Pedunculopontine tegmental nucleus neurons provide reward, sensorimotor, and alerting signals to midbrain dopamine neurons

Abstract

Dopamine (DA) neurons in the midbrain are crucial for motivational control of behavior. However, recent studies suggest that signals transmitted by DA neurons are heterogeneous. This may reflect a wide range of inputs to DA neurons, but which signals are provided by which brain areas is still unclear. Here we focused on the pedunculopontine tegmental nucleus (PPTg) in macaque monkeys and characterized its inputs to DA neurons. Since the PPTg projects to many brain areas, it is crucial to identify PPTg neurons that project to DA neuron areas. For this purpose we used antidromic activation technique by electrically stimulating three locations (medial, central, lateral) in the substantia nigra pars compacta (SNc). We found SNc-projecting neurons mainly in the PPTg, and some in the cuneiform nucleus. Electrical stimulation in the SNc-projecting PPTg regions induced a burst of spikes in presumed DA neurons, suggesting that the PPTg-DA (SNc) connection is excitatory. Behavioral tasks and clinical tests showed that the SNc-projecting PPTg neurons encoded reward, sensorimotor and arousal/alerting signals. Importantly, reward-related PPTg neurons tended to project to the medial and central SNc, whereas sensorimotor/arousal/alerting-related PPTg neurons tended to project to the lateral SNc. Most reward-related signals were positively biased: excitation and inhibition when a better and worse reward was expected, respectively. These PPTg neurons tended to retain the reward value signal until after a reward outcome, representing 'value state'; this was different from DA neurons which show phasic signals representing 'value change'. Our data, together with previous studies, suggest that PPTg neurons send positive reward-related signals mainly to the medial-central SNc where DA neurons encode motivational values, and sensorimotor/arousal signals to the lateral SNc where DA neurons encode motivational salience.

Keywords: antidromic activation; cuneiform nucleus; monkey; reward value; salience; substantia nigra pars compacta.

Figure 1

Behavioral tasks. A. One-direction-rewarded saccade task (1DR). After an initial fixation in the center of the screen, a target appears on the left or right side and the monkey was required to make a saccade to it. A reward (juice) was delivered after the saccade to the left in one block of 24 trials and to the right in the other block of trials. These blocks were alternated. The distribution of saccade latencies in each block is shown below. B. Eight-direction visually guided saccade task. The saccade target appeared at one of the 8 locations. The amount of reward was the same among the 8 directions. C. Auditory passive listening task. It consisted of 20~35 tic sounds delivered every 0.5 sec (regular tics) and occasional odd tics. The tic sounds were sometimes (50%) followed by a beep sound or a tone with a juice.

Figure 2

The locations of the stimulating electrodes in the SNc. The tips of the three electrodes are visualized in Nissl-stained coronal sections: medial (A), central (B) and lateral (C) portions of the SNc. These sections were slightly separated from caudal (A) to rostral (C) directions by 1 mm (A–B) and 0.4 mm (B–C). D. The three electrode positions are projected to the middle section shown in B (orange lines). The bottom of each orange line indicates the stimulation site. Scale bars in A–D indicate 1 mm. E–G: Activity of presumed DA neurons recorded at the medial, central and lateral SNc, respectively, during 1DR task. The activity is shown separately for the rewarded (red) and non-rewarded (blue) trials. It is aligned at the onsets of the fixation point, target, and reward.

Figure 3

Examples of reward-coding PPTg neurons projecting to the SNc. A. Phasic type. This neuron was excited by the reward-predicting target (red) and inhibited by the no-reward-predicting target (blue), and did so in a phasic manner. The same convention as in Figure 2E–G. B. Antidromic activation of the neuron in A by the stimulation at the central SNc (threshold: 60 μA, latency: 2.1 ms). The antidromic spike was blocked when the stimulation was shortly followed by a spontaneous spike (bottom, collision test). C. Tonic type. The neuron also showed reward-related activity similarly, but did so in a tonic manner. D. Antidromic activation of the neuron in C by the stimulation at the lateral SNc (threshold: 100 μA, latency: 6.2 ms).

