Abstract
Prefrontal dysfunction is a common feature of brain diseases such as schizophrenia and contributes to deficits in executive functions, including working memory, attention, flexibility, inhibitory control, and timing of behaviors. Currently, few interventions improve prefrontal function. Here, we tested whether stimulating the axons of prefrontal neurons in the striatum could compensate for deficits in temporal processing related to prefrontal dysfunction. We used an interval-timing task that requires working memory for temporal rules and attention to the passage of time. Our previous work showed that inactivation of the medial frontal cortex (MFC) impairs interval timing and attenuates ramping activity, a key form of temporal processing in the dorsomedial striatum (DMS). We found that 20-Hz optogenetic stimulation of MFC axon terminals increased curvature of time-response histograms and improved interval-timing behavior. Furthermore, optogenetic stimulation of terminals modulated time-related ramping of medium spiny neurons in the striatum. These data suggest that corticostriatal stimulation can compensate for deficits caused by MFC inactivation and they imply that frontostriatal projections are sufficient for controlling responses in time.
Highlights
The prefrontal cortex is dysfunctional in psychiatric disorders such as schizophrenia[1,2] and neurodegenerative disorders such as Huntington’s disease and Parkinson’s disease[3,4]
We found that in animals in which the medial frontal cortex (MFC) was inactivated, stimulation of MFC → dorsomedial striatum (DMS) axons at 20 Hz—but not 2 Hz—could normalize the curvature of time-response histograms and shift response times during interval timing
We found that optogenetic stimulation of MFC → DMS axons interacted with DMS time-dependent ramping activity as a function of MFC inactivation, tending to increase the slope of DMS ramping activity with 20-Hz stimulation in MFC inactivation sessions
Summary
The prefrontal cortex is dysfunctional in psychiatric disorders such as schizophrenia[1,2] and neurodegenerative disorders such as Huntington’s disease and Parkinson’s disease[3,4]. 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 MFC → DMS axonal projections can compensate for deficits in temporal control of action as well as striatal temporal processing in animals with the MFC inactivated. We interpret our results in the context of top-down frontal control of striatal activity, which could be relevant for efforts to mitigate prefrontal dysfunction
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