Electrophysiological Characteristics of Globus Pallidus Neurons

Extracellular recordings in primates have identified two types of neurons in the external segment of the globus pallidus (GPe): high frequency pausers (HFP) and low frequency bursters (LFB). The aim of the current study was to test whether the properties of HFP and LFB neurons recorded extracellularly in the primate GPe are linked to cellular mechanisms underlying the generation of action potential (AP) firing. Thus, we recorded from primate and rat globus pallidus neurons. Extracellular recordings in primates revealed that in addition to differences in firing patterns the APs of neurons in these two groups have different widths (APex). To quantitatively investigate this difference and to explore the heterogeneity of pallidal neurons we carried out cell-attached and whole-cell recordings from acute slices of the rat globus pallidus (GP, the rodent homolog of the primate GPe), examining both spontaneous and evoked activity. Several parameters related to the extracellular activity were extracted in order to subdivide the population of recorded GP neurons into groups. Statistical analysis showed that the GP neurons in the rodents may be differentiated along six cellular parameters into three subgroups. Combining two of these groups allowed a better separation of the population along nine parameters. Four of these parameters (Fmax, APamp, APhw, and AHPs amplitude) form a subset, suggesting that one group of neurons may generate APs at significantly higher frequencies than the other group. This may suggest that the differences between the HFP and LFB neurons in the primate are related to fundamental underlying differences in their cellular properties

Dispersed Activity during Passive Movement in the Globus Pallidus of the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)-Treated Primate

Parkinson's disease is a neurodegenerative disorder manifesting in debilitating motor symptoms. This disorder is characterized by abnormal activity throughout the cortico-basal ganglia loop at both the single neuron and network levels. Previous neurophysiological studies have suggested that the encoding of movement in the parkinsonian state involves correlated activity and synchronized firing patterns. In this study, we used multi-electrode recordings to directly explore the activity of neurons from the globus pallidus of parkinsonian primates during passive limb movements and to determine the extent to which they interact and synchronize. The vast majority (80/103) of the recorded pallidal neurons responded to periodic flexion-extension movements of the elbow. The response pattern was sinusoidal-like and the timing of the peak response of the neurons was uniformly distributed around the movement cycle. The interaction between the neuronal activities was analyzed for 123 simultaneously recorded pairs of neurons. Movement-based signal correlation values were diverse and their mean was not significantly different from zero, demonstrating that the neurons were not activated synchronously in response to movement. Additionally, the difference in the peak responses phase of pairs of neurons was uniformly distributed, showing their independent firing relative to the movement cycle. Our results indicate that despite the widely distributed activity in the globus pallidus of the parkinsonian primate, movement encoding is dispersed and independent rather than correlated and synchronized, thus contradicting current views that posit synchronous activation during Parkinson's disease

Movement and neuronal response quantification.

<p><b><i>A</i></b>, Illustration of the passive movement of the monkey's upper limb, indicating the displacement (x), velocity (v) and acceleration (a) values. <b><i>B</i></b>, Example of a raw accelerometer signal. Vertical dashed lines indicate the beginning and end of movement. <b><i>C</i></b>, Enlargement of the signal from <b><i>B</i></b> (black), overlaid with the filtered signal (blue) and the identification of the movement cycles (red asterisks). <b><i>D</i></b>,<b><i>E</i></b>, Movement peri-event-time-raster (top) and movement peri-event-time-histogram (mPETH) (bottom) of a GPe cell are presented using (<b><i>D</i></b>) The original duration of the movement cycles (marked by asterisks) and (<b><i>E</i></b>) scaled to 1 s cycle duration.</p

Single neuron movement encoding in the GP.

<p><b><i>A</i></b>, Mean firing rates (±SEM) of GPe (blue) and GPi (red) neurons during different parts of the experimental protocol. * p<0.001. <b><i>B</i></b>, Example of a raw spike train recorded from a GPi neuron during movement (black). The simultaneously recorded filtered accelerometer signal is superimposed (red). <b><i>C</i></b>, Example of a raster (top) and mPETH (bottom, blue) of a GPe cell. The red curve indicates the sine fit for the mPETH, and its parameters are shown (R² = 0.96): horizontal solid line indicates r₀, horizontal dashed line indicates the phase and vertical line indicates the amplitude. <b><i>D</i></b>, Compass plot of the sine fit phase (direction of arrow) and amplitude (length of the arrow) of all analyzed cells. <b><i>E</i></b>, Scatter plot of the firing rate prior to movement relative to the r₀. The regression lines are shown in solid lines, dashed line indicates equality line. In <b><i>D</i></b>,<b><i>E</i></b>, GPe neurons in blue, GPi neurons in red.</p

Interaction between pairs of pallidal neurons during movement.

