Reverse-filtering on extracellular action potential for waveform analysis.

For further understanding the role of serotonergic neurons, unit recordings using behaving primates are increasingly needed. A widely used criterion to identify serotonergic neuron relies on the duration of extracellular action potential (EAP). However, the duration is inaccurate due to the passband limitation needed to carry out the spike sorting. To restore an original waveform, we conducted 1) averaging the EAPs collected from the unfiltered raw signal and 2) reverse-filtering the EAPs collected from the filtered raw signal. The reconstructed waveforms by these analyses well agreed with each other, suggesting that either analysis is applicable to restore the EAPs. Even using multivariate analyses, the reconstructed EAPs in dorsal raphe (DR) could not be divided into different clusters possibly related to neurochemicals, suggesting that the DR neurons in the previous studies that relied on waveform criterion might contain both serotonergic and non-serotonergic neurons. Between DR and orbitofrontal cortex (OFC), there were no differences in the duration of filtered EAPs. However, against the conventional criterion, the duration of the first crest in the unfiltered / restored EAPs in DR that might contain serotonergic neurons was shorter than that in OFC. This raises a possibility that the conventional waveform criterion needs further consideration.

The effect of 5-HT1A receptor antagonist on reward-based decision-making.

When choosing the best action from several alternatives, we compare each value that depends on the balance between benefit and cost. Previous studies have shown that animals and humans with low brain serotonin (5-HT) level tend to choose smaller immediate reward. We used a decision-making schedule task to investigate whether 5-HT1A receptor is responsible for the decisions related to reward. In this task, the monkeys chose either of two different alternatives that were comprised of 1-4 drops of liquid reward (benefit) and 1-4 repeats of a color discrimination trial (workload cost), then executed the chosen schedule. By the administration of 5-HT1A antagonist, WAY100635, the choice tendency did not change, however, the sensitivity to the amount of reward in the schedule part was diminished. The 5-HT1A could have a role in maintaining reward value to keep track with the promised reward rather than modulating workload discounting of reward value.

Neurons in the monkey orbitofrontal cortex mediate reward value computation and decision-making.

Choice reflects the values of available alternatives; more valuable options are chosen more often than less valuable ones. Here we studied whether neuronal responses in orbitofrontal cortex (OFC) reflect the value difference between options, and whether there is a causal link between OFC neuronal activity and choice. Using a decision-making task where two visual stimuli were presented sequentially, each signifying a value, we showed that when the second stimulus appears many neurons encode the value difference between alternatives. Later when the choice occurs, that difference signal disappears and a signal indicating the chosen value emerges. Pharmacological inactivation of OFC neurons coding for choice-related values increases the monkey's latency to make a choice and the likelihood that it will choose the less valuable alternative, when the value difference is small. Thus, OFC neurons code for value information that could be used to directly influence choice.

Self-choice enhances value in reward-seeking in primates.

When an individual chooses one item from two or more alternatives, they compare the values of the expected outcomes. The outcome value can be determined by the associated reward amount, the probability of reward, and the workload required to earn the reward. Rational choice theory states that choices are made to maximize rewards over time, and that the same outcome values lead to an equal likelihood of choices. However, the theory does not distinguish between conditions with the same reward value, even when acquired under different circumstances, and does not always accurately describe real behavior. We have found that allowing a monkey to choose a reward schedule endows the schedule with extra value when compared to performance in an identical schedule that is chosen by another agent (a computer here). This behavior is not consistent with pure rational choice theory. Theoretical analysis using a modified temporal-difference learning model showed an enhanced schedule state value by self-choice. These results suggest that an increased reward value underlies the improved performances by self-choice during reward-seeking behavior.

Neurons in monkey dorsal raphe nucleus code beginning and progress of step-by-step schedule, reward expectation, and amount of reward outcome in the reward schedule task.

The dorsal raphe nucleus is the major source of serotonin in the brain. It is connected to brain regions related to reward processing, and the neurons show activity related to predicted reward outcome. Clinical observations also suggest that it is important in maintaining alertness and its apparent role in addiction seems to be related to reward processing. Here, we examined whether the neurons in dorsal raphe carry signals about reward outcome and task progress during multitrial schedules. We recorded from 98 single neurons in dorsal raphe of two monkeys. The monkeys perform one, two, or three visual discrimination trials (schedule), obtaining one, two, or three drops of liquid. In the valid cue condition, the length and brightness of a visual cue indicated schedule progress and reward amount, respectively. In the random cue condition, the visual cue was randomly presented with respect to schedule length and reward amount. We found information encoded about (1) schedule onset, (2) reward expectation, (3) reward outcome, and (4) reward amount in the mean firing rates. Information theoretic analysis showed that the temporal variation of the neuronal responses contained additional information related to the progress of the schedule toward the reward rather than only discriminating schedule onset or reward/no reward. When considered in light of all that is known about the raphe in anatomy, physiology, and behavior, the rich encoding about both task progress and predicted reward outcome makes the raphe a strong candidate for providing signals throughout the brain to coordinate persistent goal-seeking behavior.

Encoding of reward expectation by monkey anterior insular neurons.

