalamus 21 , substantia nigra pars compacta 22 , among others. Active manipulations of the physiological activity have also helped assess the involvement of these areas in timing, particularly in the medial prefrontal cortex 5,[22][23][24] and striatum 20 . However, because timing tasks usually require many training sessions, the neurophysiological process underlying their acquisition has been less studied.…”

Neural Correlates of Interval Timing Deficits in Schizophrenia

“…Functional magnetic resonance imaging (fMRI) studies indicate greater activation in the DLPFC in healthy participants during timing tasks (Rao et al, 2001; Hinton and Meck, 2004; Üstün et al, 2017). Additionally, the PFC is implicated in TP in animals, both in lesion studies (Buhusi et al, 2018), pharmacological studies (Matthews et al, 2012), and in animal models of SZ (Buhusi et al, 2013).…”