Dopamine (DA) is a well established modulator of prefrontal cortex (PFC) function, yet the cellular mechanisms by which DA exerts its effects in this region are controversial. A major point of contention is the consequence of D 1 DA receptor activation. Several studies have argued that D 1 receptors enhance the excitability of PFC pyramidal neurons by augmenting voltagedependent Na ϩ currents, particularly persistent Na ϩ currents. However, this conjecture is based on indirect evidence. To provide a direct test of this hypothesis, we combined voltageclamp studies of acutely isolated layer V-VI prefrontal pyramidal neurons with single-cell RT-PCR profiling. Contrary to prediction, the activation of D 1 or D 5 DA receptors consistently suppressed rapidly inactivating Na ϩ currents in identified corticostriatal pyramidal neurons. This modulation was attenuated by a D 1 /D 5 receptor antagonist, mimicked by a cAMP analog, and blocked by a protein kinase A (PKA) inhibitor. In the same cells the persistent component of the Na ϩ current was unaffected by D 1 /D 5 receptor activation-suggesting that rapidly inactivating and persistent Na ϩ currents arise in part from different channels. Single-cell RT-PCR profiling showed that pyramidal neurons coexpressed three ␣-subunit mRNAs (Nav1.1, 1.2, and 1.6) that code for the Na ϩ channel pore. In neurons from Nav1.6 null mice the persistent Na ϩ currents were significantly smaller than in wild-type neurons. Moreover, the residual persistent currents in these mutant neuronswhich are attributable to Nav1.1/1.2 channels-were reduced significantly by PKA activation. These results argue that D 1 /D 5 DA receptor activation reduces the rapidly inactivating component of Na ϩ current in PFC pyramidal neurons arising from Nav1.1/1.2 Na ϩ channels but does not modulate effectively the persistent component of the Na ϩ current that is attributable to Nav1.6 Na ϩ channels.

Cortico-basal ganglia-thalamocortical circuits are severely disrupted by the dopamine depletion of Parkinson's disease (PD), leading to pathologically exaggerated beta oscillations. Abnormal rhythms, found in several circuit nodes are correlated with movement impairments but their neural basis remains unclear. Here, we used dynamic causal modelling (DCM) and the 6-hydroxydopamine-lesioned rat model of PD to examine the effective connectivity underlying these spectral abnormalities. We acquired auto-spectral and cross-spectral measures of beta oscillations (10–35 Hz) from local field potential recordings made simultaneously in the frontal cortex, striatum, external globus pallidus (GPe) and subthalamic nucleus (STN), and used these data to optimise neurobiologically plausible models. Chronic dopamine depletion reorganised the cortico-basal ganglia-thalamocortical circuit, with increased effective connectivity in the pathway from cortex to STN and decreased connectivity from STN to GPe. Moreover, a contribution analysis of the Parkinsonian circuit distinguished between pathogenic and compensatory processes and revealed how effective connectivity along the indirect pathway acquired a strategic importance that underpins beta oscillations. In modelling excessive beta synchrony in PD, these findings provide a novel perspective on how altered connectivity in basal ganglia-thalamocortical circuits reflects a balance between pathogenesis and compensation, and predicts potential new therapeutic targets to overcome dysfunctional oscillations.

Striatal cholinergic interneurons are critical elements of the striatal circuitry controlling motor planning, movement, and associative learning. Intrastriatal release of dopamine and inhibition of interneuron activity is thought to be a critical link between behaviorally relevant events, such as reward, and alterations in striatal function. However, the mechanisms mediating this modulation are unclear. Using a combination of electrophysiological, molecular, and computational approaches, the studies reported here show that D 2 dopamine receptor modulation of Na ϩ currents underlying autonomous spiking contributes to a slowing of discharge rate, such as that seen in vivo. Four lines of evidence support this conclusion. First, D 2 receptor stimulation in tissue slices reduced the autonomous spiking in the presence of synaptic blockers. Second, in acutely isolated neurons, D 2 receptor activation led to a reduction in Na ϩ currents underlying pacemaking. The modulation was mediated by a protein kinase C-dependent enhancement of channel entry into a slow-inactivated state at depolarized potentials. Third, the sodium channel blocker TTX mimicked the effects of D 2 receptor agonists on pacemaking. Fourth, simulation of cholinergic interneuron pacemaking revealed that a modest increase in the entry of Na ϩ channels into the slowinactivated state was sufficient to account for the slowing of pacemaker discharge. These studies establish a cellular mechanism linking dopamine and the reduction in striatal cholinergic interneuron activity seen in the initial stages of associative learning.

The prelimbic-medial orbital areas (PL/MO) of the prefrontal cortex are connected to the medial part of the subthalamic nucleus (STN) through a direct projection and an indirect circuit that involves the core of the nucleus accumbens (NAcc) and the ventral pallidum (VP). In the present study, the influence of the PL/MO on the discharge of STN cells has been characterized. The major pattern of the responses observed after stimulation of PL/MO consisted of two excitatory peaks often separated by a brief inhibitory period. The early excitation was most likely to be caused by the activation of direct cortical inputs because its latency matches the conduction time of the prefrontal STN projections. The late excitation resulted from the activation of the indirect PL/MO-STN pathway that operates through a disinhibitory process. Indeed, the late excitation was no longer observed after acute blockade of the glutamatergic corticostriatal transmission by CNQX application into the NAcc. A similar effect was obtained after the blockade of the GABAergic striatopallidal transmission by bicuculline application into the VP. Finally, the brief inhibition that followed the early excitation was likely to result from the activation of a feedback inhibitory loop through VP because this inhibition was no longer observed after the blockade of STN inputs by CNQX application into the VP. This study further indicates the implication of STN in prefrontal basal ganglia circuits and underlines that in addition to a direct excitatory input, medial STN receives an indirect excitatory influence from PL/MO through an NAcc-VP-STN disinhibitory circuit. Key words: basal ganglia circuits; prefrontal cortex; subthalamic nucleus; ventral striatum; nucleus accumbens; ventral pallidum; in vivo single unit recordings; ratThe subthalamic nucleus (STN) is a major component of the basal ganglia, and its critical role in the control of movement is well established. Pathological damage to the STN in humans or STN lesions in monkeys induce hemiballism (Whittier, 1947;Carpenter et al., 1950;Crossman, 1987). In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys, an animal model of Parkinson's disease, abnormal activity of STN neurons has been observed, and lesions or high-frequency stimulation of the STN ameliorates akinesia and rigidity (Bergman et al., 1990;Benazzouz et al., 1993). High-frequency stimulation of the STN is now successf ully applied to improve akinesia and rigidity in Parkinsonian patients (Limousin et al., 1995).In current models of the basal ganglia circuitry, the striatum and the STN are the two major structures through which cortical signals are transmitted to the output structures of the basal ganglia, i.e., the substantia nigra pars reticulata (SN R) and the internal segment of the globus pallidus (GPi) (Alexander and Crutcher, 1990; Parent and Hazrati, 1995a,b). Indeed, both the striatum and the STN receive direct excitatory cortical inputs and send projections to the SN R and the GPi. Because the projection neurons of the stri...