Primary motor cortex of the parkinsonian monkey: differential effects on the spontaneous activity of pyramidal tract-type neurons

Abstract

Dysfunction of primary motor cortex (M1) is thought to contribute to the pathophysiology of parkinsonism. What specific aspects of M1 function are abnormal remains uncertain, however. Moreover, few models consider the possibility that distinct cortical neuron subtypes may be affected differently. Those questions were addressed by studying the resting activity of intratelencephalic-type corticostriatal neurons (CSNs) and distant-projecting lamina 5b pyramidal-tract type neurons (PTNs) in the macaque M1 before and after the induction of parkinsonism by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Contrary to previous reports, the general population of M1 neurons (i.e., PTNs, CSNs, and unidentified neurons) showed reduced baseline firing rates following MPTP, attributable largely to a marked decrease in PTN firing rates. CSN firing rates were unmodified. Although burstiness and firing patterns remained constant in M1 neurons as a whole and CSNs in particular, PTNs became more bursty post-MPTP and less likely to fire in a regular-spiking pattern. Rhythmic spiking (found in PTNs predominantly) occurred at beta frequencies (14-32 Hz) more frequently following MPTP. These results indicate that MPTP intoxication induced distinct modifications in the activity of different M1 neuronal subtypes. The particular susceptibility of PTNs suggests that PTN dysfunction may be an important contributor to the pathophysiology of parkinsonian motor signs.

Figure 1.

(A) Surface map of electrode penetrations in M1. Separate maps are shown for each of the 3 cell types (CSN; PTNs; NA, not activated cells) in the 2 monkeys. The diameters of circles and crosses indicate the numbers of cells of each type sampled at each location in the normal state and after MPTP treatment, respectively. The maps were derived from photographs of the cortical surface taken after perfusion, histological sections, and the chamber locations for recording tracks. (B) Antidromic activation of M1 neurons from stimulating electrodes in the striatum (CSN) and peduncle (PTN). Antidromically elicited action potentials (*) occurred at a constant latency after stimulation (∇). Antidromic spikes collided (↓) with spontaneous spikes when stimulation was delivered after a spontaneous spike at any delay shorter that the cell’s antidromic latency plus the refractory period.

Figure 2.

Spike waveforms, raster diagrams, ISI histograms, and SDHs for 3 example M1 cells corresponding to a regular tonic discharge pattern (“top”), a random discharge pattern (“middle”), and a bursty discharge pattern (“bottom”). “Right column”: A cell’s discharge pattern was classified according to which of 3 reference functions fit the SDH best: a Gaussian distribution (“solid black”) for regular tonic; a Poisson distribution (mean = 1; “dashed gray”) for random; and a more skewed Poisson distribution (mean = 0.8; “dotted black”) for bursty.

Figure 3.

Task performance was impaired following MPTP administration. Kinematic measures (cross-session means ± standard error of the mean) from pre-MPTP (“black”) and post-MPTP (“gray”) periods for flexion and extension movements in the visuomotor step-tracking task. RTs, peak velocities (Vel_max), and movement amplitudes (Ampl) were compared between states (two-way ANOVA, MPTP × direction). ***Main effect of MPTP at P < 0.001. ###MPTP × direction interaction at P < 0.001.

Figure 4.

(A) Photomicrograph of a histologic section through the brainstem immunoreacted for TH (from monkey L). Compared with the control hemisphere (right), the studied hemisphere (left) displayed a severe loss of TH-positive neurons in the SNc. Subpanels on the right provide magnified views centered on the left and right SNc (top and bottom, respectively). The shaded line through the section marked by an asterisk reflects an artifact from histologic processing. (B) The density of TH-positive neurons in SNc of both hemispheres (control vs. MPTP) was estimated using unbiased stereological analysis.

Figure 5.

MPTP reduced baseline firing rates preferentially in PTNs. Frequency distributions and mean ± standard error of the mean comparisons of the spontaneous firing rates of M1 neurons in pre-MPTP (black) and post-MPTP (gray) states. Separate panels show results for all M1 cells (top), CSN (middle), and PTN (bottom). Horizontal box plots show the middle 2 quartiles of the firing rate distributions. The central white line within each box corresponds to the median value and horizontal “whiskers” outside each box show the extent of the overall distribution (excluding outliers). In the post-MPTP state, there was a significant decrease of the mean spontaneous firing rate for the general population of M1 neurons (*Mann–Whitney U-test, P < 0.05) and a much larger reduction for PTNs (***Mann–Whitney U-test, P < 0.001).

Figure 6.

MPTP altered the firing patterns of PTNs. The fraction of neurons that discharged with regular (white), random (gray), and burst (black) patterns did not change follow MPTP administration for the general population of M1 cells (top) or for CSNs (middle). For PTNs (bottom), the fraction of neurons firing in a regular pattern decreased significantly and cells firing in random or bursty patterns increased proportionately (*; χ² test, P < 0.05).

Figure 7.

PTNs fired action potentials in bursts more frequently following MPTP. Distributions and mean ± standard error of the mean comparisons of the percent of time in bursts of M1 neurons in the normal (black) and MPTP (gray) states. PTNs showed a significant increase in the percent of time in bursts following MPTP administration (*Mann–Whitney U-test, P < 0.05). The figure follows the conventions outlined for Figure 5.

Figure 8.

MPTP altered the magnitude and time course of burst discharges in PTNs. (A) Raster representation of typical M1 activity with bursts. (Example is from a PTN post-MPTP.) Black vertical ticks indicate times of individual action potentials. Horizontal red bars show times of bursts as determined by the Legendy surprise method. (B) Population averages of the burst-triggered mean frequency of firing (±95% confidence intervals) for CSNs and PTNs in normal (“black trace”) and MPTP (“red trace”) states. The mean instantaneous frequency of firing functions were aligned on burst onset times for all bursts detected by the Legendy surprise method. Mean preburst firing rates (between −300 and −100 ms) were subtracted from individual cell averages to aid comparison of the burst characteristics. Inset: P values from t-tests comparing pre- and post-MPTP periburst population averages bin-by-bin (1 ms). Green horizontal line: P = 0.05.

Figure 9.

Examples of rhythmic firing in 2 PTNs. Autocorrelation functions of the spike trains and power spectra illustrate the tendency of many PTNs to fire individual action potentials at regular ISIs, leading to significant peaks in the standard spectra (right, see Materials and Methods). Horizontal dashed line: threshold for statistical significance relative to the mean ± SD between 300 and 500 Hz.

Figure 10.

Rhythmically spiking cortical neurons were more likely to fire at beta frequencies following MPTP. Distributions of the preferred frequency of rhythmic firing in the general population of M1 neurons and in PTNs pre-MPTP (black) and post-MPTP (gray). Cumulative frequency distributions (bottom) illustrate the increased concentration of rhythmic frequencies in the beta frequency band (light-gray rectangle) following MPTP administration (*P < 0.05; Kolmogorov–Smirnov 2-sample test). Although this plot also appeared to show a post-MPTP increase in rhythmic firing at frequencies <13 Hz, the small number of cells (7 cells total) prevented reliable statistical tests of this possibility.