Negative reward signals from the lateral habenula to dopamine neurons are mediated by rostromedial tegmental nucleus in primates - PubMed (original) (raw)

Comparative Study

Negative reward signals from the lateral habenula to dopamine neurons are mediated by rostromedial tegmental nucleus in primates

Simon Hong et al. J Neurosci. 2011.

Abstract

Lateral habenula (LHb) neurons signal negative "reward-prediction errors" and inhibit midbrain dopamine (DA) neurons. Yet LHb neurons are largely glutamatergic, indicating that this inhibition may occur through an intermediate structure. Recent studies in rats have suggested a candidate for this role, the GABAergic rostromedial tegmental nucleus (RMTg), but this neural pathway has not yet been tested directly. We now show using electrophysiology and anatomic tracing that (1) the monkey has an inhibitory structure similar to the rat RMTg; (2) RMTg neurons receive excitatory input from the LHb, exhibit negative reward-prediction errors, and send axonal projections near DA soma; and (3) stimulating this structure inhibits DA neurons. Surprisingly, some RMTg neurons responded to reward cues earlier than the LHb, and carry "state-value" signals not found in DA neurons. Thus, our data suggest that the RMTg translates LHb reward-prediction errors (negative) into DA reward-prediction errors (positive), while transmitting additional motivational signals to non-DA networks.

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Figures

Figure 1.

Figure 1.

Neural recording configuration. A The MRI image of the brain section corresponding to the anatomical section in B. The white rectangular area on the upper right part of the brain is the recording chamber. The MRI chamber was filled with gadolinium to enhance its MRI image. The image is from monkey B. B, The schematic of our recording approach to the RMTg. The arrow indicates a representative path of the recording electrode. C, The gross anatomy of the circuit that we examined. STR, Striatum; GPb, border part of the globus pallidus; PN, pontine nuclei; SC, superior colliculus; IC, inferior colliculus; CC, corpus callosum.

Figure 2.

Figure 2.

Behavioral task and animals' task performance. A, Sequence of events in the 1DR version of the visually guided saccade task. The monkey first fixated at the central spot (the dotted circle indicates the eye position). As the fixation point disappeared, a target appeared randomly on the right or left and the monkey, was required to make a saccade to it immediately. Correct saccades in one direction were followed by a tone and juice reward; saccades in the other direction followed by a tone alone. The rewarded direction was fixed in a block of 24 trials and was changed in the subsequent block. B, Distribution of saccade latencies in rewarded trials (in red) and in unrewarded trials (in blue) (data from monkey B). Saccades in the first trials after the changes in position-reward contingency have been excluded.

Figure 3.

Figure 3.

Responses of representative LHb, RMTg, and DA neurons to target onset in the 1DR task. The averaged activity of each neuron, expressed as an SDF, is shown separately for the reward trials (red) and no-reward trials (blue) as the response to the onset of the left target (left) and the right target (right). The neurons were recorded from the left hemisphere.

Figure 4.

Figure 4.

Sample electrode penetration aimed at the RMTg. Spike activity was recorded from five neurons along the penetration. A, Reconstructed positions or neurons. B, Magnified part around the recording positions in A. For each neuron located from top to down, the activity in the 1DR task is shown on the left in C–G, separately for reward trials (red) and no-reward trials (blue). The neuronal activity is aligned at the time of the fixation point onset (left), target onset (center), and reward onset (right; gray vertical lines). The green lines indicate the time window used to quantify the neuronal response to the target onset (150–300 ms after target onset). The effect of the LHb electrical stimulation is shown on the right side for each neuron as a peristimulation time histogram (bin width, 1 ms). The stimulation current was 50μA for neurons in C–F, and 100 μA for neurons in G. 3N, Third nucleus; cp, cerebral peduncle; PN, pontine nuclei; NRTP, nucleus reticularis tegmenti pontis; ml, medial lemniscus; MGN, medial geniculate nucleus; scpx, superior cerebellar peduncle decussation; SN, substantia nigra.

Figure 5.

Figure 5.

A–H, Classification of RMTg neuron types. For each monkey (B and C), the averaged neuronal activity in the 1DR task is shown separately for reward-negative neurons (left) and reward-positive neurons (right). Each group of neurons is further classified into the change-of-value type (top) or the state value type (bottom). The neuronal activity is aligned at fixation point onset, target onset, and reward onset. The thin SDFs indicate the average activity in the first trials after the reversal of the position-reward contingency, while the thick SDFs indicate the average activity except for the first trials. The average activity is shown separately for the reward trials (red) and no-reward trials (blue).

Figure 6.

Figure 6.

