Appetitive and aversive information coding in the primate dorsal raphé nucleus

Abstract

Serotonin is known to play a key role in the regulation of emotional behavior. There have been conflicting hypotheses about whether the central serotonergic system is involved in positive or negative emotional information processing. To reveal whether and how such opposing information processing can be achieved by single neurons in the dorsal raphé nucleus (DRN), the major source of serotonin in the forebrain, we recorded the activity of DRN neurons while monkeys were conditioned in a Pavlovian procedure with two distinct contexts: an appetitive block where a reward was available; and an aversive one where an airpuff was delivered. We found that single DRN neurons were involved in several aspects of both appetitive and aversive information processing. First, more than half of the recorded DRN neurons discriminated between appetitive and aversive contexts by tonic changes in their activity. In the appetitive context, they then kept track of the expected reward value indicated by the conditioned stimuli. Some of them also encoded an error between the obtained and expected values. In the aversive context, the same neurons maintained tonic modulation in their activity throughout the block. However, modulation of their responses to aversive task events depending on airpuff probability was less common. Together, these results indicate that single DRN neurons encode both appetitive and aversive information, but over differing time scales: relatively shorter for appetitive, and longer for aversive. Such temporally distinct processes of value coding in the DRN may provide the neural basis of emotional information processing in different contexts.

Keywords: Pavlovian conditioning; dorsal raphé nucleus; monkey; serotonin; single-unit recording.

Figure 1.

Behavioral task and location of the DRN. A, Pavlovian trace-conditioning task with two different blocks. B, Experimental procedure. Once a neuron was isolated, either an appetitive or aversive block (in this example, appetitive) started. After the block was completed, there was a delay of several minutes, and the next block (in this example, aversive) started. The baseline activity of the neuron was defined as the mean firing rate during the 500 ms before the initiation of the appetitive and aversive blocks. C, Average normalized frequencies of behavioral responses in monkey H. The orange lines indicate licking, and the green lines indicate blinking. Shaded areas indicate the SEM. D, Average normalized magnitudes of anticipatory licking and blinking during the late trace period (500 ms before US presentation) in monkey H (top) and monkey S (bottom). Asterisks indicate a significant difference between two points (*p < 0.05, **p < 0.01 after Bonferroni correction). Error bars indicate the SEM. E, Location of the recording chambers targeting the DRN drawn on parasagittal MR images for both monkeys. F, Histological reconstruction of the recording sites on Nissl-stained sections (monkey S). The thick arrows indicate electrode penetration. The small arrows indicate microlesions made after recording from a neuron. The two sections are 450 μm apart. The border of the DRN was drawn based on the study by Molliver (1987). MLF, Medial longitudinal fasciculus; PAG, periaqueductal gray; IV, trochlear nucleus.

Figure 2.

Activity of DRN neurons in the appetitive and aversive blocks. Action potentials are shown by raster plots in the chronological order of each trial type. The changes in firing rate are shown by the perievent histograms smoothed with a Gaussian kernel (δ = 5 ms, width = 5 δ). For each trial type, the data are aligned to CS onset or to outcome onset. The activities on the reward, tone, and airpuff trials are shown in blue, purple, and red, respectively. In the raster, tone trials are shaded in purple. A, This neuron showed stronger tonic activity during the ITI and TC periods of the appetitive block than of the aversive block. It also exhibited a stronger response to the 100% reward CS than to the 50% and 0% reward CSs. B, This neuron showed stronger tonic activity during the ITI and TC periods of the aversive block than of the appetitive block. It also exhibited a stronger inhibition to the 100% reward CS than to the 50% and 0% reward CSs. C, This neuron showed modulation in the CS response by outcome probability in both the appetitive and aversive blocks.

Figure 3.

Context-dependent modulation during the ITI and TC periods. A, The distribution histogram of the ROC areas comparing TC activity in the appetitive and aversive blocks. The area under the ROC of >0.5 indicates that TC activity was stronger in the appetitive block than in the aversive block. Neurons were sorted into the following three categories based on significant block discrimination during the TC period (p < 0.05): appetitive block preference (blue); aversive block preference (red); and no preference (white). B, The differences in activity between the appetitive and aversive blocks during the ITI and TC periods were positively correlated. C–E, The differences in ITI and TC activities were consistent regardless of the preceding outcomes (i.e., after rewards, tones, or airpuffs). Average normalized ITI and TC activities of neurons with aversive block preference (C), no preference (D), and appetitive block preference (E) during the TC period are shown separately for the appetitive and aversive blocks. The data are further separated depending on the outcomes in the preceding trials. F–H, Proportions of neurons exhibiting significant modulations in ITI and TC activities depending on previous outcomes in the appetitive and aversive blocks.