The insula, a cortical brain region that is known to encode information about autonomic, visceral, and olfactory functions, has recently been shown to encode information during reward-seeking tasks in both single neuronal recording and functional magnetic resonance imaging studies. To examine the reward-related activation, we recorded from 170 single neurons in anterior insula of 2 monkeys during a multitrial reward schedule task, where the monkeys had to complete a schedule of 1, 2, 3, or 4 trials to earn a reward. In one block of trials a visual cue indicated whether a reward would or would not be delivered in the current trial after the monkey successfully detected that a red spot turned green, and in other blocks the visual cue was random with respect to reward delivery. Over one-quarter of 131 responsive neurons were activated when the current trial would (certain or uncertain) be rewarded if performed correctly. These same neurons failed to respond in trials that were certain, as indicated by the cue, to be unrewarded. Another group of neurons responded when the reward was delivered, similar to results reported previously. The dynamics of population activity in anterior insula also showed strong signals related to knowing when a reward is coming. The most parsimonious explanation is that this activity codes for a type of expected outcome, where the expectation encompasses both certain and uncertain rewards.

The influence of passband limitation on the waveform of extracellular action potential.

The duration of the extracellular action potential (EAP) in single neuronal recording has often been used as a clue to infer biochemical, physiological or functional substrate of the recorded neurons, e.g. neurochemical type. However, when recording a neuronal activity, the high-pass filter is routinely used to achieve higher signal-to-noise ratio. Signal processing theory predicts that passband limitation stretches the waveform of discrete brief impulse. To examine whether the duration of filtered EAP could be the reliable measure, we investigated the influence of high-pass filter both by simulation and unfiltered unit recording data from monkey dorsal raphe. Consistent with the findings in recent theoretical study, the unfiltered EAPs displayed the sharp wave without following bumps. The duration of unfiltered EAP was not correlated with that of filtered EAP. Thus the duration of original EAP cannot be estimated from filtered EAP. It is needed to reexamine the EAP duration measured for classifying the neurons whose activities were recorded under the passband limitation in the related studies.

Differential encoding of factors influencing predicted reward value in monkey rostral anterior cingulate cortex.

BACKGROUND: The value of a predicted reward can be estimated based on the conjunction of both the intrinsic reward value and the length of time to obtain it. The question we addressed is how the two aspects, reward size and proximity to reward, influence the responses of neurons in rostral anterior cingulate cortex (rACC), a brain region thought to play an important role in reward processing. METHODS AND FINDINGS: We recorded from single neurons while two monkeys performed a multi-trial reward schedule task. The monkeys performed 1-4 sequential color discrimination trials to obtain a reward of 1-3 liquid drops. There were two task conditions, a valid cue condition, where the number of trials and reward amount were associated with visual cues, and a random cue condition, where the cue was picked from the cue set at random. In the valid cue condition, the neuronal firing is strongly modulated by the predicted reward proximity during the trials. Information about the predicted reward amount is almost absent at those times. In substantial subpopulations, the neuronal responses decreased or increased gradually through schedule progress to the predicted outcome. These two gradually modulating signals could be used to calculate the effect of time on the perception of reward value. In the random cue condition, little information about the reward proximity or reward amount is encoded during the course of the trial before reward delivery, but when the reward is actually delivered the responses reflect both the reward proximity and reward amount. CONCLUSIONS: Our results suggest that the rACC neurons encode information about reward proximity and amount in a manner that is dependent on utility of reward information. The manner in which the information is represented could be used in the moment-to-moment calculation of the effect of time and amount on predicted outcome value.

Mode changes in activity of single neurons in anterior insular cortex across trials during multi-trial reward schedules.

We previously showed that spike count response distributions in anterior cingulate neurons can be fitted by a mixture of a few Poisson distributions in our reward schedule task. Here we report that the neuronal responses in insular cortex, an area connected to anterior cingulate cortex, can also be nicely fitted. The ratio of Poisson distributions changed with schedule progress, suggesting that neuronal responses in these areas fall into discrete firing modes. More insular neurons show mode changes across the schedules. The selection of firing modes might be related to cognitive processes, but seems independent across the two areas.

Neuronal firing in anterior cingulate neurons changes modes across trials in single states of multitrial reward schedules.

The recorded responses of single neurons often vary considerably in the numbers of spikes emitted across repeats of a single experimental condition. Because of this irregularity and for theoretical convenience the responses are often approximated using a Poisson process. However, it has been frequently pointed out that many details of the responses, including the distribution of spike counts across similar trials, are not consistent with a Poisson process, even an inhomogeneous one. Wiener and Richmond (2003, J Neurosci 23:2394-2406) showed that the spike count distributions could usually be fitted nicely by mixtures of a few (1-3) Poisson distributions, a step they regarded as a computational convenience. Now, we find that a substantial proportion (47%) of the neuronal responses from anterior cingulate cortex, which we conceptualize as part of a system related to the balance between work and reward, have responses with multimodal firing rate distributions. When these distributions are modeled as mixtures of Poisson distributions, the proportions of the different Poisson distributions are related to behavioral state, and might be related to cognitive factors. This suggests that the neurons undergo behaviorally-related mode changes.