Population activity of LHb and DA. A–D, Population responses of LHb neurons (monkey B, n = 14, A; monkey C, n = 16, C) and DA neurons (monkey B, n = 5, B; monkey C, n = 25, D). The SDFs are shown for each reward contingency (red, rewarded trials; blue, unrewarded trials). Thick SDFs indicate activity excluding the first trial in each block. Thin SDFs indicate the average activity of the first trial of the block. The two vertical green lines show the time window used to test these responses (reward positive or reward negative). The analysis in C contains some multiunit recordings.

Figure 7.

Figure 7.

Within-block changes of neural responses and behavioral (saccade) latencies. A–F, Changes in baseline subtracted averaged post-target responses (A, D), averaged reward on–off responses (B, E), and averaged saccade latency (C, F) after the reversal of position-reward contingency are shown. The data from two monkeys are shown separately (left half from monkey B, right half from monkey C). Red and blue lines indicate the data in rewarded and unrewarded trials, respectively. The data from ipsilateral and contralateral saccades are combined. Error bars indicate SEM. LHb data from monkey C contain some multiunit recordings.

Figure 8.

Figure 8.

Average spike wavelength, irregularity index, and mean baseline firing rate of different groups of neurons. Whereas most of RMTg neuron groups showed similar average spike width to that of LHb neurons, change-of-value reward-negative neurons had a slightly longer average spike width than LHb neurons (p < 0.05, ANOVA). The spike widths of DA neurons are significantly longer than those of LHb neurons (p < 0.01, ANOVA). Note that the scale of the abscissa for DA neurons' spike width is compressed. The absence of signals after 2 ms in some DA neuron spike shapes is due to changes in our recording settings. The width of the spike is defined as the time between the two negative peaks. The average irregularity in spike timing (IR) was smallest in DA neurons followed by LHb neurons. In the histograms for “All RMTg” and “All state value type RMTg,” different subclasses of the group are represented in different colors (positive, red; negative, blue; null, yellow).

Figure 9.

Figure 9.

Orthodromic responses along the LHb–RMTg–DA circuit. A–D, Averaged activity of a single neuron in each area during the 1DR task: an LHb neuron (A), a reward-negative RMTg neuron (B), a reward-positive RMTg neuron (C), and a DA neuron (D). E–H, Orthodromic responses. E, F, Response of the reward-negative RMTg neuron (B) to the electrical stimulation in the LHb. G, Response of the reward-positive RMTg neuron (C) to the stimulation in the LHb. H, Response of the DA neuron (D) to the stimulation in the RMTg. In F–H, the orthodromic responses are shown as peristimulus time histograms (bin width, 1 ms). In E, the orthodromic response to the LHb stimulation is shown as the actual voltage changes (negative, black; positive, white) associated with the extracellular action potentials of the reward-negative RMTg neuron (B). The yellow lightning bolt symbols in F–H indicate the stimulation site; the sharp needle shape indicates the recording site. I indicates the threshold current, and τ indicates the latency for the orthodromic response.

Figure 10.

Figure 10.

Antidromic responses along the LHb–RMTg–DA circuit. A–C, Averaged activity during the 1DR task for an LHb neuron (A), a reward-negative RMTg neuron (B), and a DA neuron (C). The same format as Figure 5 is used. D, Antidromic responses of the LHb neuron to the electrical stimulation in the RMTg. The stimulation was delivered with a fixed time delay after the spontaneous spike of the LHb neuron. Antidromic spikes occurred when the delay was long enough (top), but was blocked due to collision when the delay was shorter (bottom). E, Antidromic responses of the RMTg neuron to the stimulation in the SNc where the DA neuron (C) was recorded. Conversely, stimulation at the recording site of the RMTg neuron induced an inhibition in the DA neuron (F). Note that the CTB injection site shown in Figure 14 was aimed at the recording site of this DA neuron.

Figure 11.

Figure 11.

Estimated locations of the recorded neurons in the RMTg in monkey C. NRTP, Nucleus reticularis tegmenti pontis; ml, medial lemniscus; 3N, third nucleus; mlf, medial longitudinal fasciculus; PPTg, pedunculopontine tegmental nucleus; scpx, superior cerebellar peduncle decussation; MR, median raphe.

Figure 12.

Figure 12.

Neural latency of reward/no-reward discrimination. A–D, A time-varying proportion of neurons that showed significantly different activity between rewarded trials and unrewarded trials for the four neuron groups indicated above each figure. The horizontal gray line in each panel indicates the criterion level (p = 0.01). The red vertical bar and corresponding time in each panel is the time point of significant deviation from the background. Time 0 indicates target onset. For details, see Materials and Methods. E, Comparison of the reward-differential latency in different groups of neurons. The parts from 0 to 300 ms from each of the neural groups (A–D) are blown up and superimposed. The time point of significant deviation from the background for each group is indicated as a dot.