Figure 4.

Trial-by-trial changes in context-dependent modulation of ITI activity. A, B, Averaged (±SEM) ITI activity relative to the baseline before the initiation of the block (therefore, the data of the first trial were zero) for neurons with aversive block preference (A) and appetitive block preference (B) in TC activity is shown separately for the appetitive (blue) and aversive (red) blocks. Data were smoothed by 3-point averaging except on the first trial. C, An example neuron from B. The raster plots show ITI, TC, and CS activities during the first 15 trials including all trial types in the appetitive (blue) and aversive (red) blocks.

Figure 5.

Responses to CSs. A, Average normalized activity of 60 neurons that exhibited positive correlations between reward probability and CS response (p < 0.05). Histograms are shown for 100% (blue), 50% (cyan), and 0% (gray) reward CSs. B, The magnitudes of the mean (±SEM) responses of the positive reward CS coding neurons. Asterisks indicate significant differences between responses to two CSs (*p < 0.05, **p < 0.01 after Bonferroni correction). C, D, Same as A and B, but of 55 negative reward CS coding neurons. E, F, Averaged activity of 12 positive airpuff CS coding neurons. Histograms are shown for 100% (red), 50% (pink), and 0% (gray) airpuff CSs. G, H, Same as E and F, but of 12 negative airpuff CS coding neurons. I, Correlation coefficients between the outcome probability (i.e., 0%, 50%, and 100%) and CS responses. The abscissa indicates the correlation coefficient between reward probability and CS response. The ordinate indicates the correlation coefficient between airpuff probability and CS response. The open circles, squares, and black dots indicate neuronal responses with a statistically significant correlation with reward probability only, airpuff probability only, and both, respectively (p < 0.05); gray dots are neurons with no significant correlations. The marginal histograms show the distributions of the correlation coefficients. The white and black bars indicate neurons with a statistically significant correlation for reward or airpuff probability only and both, respectively. The gray bars indicate no significant correlation.

Figure 6.

Correlated modulation of TC activity and CS responses. A, Significant correlation between CS discrimination and changes in TC activity relative to ITI activity in the appetitive block. The blue and red dots and open circles indicate neurons with appetitive and aversive block preferences or no preferences in TC activity, respectively. B, Same as A, but in the aversive block. There were no significant correlations between CS discrimination and changes in TC activity.

Figure 7.

Responses to USs. A, Proportions of neurons that showed significant changes in excitatory (white) or inhibitory (gray) responses to the USs and tones relative to the preceding trace period activity (p < 0.05). The data are shown separately for outcome predictability (i.e., 100%, 50%, and 0%) in the appetitive (left) and aversive (right) blocks. B, The directions of changes in the response to free rewards and airpuffs were the same for many neurons. C, Changes in the US response by the preceding CS. The abscissa indicates the correlation coefficient between the reward predictability implied by appetitive CSs and the reward response. The ordinate indicates the correlation coefficient between the airpuff predictability implied by aversive CSs and the airpuff response. The open circles, squares, and black dots indicate neurons with a statistically significant correlation for the appetitive block only, aversive block only, and both, respectively (p < 0.05); gray dots are neurons with no significant correlations. The marginal histograms show the distributions of the correlation coefficients. The white and black bars indicate neurons with statistically significant correlations for reward or airpuff only and for both, respectively. The gray bars indicate no significant correlation.

Figure 8.

Responses to reward omission. A, B, Average normalized activity of neurons whose response to the omission of an expected reward (i.e., a tone in the 50% reward trials) was significantly more (A) or less (B) than the immediately preceding trace period activity and significantly different from the response to a free tone in the appetitive block (p < 0.05). The three columns on the left show activity in the appetitive block; those on the right show activity in the aversive block. For each, the data are aligned to CS onset (left), reward or airpuff onset (middle), and tone onset (right).