Organizing behavior in time is a fundamental process that is highly conserved across species. Here we study the neural basis of timing processes. First, we found that rodents had a burst of stimulus-triggered 4 Hz oscillations in the medial frontal cortex (MFC) during interval timing tasks. Second, rodents with focally disrupted MFC D 1 dopamine receptor (D1DR) signaling had impaired interval timing performance and weaker stimulus-triggered oscillations. Prior work has demonstrated that MFC neurons ramp during interval timing, suggesting that they underlie temporal integration. We found that MFC D1DR blockade strongly attenuated ramping activity of MFC neurons that correlated with behavior. These macro-and micro-level phenomena were linked, as we observed that MFC neurons with strong ramping activity tended to be coherent with stimulus-triggered 4 Hz oscillations, and this relationship was diminished with MFC D1DR blockade. These data provide evidence demonstrating how D1DR signaling controls the temporal organization of mammalian behavior.

Summary Disrupted mesocortical dopamine contributes to cognitive symptoms of Parkinson’s disease (PD). Past work has implicated medial frontal neurons expressing D1 dopamine receptors (D1DRs) in temporal processing. Here, we investigate if these neurons can compensate for behavioral deficits resulting from midbrain dopamine dysfunction. We report three main results. First, both PD patients and mice with ventral tegmental area (VTA) dopamine depletion had attenuated delta activity (1–4 Hz) in the medial frontal cortex (MFC) during interval timing. Second, we found that optogenetically stimulating MFC D1DR neurons could increase ramping activity among MFC neurons. Finally, stimulating MFC D1DR neurons specifically at delta frequencies (2 Hz) compensated for deficits in temporal control of action caused by VTA dopamine depletion. Our results suggest that cortical networks can be targeted by frequency-specific brain stimulation to improve dopamine-dependent cognitive processing.

Parker KL, Chen KH, Kingyon JR, Cavanagh JF, Narayanan NS. Medial frontal ϳ4-Hz activity in humans and rodents is attenuated in PD patients and in rodents with cortical dopamine depletion. J Neurophysiol 114: 1310 -1320, 2015. First published July 1, 2015; doi:10.1152/jn.00412.2015.-The temporal control of action is a highly conserved and critical mammalian behavior. Here, we investigate the neuronal basis of this process using an interval timing task. In rats and humans, instructional timing cues triggered spectral power across delta and theta bands (2-6 Hz) from the medial frontal cortex (MFC). Humans and rodents with dysfunctional dopamine have impaired interval timing, and we found that both humans with Parkinson's disease (PD) and rodents with local MFC dopamine depletion had attenuated delta and theta activity. In rodents, spectral activity in this range could functionally couple single MFC neurons involved in temporal processing. Without MFC dopamine, these neurons had less functional coupling with delta/theta activity and less temporal processing. Finally, in humans this 2-to 6-Hz activity was correlated with executive function in matched controls but not in PD patients. Collectively, these findings suggest that cue-evoked low-frequency rhythms could be a clinically important biomarker of PD that is translatable to rodent models, facilitating mechanistic inquiry and the development of neurophysiological biomarkers for human disease. medial frontal cortex; dopamine; Parkinson's disease; interval timing TEMPORAL CONTROL OF action, or guiding movements in time to achieve behavioral goals, is a crucial function of mammalian nervous systems. This process depends on the integrated activity of corticostriatal systems (Buhusi and Meck 2005;Jahanshahi et al. 2010;Matell et al. 2003) and requires intact dopaminergic signaling (Drew et al. 2003). Patients with Parkinson's disease (PD) with depleted dopamine have dramatically impaired temporal control (Malapani et al. 1998). Despite these data, the neural circuitry influenced by dopamine during temporal computations is not understood.Here we study this issue in PD patients and in animal models by investigating the neural basis of an elementary cognitive task: interval timing. In this task, participants estimate an interval of several seconds as instructed by a cue. In the range of seconds, interval timing requires executive resources, such as working memory and attention to time (Brown 2006;Parker et al. 2013), and is consistently impaired in patients with PD (Buhusi and Meck 2005;Malapani et al. 1998;Merchant et al. 2008). Because this task is highly conserved across mammalian species (Buhusi and Meck 2005;Merchant et al. 2013), it can be rapidly trained in rodent models, facilitating mechanistic hypothesis testing (Drew et al. 2003;Narayanan et al. 2012).Controlling the timing of action requires the integrated activity of corticostriatal circuits (Hinton and Meck 2004;Matell and Meck 2004) that are dysfunctional in PD patients (Jahanshahi et al. 2010). Recent work...

Broca's area has long been implicated in sentence comprehension. Damage to this region is thought to be the central source of "agrammatic comprehension" in which performance is substantially worse (and near chance) on sentences with noncanonical word orders compared with canonical word order sentences (in English). This claim is supported by functional neuroimaging studies demonstrating greater activation in Broca's area for noncanonical versus canonical sentences. However, functional neuroimaging studies also have frequently implicated the anterior temporal lobe (ATL) in sentence processing more broadly, and recent lesion-symptom mapping studies have implicated the ATL and mid temporal regions in agrammatic comprehension. This study investigates these seemingly conflicting findings in 66 left-hemisphere patients with chronic focal cerebral damage. Patients completed two sentence comprehension measures, sentence-picture matching and plausibility judgments. Patients with damage including Broca's area (but excluding the temporal lobe; n = 11) on average did not exhibit the expected agrammatic comprehension pattern-for example, their performance was >80% on noncanonical sentences in the sentence-picture matching task. Patients with ATL damage ( n = 18) also did not exhibit an agrammatic comprehension pattern. Across our entire patient sample, the lesions of patients with agrammatic comprehension patterns in either task had maximal overlap in posterior superior temporal and inferior parietal regions. Using voxel-based lesion-symptom mapping, we find that lower performances on canonical and noncanonical sentences in each task are both associated with damage to a large left superior temporal-inferior parietal network including portions of the ATL, but not Broca's area. Notably, however, response bias in plausibility judgments was significantly associated with damage to inferior frontal cortex, including gray and white matter in Broca's area, suggesting that the contribution of Broca's area to sentence comprehension may be related to task-related cognitive demands.