Cortical stimulation evokes abnormal responses in the dopamine-depleted rat basal ganglia

Abstract

The motor cortex (MC) sends massive projections to the basal ganglia. Motor disabilities in patients and animal models of Parkinson's disease (PD) may be caused by dopamine (DA)-depleted basal ganglia that abnormally process the information originating from MC. To study how DA depletion alters signal transfer in the basal ganglia, MC stimulation-induced (MC-induced) unitary responses were recorded from the basal ganglia of control and 6-hydroxydopamine-treated hemi-parkinsonian rats anesthetized with isoflurane. This report describes new findings about how DA depletion alters MC-induced responses. MC stimulation evokes an excitation in normally quiescent striatal (Str) neurons projecting to the globus pallidus external segment (GPe). After DA-depletion, the spontaneous firing of Str-GPe neurons increases, and MC stimulation evokes a shorter latency excitation followed by a long-lasting inhibition that was invisible under normal conditions. The increased firing activity and the newly exposed long inhibition generate tonic inhibition and a disfacilitation in GPe. The disfacilitation in GPe is then amplified in basal ganglia circuitry and generates a powerful long inhibition in the basal ganglia output nucleus, the globus pallidus internal segment. Intra-Str injections of a behaviorally effective dose of DA precursor l-3,4-dihydroxyphenylalanine effectively reversed these changes. These newly observed mechanisms also support the generation of pauses and burst activity commonly observed in the basal ganglia of parkinsonian subjects. These results suggest that the generation of abnormal response sequences in the basal ganglia contributes to the development of motor disabilities in PD and that intra-Str DA supplements effectively suppress abnormal signal transfer.

Figure 1.

A, An x-ray image shows a pair of stimulus electrodes in the motor cortex (MC stim.) and in the striatum (Str stim.), a reference (Ref.) electrode in the lateral ventricle, a recording electrode in the STN, two silver balls for electrocorticogram recording, and a ground wire located lateral to the right parietal bone. Some anatomical landmarks are also labeled. The results of Str stimulation were not included in this report. B, A photomicrograph of a Nissl-stained sagittal section shows a lesion mark in STN. ZI, Zona incerta; ic, internal capsule; ot, optic tract. C, A schematic presentation of typical MC-induced response components in the globus pallidus and STN. The heavy line and two dotted lines mark the prestimulus mean firing rate and 95% confidence interval, respectively. The short duration responses shown in the drawing exceed the confidence interval. The long inhibition and the slow excitation exceed 50% of the prestimulus mean firing rate. The dark gray area of each response component marks the latency, the duration, and the strength (i.e., the numbers of spikes that fill the area). The slow excitation was not quantified in this report.

Figure 2.

MC-induced responses in GPe. A, B, Population PSTHs of two major response patterns obtained in control rats. In these and subsequent figures, population PSTH (i.e., average PSTH of multiple neurons) was constructed from 100 stimulation trials. The bin width of PSTHs is 1 ms unless otherwise noted, and MC stimulation was given at time = 0 (arrow). The response pattern, the number of neurons included in each population PSTH, and the average prestimulus firing frequency with 95% confidence interval (solid line and dashed lines) are shown in each figure. Ex., Excitation; Inh., inhibition. C, D, Population responses of two major response patterns obtained in 6-OHDA rats. Ex., Excitation; Inh., inhibition. E, Population PSTHs of all MC-responsive GPe neurons in control and 6-OHDA rats. The green PSTH shows the delta between the control and 6-OHDA PSTHs. F, A population PSTH of neurons that responded with an early excitation, a short inhibition, and a late excitation in 6-OHDA rats after injection of CPP, an NMDA antagonist, into the recording sites. For comparison, the same PSTH (in green) shown in C is scaled to have the same prestimulus firing rate and overlaid.

Figure 3.

MC-induced responses in STN. A, B, Population PSTHs of two major response patterns obtained in control rats. C–E, Population PSTHs of three major response patterns obtained in 6-OHDA rats. The neurons showing a long inhibition alone were observed only in 6-OHDA rats. Ex., Excitation; Inh., inhibition. F, Population PSTHs of all MC-responsive STN neurons in control and 6-OHDA rats. The green PSTH shows the delta between the control and 6-OHDA PSTHs.

Figure 4.

MC-induced responses in Str. A, A population PSTH shows MC-induced excitatory response of 23 Str neurons in control rats. B, A PSTH shows a population PSTH constructed from 20 spontaneously active Str neurons recorded in 6-OHDA rats. The response consisted of an excitation, a long inhibition, and a slow excitation. The latency of these excitations was significantly shorter than in the controls.

Figure 5.

A, Population PSTHs compare MC-induced responses of six GPe neurons in 6-OHDA rats recorded before and after intra-Str injection of muscimol. Neurons responding with an early excitation, a short inhibition, and a late excitation to MC stimulation were selected for the experiment. A, D, The bin width of the PSTHs is 4 ms and the green PSTH shows the delta of the before and after PSTHs. B, C, Behavioral effects of intra-Str injection of methyl l-DOPA. Methyl l-DOPA altered the preferred turning direction from left to right and increased the total distance of ambulation of two 6-OHDA rats (a and b are before and a+ and b+ are after the injection.) D, Population PSTHs of six GPe neurons that responded with an early excitation, a short inhibition, and a late excitation to MC stimulation in 6-OHDA rats recorded before and after intra-Str injection of methyl l-DOPA.

Figure 6.

MC-induced responses in GPi. A, B, Population PSTHs of two major response patterns obtained in control rats. C, D, Population PSTHs of two major response patterns obtained in 6-OHDA rats. A majority of GPi neurons recoded from 6-OHDA rats did not show the short inhibition but had a prominent long inhibition (C). The neurons showing only a long inhibition were observed in 6-OHDA rats but not in control rats (D). Ex., Excitation; Inh., inhibition. E, Population PSTHs of all MC responsive GPi neurons in control and 6-OHDA rats. E, F, The green PSTH shows the delta between the control and 6-OHDA PSTHs. F, Population PSTHs of six GPi neurons that responded with an early excitation and a long inhibition to MC stimulation in 6-OHDA rats recorded before and after intra-Str injection of methyl l-DOPA. The bin width of the PSTHs in F is 4 ms.

Figure 7.

A, B, Diagrams show major synaptic connections from MC to GPi and a summary of observations from the present study. The connections are based on the data obtained in previous studies (for review, see Kita, 1994, 2007). MC provides strong inputs to Str and STN. In the control group, MC stimulation induces a shorter latency excitation in STN compared with Str due to the unique membrane properties of STN neurons (Farries et al., 2010). The early excitation in STN evokes an early excitation in GPe and GPi before the Str-mediated inhibition begins. The MC-induced excitation in Str neurons projecting to GPi has a longer duration than that in Str neurons projecting to GPe under normal conditions (Flores-Barrera et al., 2010). The late excitation in STN, which may be formed by various forces, drives the late excitation in GPe and GPi. B, In 6-OHDA rats, MC-induced excitation in Str neurons projecting to GPi decreased (Flores-Barrera et al., 2010). Also, spontaneous firing of Str neurons projecting to GPe increased, which induced a tonic inhibition and disinhibition in GPe neurons. The mean latency of the excitation evoked in those neurons was significantly shorter than in the control group and, as a consequence, the early excitation in GPe was reduced. These changes produce a cascade of changes in GPe and GPi. The short inhibition in GPi was almost abolished after DA depletion, and the mechanisms driving this change are still under investigation.