Role of Striatum in the Pause and Burst Generation in the Globus Pallidus of 6-OHDA-Treated Rats

Abstract

Electrophysiological studies in patients and animal models of Parkinson's disease (PD) often reported increased burst activity of neurons in the basal ganglia. Neurons in the globus pallidus external (GPe) segment in 6-hydroxydopamine (6-OHDA)-treated hemi-parkinsonian rats fire with strong bursts interrupted by pauses. The goal of this study was to evaluate the hypothesis that dopamine (DA)-depletion increases burst firings of striatal (Str) neurons projecting to the GPe and that the increased Str-GPe burst inputs play a significant role in the generation of pauses and bursts in GPe and its projection sites. To evaluate this hypothesis, the unitary activity of Str and GPe was recorded from control and 6-OHDA-treated rats anesthetized with 0.5-1% isoflurane. The occurrence of pauses and bursts in the firings of GPe neurons was significantly higher in 6-OHDA than in normal rats. Muscimol injection into the Str of 6-OHDA rats increased average firing rate and greatly reduced the pauses and bursts in GPe. Recordings from Str revealed that most of the presumed projection neurons in control rats have very low spontaneous activity, and even the occasional neurons that did exhibit spontaneous burst firings did so with an average rate of less than 2 Hz. In DA-depleted Str, neurons having stronger bursts and a higher average firing rate were encountered more frequently. Juxtacellular labeling revealed that most of these neurons were medium spiny neurons projecting only to GPe. Injection of a behaviorally effective dose of methyl-l-DOPA into the Str of 6-OHDA rats significantly increased the average firing rate and decreased the number of pauses of GPe neurons. These data validate the hypothesis that DA-depletion increases burst firings of Str neurons projecting to the GPe and that the increased Str-GPe burst inputs play a significant role in the generation of pauses and bursts in GPe. These results suggest that treatment to reduce burst Str-GPe inhibitory inputs may help to restore some PD disabilities.

Keywords: basal ganglia; burst; dopamine depletion; firing pattern; globus pallidus; pauses; striatum; unitary activity.

Figure 1

Spontaneous firing patterns of a GPe neuron from a control (A–C) and from a 6-OHDA rat (D–F) having similar average firing rates. In (A,D), actual digitized spikes are shown in red. Blue phantom spikes occupying pauses have an inter-spike-interval equal to the mean inter-spike-intervals of actual spikes. The phantom spikes were used for the detection of pauses (details in the section Materials and Methods). Autocorrelograms (B,E) and spike interval histograms (C,F) show that the neuron from the 6-OHDA rat has a larger peak at shorter inter-spike-intervals.

Figure 2

Spontaneous firing patterns of a GPe neuron from a 6-OHDA rat before (A–D) and after (E–H) intra-Str injection of muscimol (0.04 μg in 0.2 μl saline). (A,E): Digitized spikes show that muscimol injection increased the average firing rate, decreased the pauses, and decreased the burst index of the GPe neuron. (B,F): Fourier analysis shows a decrease in the power density of the less than 3 Hz components after muscimol injection. Power is indicated as a fraction of the total power in the 0 to 50-Hz band. Autocorrelograms (C,G) and spike interval histograms (D,H) show that muscimol did not abolish the high frequency firing components having a peak of inter-spike-interval distributions at ≈18 ms. The cumulative interval graphs show that the fraction of total time occupied by short intervals increased after the intra-Str muscimol injection.

Figure 3

Spontaneous firing patterns of a Str neuron from a control (A–C) and from a 6-OHDA rat (D–F). (A,D): digitized spikes show groups of firings with very high burst indices in both neurons from the control and from the 6-OHDA Str. Spike interval histograms (C,F) show that the neurons from both rats have similar shorter inter-spike-interval distributions.

Figure 4

An example of juxtacellulary stained spontaneously active Str neurons. (A): Photomontage shows a medium spiny neuron. (B): A camera lucida drawing of the axonal arbor of the neuron in GPe.

Figure 5

Spontaneous firing patterns of a GPe neuron from a 6-OHDA rate before (A–D) and after (E–H) intra-Str injection of methyl-l-DOPA (4 μg in 0.2 μl saline, 0.04 μl/min). (A,E): Digitized spikes show that methyl-l-DOPA increased the average firing rate, decreased the pauses, and decreased the burst index of the GPe neuron after the injection. (B,F): Fourier analysis shows a decrease in the power density of the less than 3 Hz components after injection. Autocorrelograms (C,G) and spike interval histograms (D,H) show that methyl-l-DOPA did not abolish the high frequency firing components. The cumulative interval graphs show that the fraction of total time occupied by short intervals increased after the intra-Str methyl-l-DOPA injection.