Figure 4

Activity of reward-related neurons in the PPTg area projecting to the SNc (n=16). They were classified into four types and the average activity is shown for each type: tonic positive type (A, n=9/16), phasic positive type (A, n=4/16), tonic negative type (C, n=1/16), and post-reward type (D, n=2/16). The same convention as in Figure 3.

Figure 5

An example of saccade-related PPTg neuron projecting to the SNc. A. The neuron’s activity is aligned on the onset of saccades, shown separately for the 8 directions. B. Antidromic activation of the neuron by the stimulation at the lateral SNc (threshold: 40 μA, latency: 2.4 ms).

Figure 6

Examples of sound-responsive neurons projecting to the SNc. A. This PPTg neuron responded to the beep sound and the tone with juice, but the responses habituated as the stimuli were repeated (shown by spike rasters arranged from bottom to top). B. Antidromic activation of the neuron in A by the stimulation at the lateral SNc (threshold: 200 μA, latency: 0.9 ms). C. This CuN neuron responded to all sounds with some habituation. D. Antidromic activation of the neuron in C by the stimulation at the lateral SNc (threshold: 200 μA, latency: 0.7 ms).

Figure 7

Orthodromic activation of presumed DA neurons by PPTg stimulation. Electrical stimulation (single pulse, 100 μA) was applied to the site where the reward-related neuron shown in Figure 4C was recorded. The electrode, which had been used for the antidromic activation of the PPTg neuron, was used for recording multi-unit activity of DA neurons. The DA neurons were excited by the PPTg stimulation.

Figure 8

Latency distribution of the antidromic activation of neurons in the PPTg area by the stimulation of the SNc.

Figure 9

Histologically reconstructed locations of SNc-projecting neurons in and around the PPTg (monkey Z). The locations of the neurons are projected to two Nissl-stained coronal sections in the central PPTg area (A and B). Section A is rostral to section B by 0.5 mm. Inset figure indicates the image of the whole section. Indicated for each neuron are 1) information encoded by the neuron (by color) and 2) the location of the antidromic activation site in the SNc (M, C, L). A marking lesion is visible in each of section A and B (orange arrow). SC (superior colliculus), IC (inferior colliculus), CuN (cuneiform nucleus), PAG (periaqueductal gray), PPTg (pedunculopontine tegmental nucleus), scp (superior cerebellar peduncle), mlf (medial longitudinal fasciculus). Scale bars indicate 1 mm.

Figure 10

Locations of antidromically activated PPTg/CuN neurons of monkey Z. The same figure as in Figure 9, but more detailed descriptions of the neural types are presented. Scale bar indicates 1 mm.

Figure 11

MRI-based reconstruction of the locations of SNc-projecting neurons in and around the PPTg (monkey R). The brain structures are reconstructed on the basis of an MR image of this monkey (inset figure) and histological sections in monkey Z (as shown in Figure 9). SC (superior colliculus), CuN (cuneiform nucleus), PAG (periaqueductal gray), PPTg (pedunculopontine tegmental nucleus), scp (superior cerebellar peduncle), mlf (medial longitudinal fasciculus), mcp (middle cerebellar peduncle). Scale bar indicates 2 mm.

Figure 12

Locations of antidromically activated PPTg neurons of monkey R. The same figure as in Figure 11 with a more detailed description of the neural types is presented. Scale bar indicates 2 mm.

Figure 13

Differential PPTg/CuN inputs to DA neurons in the SNc. PPTg/CuN neurons encoding reward value signals tend to project to the medial and central parts of the SNc. PPTg/CuN neurons encoding sensorimotor and arousal/alerting signals tend to project to the lateral and central parts of the SNc.