Figure 13.

Figure 13.

Identification of RMTg. A, The coronal brain slice showing the RMTg and other neighboring structures in the midbrain/pons. Note that some of the electrode tracts are visible on the top right part of the slice (arrow) approaching the target at about 35° angle. B, Magnified part of the brain section shown in A. This histology section shows two electrolytic marking lesions on the right side of the brain under the scpx (the two rightmost arrows). The lesions were made at the conclusion of the recording to demarcate the dorsal and ventral aspects of the RMTg along the recording tract. The leftmost arrows indicate the corresponding points of marks that are visible on a nearby slice shown in E and F. They have been projected onto this section. C, Estimated sites where we recorded RMTg neurons around slice 364 shown in B (the inset shows a magnified portion of the recording sites). We found numerous RMTg neurons responding to reward-related events under the scpx and beside the interpeduncular nucleus. Many of those neurons showed orthodromic responses to the stimulation in the LHb (stars). Some of them also showed antidromic responses to the stimulation in the SNc (2 black circles on the right side). Recording sites at two anterior–posterior levels separated by 1 mm have been combined. Marking lesion sites are indicated by arrows. D, Retrogradely labeled neurons after injection of CTB in the SNc. A cluster of retrogradely labeled neurons was found at the site of the RMTg. Another cluster of labeled neurons was found above the scpx close to the midline (arrowhead). See Figure 14 for the CTB injection site. E, In a section 0.75 mm posterior to that in A and B, two electrolytic marking lesions are visible on the left side of the brain (arrows). Scale bars: B–D, 1 mm. cp, Cerebral peduncle; ml, medial lemniscus; mlf, medial longitudinal fasciculus; MGN, medial geniculate nucleus; NRTP, nucleus reticularis tegmenti pontis; PN, pontine nuclei; 3N, third nucleus; IP, interpeduncular nucleus; scpx, superior cerebellar peduncle decussation; SN, substantia nigra.

Figure 14.

Figure 14.

A, Injection site of CTB in right substantia nigra (SN). The injection site is indicated by an arrow in the figure. The injection was aimed at the location where a DA neuron (Fig. 10_C_) was recorded in one of the previous recording sessions where we verified bidirectional connectivity between the RMTg and SNc (Fig. 10_E_,F). B, To further insure the accuracy of the injection, we first recorded spike activity of a putative DA neuron before injecting CTB. C, This was possible because we used an injection tube that was attached to a recording electrode. Some spreading of the CTB was detected along the injection cannula, but it was deemed not to affect the results. LGN, Lateral geniculate nucleus; cp, cerebral peduncle.

Figure 15.

Figure 15.

Speculative circuit diagram showing functional connectivity among subcortical motivation-related areas. “Change” indicates the change-of-value type, and “state” indicates the state-value type. For each of them, a minus sing indicates the reward-negative type and a plus sign indicates the reward-positive type. Excitatory connections are indicated by arrows; inhibitory connections are indicated by lines with filled circles. A dominant pathway is the border part of the globus pallidus (GPb)→LHb change(−)→RMTg change(−)→DA, because the reward-negative neurons were more numerous than the reward-positive type in the RMTg. The reward-positive RMTg neurons showed mixed responses (Table 1) in reaction to the stimulation in the LHb. This result can be explained if we assume two antagonizing connections to the reward-positive neuron: an excitatory input coming directly from the LHb and an inhibitory input from the RMTg change(−) type. We speculate that the state value signals originate partly from the VP and LHb. This is based on our unpublished observations that some neurons in the VP and some neurons in the more medial part of LHb represent state values, and these areas are considered to project to the RMTg. We also speculate that the state value RMTg neurons modulate 5-HT neurons in the DRN, because neurons in the DRN encode state values, and the RMTg is known to project to the DRN. VP RWD+, Ventral pallidum reward-positive neurons.

Figure 16.

Figure 16.

Speculative circuit diagram showing the functional connectivity in the basal ganglia and surrounding motivation-related areas. There are two functionally distinct motivation circuits, one for motor execution (matrix part of striatum→GPi→the motor thalamus or brainstem nuclei) and the other for reward evaluation (patch part of striatum→border part of the globus pallidus (GPb)→LHb→RMTg→DA). Excitatory, inhibitory, and modulatory connections are illustrated with arrow heads, filled circles, and half circles, respectively. The ellipsis indicates many known inputs to the RMTg whose functions have yet to be examined. For simplicity, some known connections, such as the projection from the nucleus accumbens to the VP and the projections of the VP to DA neurons and to the LHb, are omitted. STR, Striatum; N-RPE, negative reward prediction error; P-RPE, positive reward prediction error; D-Raphe, dorsal raphe.

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