<p><b><i>A</i></b>, Compass plot of interaction between responses to movement of all recorded pairs of neurons. Each arrow represents a pair of neurons: direction indicates the offset phase (Δθ) and length represents the multiplication of amplitudes of the sine fits (A1 and A2) on a logarithmic scale. <b><i>B</i></b>, Histogram of signal correlation. <b><i>C</i></b>, Histogram of noise correlation. Gray dashed lines in <b><i>B</i></b> and <b><i>C</i></b> indicate the mean value.</p

Histograms of several extracellular and intracellular properties of GP cells.

<p><b><i>A</i></b>, Half-width of the extracellular AP (AP_ex) calculated as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012001#pone-0012001-g004" target="_blank">figure 4</a>. <b><i>B</i></b>, Half-width of the intracellular AP (AP_in) calculated as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012001#pone-0012001-g004" target="_blank">figure 4</a>. <b><i>C</i></b>, The intracellular AP adaptation ratio calculated as the ratio between the amplitude of the last AP and that of the first AP in a train of APs generated by current injection. <b><i>D</i></b>, The slow phase of the AHP (AHP_s). AHP amplitude was measured from threshold. <b><i>E</i></b>, Sag of membrane potential induced by activation of I_h. Sag was calculated as the difference between the maximal deflection of the membrane potential following a hyperpolarizing step and the deflection at the end of the pulse. <b>F</b>, Maximal frequency calculated for each cell from F-I curves, similar to those in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0012001#pone-0012001-g006" target="_blank">figure 6</a>.</p

Extracellular properties of different cellular populations of the primate GPe.

<p><b>A</b>. Traces from representative neurons from the two major neuron types in the GPe: high frequency pauser (HFP–left) and low frequency burster (LFB–right), shown at long and short time scales (top, 1 s trace; bottom, 100 ms trace). <b>B</b>. Autocorrelation functions of the neurons in A (maximal offset ±1 s). <b>C</b>. Mean firing rate of the two groups. <b>D</b>. Mean ISI distribution coefficient of dispersion of the two groups. <b>E</b>. Mean spike shape of the neurons shown above (HFP–black, LFB–gray). <b>F</b>. Mean spike duration of the two groups, Error bars indicate SEM, ** p≪0.01 Mann-Whitney U-test.</p

Representative intracellular and extracellular APs.

<p><b>A</b>, Spontaneous AP recorded in the whole-cell mode superimposed at an extended time scale for each cell type ( ─ type A; ─ type B; ─ type C). <b>B</b>, Spontaneous AP recorded in cell-attached mode superimposed at an extended time scale for each cell type (─ type A; ─ type B; ─ type C).</p

The width of the intracellular AP can be extracted from extracellular recordings.

<p><b>A</b>, The intracellular AP recorded in the whole-cell mode (top trace) and the transmembrane current recorded in the cell-attached mode (bottom trace, black line). The first derivative of the intracellular trace is superimposed on the extracellular trace (bottom trace, gray line). The half-width of the intracellular AP is indicated by the horizontal line. The vertical lines locate the half-width of the intracellular AP on the extracellular trace. <b>B</b>, Correlation between the half-width of the extracellular and intracellular recordings of the AP for all neurons recorded (n = 76). <b>C</b>, Distribution of the intracellular AP half-width for all neurons recorded. <b>D</b>, Distribution of the extracellular AP half-width for all neurons recorded.</p

Representative recordings from GP neurons of three visually separated subgroups.

<p><i>Ai</i>, <i>Bi</i>, and <i>Ci</i>, responses of GP cells to depolarizing current steps (50 pA increment, 600 ms) applied from 0 to 550 pA using whole-cell configuration of the patch-clamp technique. Representative membrane potentials recorded in response to 100 pA are given for each cell type. Sampled at 20 kHz and filtered at 10 kHz. <i>Aii</i>, <i>Bii</i>, and <i>Cii</i>, responses of GP cells to hyperpolarizing current steps applied from 0 to −450 pA (50 pA increment, 600 ms) using the whole-cell configuration of the patch-clamp technique.</p