Rodent Medial Frontal Control of Temporal Processing in the Dorsomedial Striatum

Abstract

Although frontostriatal circuits are critical for the temporal control of action, how time is encoded in frontostriatal circuits is unknown. We recorded from frontal and striatal neurons while rats engaged in interval timing, an elementary cognitive function that engages both areas. We report four main results. First, "ramping" activity, a monotonic change in neuronal firing rate across time, is observed throughout frontostriatal ensembles. Second, frontostriatal activity scales across multiple intervals. Third, striatal ramping neurons are correlated with activity of the medial frontal cortex. Finally, interval timing and striatal ramping activity are disrupted when the medial frontal cortex is inactivated. Our results support the view that striatal neurons integrate medial frontal activity and are consistent with drift-diffusion models of interval timing. This principle elucidates temporal processing in frontostriatal circuits and provides insight into how the medial frontal cortex exerts top-down control of cognitive processing in the striatum. The ability to guide actions in time is essential to mammalian behavior from rodents to humans. The prefrontal cortex and striatum are critically involved in temporal processing and share extensive neuronal connections, yet it remains unclear how these structures represent time. We studied these two brain areas in rodents performing interval-timing tasks and found that time-dependent "ramping" activity, a monotonic increase or decrease in neuronal activity, was a key temporal signal. Furthermore, we found that striatal ramping activity was correlated with and dependent upon medial frontal activity. These results provide insight into information-processing principles in frontostriatal circuits.

Corticostriatal stimulation compensates for medial frontal inactivation during interval timing

“…As in our past work, GLMM analyses revealed that DMS firing rates were affected by optogenetic stimulation (F = 8.3, p = 0.0003; see Table 2 for stats) and time in the interval (i.e., time-related ramping; F = 333.7, p = 1e -74 ). Of note, there was an interaction between MFC inactivation and firing rates over time (F = 35.6, p = 2e -9 ) 13 and between MFC inactivation and optogenetic stimulation of MFCàDMS axons (F = 5.5, p = 0.004, Table 2). Importantly, our model indicated that there was an interaction between time, optogenetic stimulation, and MFC inactivation (F = 11.4, p = 0.00001; Table 2).…”

“…In these rats, both sides of the MFC had been injected with AAV-CamKIIa-ChR2 (MFC-ChR2) and the animals had been implanted with bilateral MFC infusion cannulae and left DMS optrodes. After the rats were acclimatized to infusion and recording procedures, the MFC were bilaterally infused with either saline or the GABA A agonist muscimol, which reversibly and completely inactivates the MFC 13,24,25 .…”

“…Twelve male Long-Evans rats were trained on an interval-timing task as described in detail previously 13,25,35,45 . Briefly, animals were initially autoshaped to press a lever for water reward using a fixed-ratio task.…”

“…To answer this question, we used interval timing, which assesses the ability of subjects to estimate an interval of several seconds based on a motor response. Interval timing is a highly translational function because it involves both prefrontal and striatal regions in rodents as well as in humans and other primates [11][12][13][14] and the neuronal correlates in frontostriatal circuits are similar across species [15][16][17] . In addition, interval timing is relevant to our research question because it is reliably disrupted in human diseases that impair prefrontal function [16][17][18][19][20] .…”

“…A recent study from our group demonstrated that pharmacological inactivation of the rodent medial frontal cortex (MFC; dorsal prelimbic + anterior cingulate) 21,22 impaired interval timing and attenuated a key neuronal correlate of temporal processing in the dorsomedial striatum (DMS): time-related ramping activity 13,23 . These data indicate that temporal processing by DMS neurons requires input via MFC axons, and predict that stimulating MFCàDMS axon projections can compensate for deficits in temporal control of action as well as striatal temporal processing in animals with the MFC inactivated.…”