In the subthalamic nucleus (STN) of Parkinson's disease (PD) patients, a pronounced synchronization of oscillatory activity at beta frequencies (15-30 Hz) accompanies movement difficulties. Abnormal beta oscillations and motor symptoms are concomitantly and acutely suppressed by dopaminergic therapies, suggesting that these inappropriate rhythms might also emerge acutely from disrupted dopamine transmission. The neural basis of these abnormal beta oscillations is unclear, and how they might compromise information processing, or how they arise, is unknown. Using a 6-hydroxydopamine-lesioned rodent model of PD, we demonstrate that beta oscillations are inappropriately exaggerated, compared with controls, in a brain-state-dependent manner after chronic dopamine loss. Exaggerated beta oscillations are expressed at the levels of single neurons and small neuronal ensembles, and are focally present and spatially distributed within STN. They are also expressed in synchronous population activities, as evinced by oscillatory local field potentials, in STN and cortex. Excessively synchronized beta oscillations reduce the information coding capacity of STN neuronal ensembles, which may contribute to parkinsonian motor impairment. Acute disruption of dopamine transmission in control animals with antagonists of D 1 /D 2 receptors did not exaggerate STN or cortical beta oscillations. Moreover, beta oscillations were not exaggerated until several days after 6-hydroxydopamine injections. Thus, contrary to predictions, abnormally amplified beta oscillations in cortico-STN circuits do not result simply from an acute absence of dopamine receptor stimulation, but are instead delayed sequelae of chronic dopamine depletion. Targeting the plastic processes underlying the delayed emergence of pathological beta oscillations after continuing dopaminergic dysfunction may offer considerable therapeutic promise.

Studies in dopamine-depleted rats indicate that the external globus pallidus (GPe) contains two main types of GABAergic projection cell; so-called "prototypic" and "arkypallidal" neurons. Here, we used correlative anatomical and electrophysiological approaches in rats to determine whether and how this dichotomous organization applies to the dopamine-intact GPe. Prototypic neurons coexpressed the transcription factors Nkx2-1 and Lhx6, comprised approximately two-thirds of all GPe neurons, and were the major GPe cell type innervating the subthalamic nucleus (STN). In contrast, arkypallidal neurons expressed the transcription factor FoxP2, constituted just over one-fourth of GPe neurons, and innervated the striatum but not STN. In anesthetized dopamine-intact rats, molecularly identified prototypic neurons fired at relatively high rates and with high regularity, regardless of brain state (slow-wave activity or spontaneous activation). On average, arkypallidal neurons fired at lower rates and regularities than prototypic neurons, and the two cell types could be further distinguished by the temporal coupling of their firing to ongoing cortical oscillations. Complementing the activity differences observed in vivo, the autonomous firing of identified arkypallidal neurons in vitro was slower and more variable than that of prototypic neurons, which tallied with arkypallidal neurons displaying lower amplitudes of a "persistent" sodium current important for such pacemaking. Arkypallidal neurons also exhibited weaker driven and rebound firing compared with prototypic neurons. In conclusion, our data support the concept that a dichotomous functional organization, as actioned by arkypallidal and prototypic neurons with specialized molecular, structural, and physiological properties, is fundamental to the operations of the dopamine-intact GPe.

Local field potentials (LFPs) recorded from the subthalamic nucleus (STN) of untreated patients implanted with stimulation electrodes for the treatment of Parkinson's disease (PD) demonstrate strong coherence with the cortical electroencephalogram over the beta-frequency range (15-30 Hz). However, studies in animal models of PD emphasize increased temporal coupling in cortico-basal ganglia circuits at substantially lower frequencies, undermining the potential usefulness of these models. Here we show that 6-hydroxydopamine (6-OHDA) lesions of midbrain dopamine neurons are associated with significant increases in the power and coherence of beta-frequency oscillatory activity present in LFPs recorded from frontal cortex and STN of awake rats, as compared with the healthy animal. Thus, the pattern of synchronization between population activity in the STN and cortex in the 6-OHDA-lesioned rodent model of PD closely parallels that seen in the parkinsonian human. The peak frequency of coherent activity in the beta-frequency range was increased in lesioned animals during periods of spontaneous and sustained movement. Furthermore, administration of the dopamine receptor agonist apomorphine to lesioned animals suppressed beta-frequency oscillations, and increased coherent activity at higher frequencies in the cortex and STN, before producing the rotational behaviour indicative of successful lesion. Taken together, these results support a crucial role for dopamine in the modulation of population activity in cortico-basal ganglia circuits, whereby dopaminergic mechanisms effectively filter out synchronized, rhythmic activity at beta-frequencies at the systems level, and shift temporal couplings in these circuits to higher frequencies. These changes may be important in regulating movement.