Effects of 5-HT 4 receptor antagonist in the caudate nucleus on the performance of macaques in a delayed reward task

doi:10.21203/rs.3.rs-3974683/v1

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Effects of 5-HT 4 receptor antagonist in the caudate nucleus on the performance of macaques in a delayed reward task

https://doi.org/10.21203/rs.3.rs-3974683/v1

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published 23 Aug, 2024

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Temporal discounting, in which the recipient of a reward perceives the value of that reward to decrease with delay in its receipt, is associated with impulsivity and psychiatric disorders such as depression. Here, we investigate the role of serotonin 5-HT₄ receptors (5-HT₄R) in modulating temporal discounting in the macaque dorsal caudate nucleus (dCDh), the neurons of which have been shown to represent temporally discounted value. We first mapped the 5-HT₄R distribution in macaque brains using positron emission tomography (PET) imaging and confirmed dense expression of 5-HT₄R in the dCDh. We then examined the effects of a specific 5-HT₄R antagonist infused into the dCDh. Blockade of 5-HT₄R significantly increased error rates in a goal-directed delayed reward task, indicating an increase in the rate of temporal discounting. This increase was specific to the 5-HT₄R blockade because saline controls showed no such effect. The results demonstrate that 5-HT₄Rs in the dCDh are involved in reward-evaluation processes, particularly in the context of delay discounting, and suggest that serotonergic transmission via 5-HT₄R may be a key component in the neural mechanisms underlying impulsive decisions, potentially contributing to depressive symptoms.

Biological sciences/Neuroscience/Motivation

Biological sciences/Neuroscience/Reward

serotonin

motivation

temporal discounting

monkey

Temporal discounting, a phenomenon in which the perceived value of a reward decreases as the delay to its receipt increases, plays a central role in decision making and in understanding intertemporal choices. This concept is crucial when individuals are faced with a choice between smaller immediate rewards and larger delayed ones. Characterized by a hyperbolic pattern of discounting, the perceived value of rewards declines more steeply for shorter delays and less steeply for longer delays^1,2. Steep delay discounting is associated with impulsive behavior, often manifesting as a preference for smaller, more immediate rewards. This tendency is associated with various maladaptive behavioral characteristics, including depression^3,4.

Serotonin (5-hydroxytryptamine; 5-HT) is thought to be an important modulator of temporal discounting. Studies have shown that reduced serotonin levels lead to more impulsive choices^5–7, whereas increased levels can attenuate such impulsivity^5,8. Serotonergic dysfunction is also considered a key mechanism in depression, and recent evidence has highlighted the 5-HT₄ receptor (5-HT₄R) as being particularly relevant in major depressive disorder⁹, with evidence suggesting that 5-HT₄R agonism results in rapid antidepressant-like effects in rodents^8,10. In addition, experimental models suggest that 5-HT₄R levels are sensitive to central 5-HT modulation^11,12. Positron emission tomography (PET) studies in humans and monkeys have shown high densities of 5-HT₄R in the dorsal striatum, including in the caudate and putamen^13–15. The strong expression of 5-HT₄R suggests a potential role of these regions in modulating decisions involving temporal discounting.

Neuronal recording studies in monkeys have shown that neurons in the dorsal striatum, particularly the caudate nucleus, represent temporally discounted reward values^16,17. This neuronal activity is directly involved in decision making based on delayed rewards¹⁷. However, the specific relationship between 5-HT₄R in the caudate nucleus and temporal discounting remains unclear.

To bridge this gap, we investigated the role of 5-HT₄R in goal-directed performance with delayed rewards. First, we mapped the distribution of 5-HT₄R in macaque monkeys using PET imaging. We then examined the effects of manipulating 5-HT transmission via 5-HT₄R, achieved by infusing a specific antagonist into the caudate nucleus. Our findings provide the first evidence for a role of striatal 5-HT₄R in temporal discounting, potentially offering new insights into the serotonergic modulation of decision-making processes and advancing our understanding of psychiatric disorders like depression.

Mapping 5-HT₄R in the striatum of monkeys

First, we performed PET imaging using the selective radioligand [¹¹C]SB207145 to map 5-HT₄R in three monkeys. Quantification of specific radioligand binding was achieved using an original multilinear reference tissue model, with the cerebellum serving as the reference region¹⁸. In accordance with findings reported in prior studies in humans¹⁵, 5-HT₄R was found to be densely distributed in the anterior part of the dorsal striatum and mid caudate nucleus, but was present in relatively low densities in the ventral striatum and mid to posterior putamen (Fig. 1).

Assessing temporal discounting using the delayed reward task

The temporal discounting effect in the monkeys was assessed using the delayed reward task (Fig. 2A). In the basic task, the subject was required to release a lever in response to a color change from red to green. A visual cue, indicative of the trial type, was presented at the start and persisted throughout each trial. Eight distinct cues corresponded to varying combinations of reward size (one or four drops) and delay duration (0, 3.3, 6.9, or 10.5 s) (Fig. 2A, bottom). In this and similar tasks, the error rate – the proportion of trials in which the bar was released too early or too late – was taken as a quantitative measure of the monkey’s motivation for action. This rate serves as a proxy for decision utility, reflecting the animal’s anticipation of the impending reward. In our previous studies, the error rate was found to be inversely related to the motivational value¹⁹. In previous behavioral studies, the subjective value of delayed rewards was formulated as a hyperbolic discounting model ^20–22:

DV = R/(1 + kD) (1)

where DV is the value of the delayed reward (i.e., temporally discounted value), R is the magnitude of the reward, k is a discount parameter, and D is the delay to the reward. Accordingly, to describe error rates in the delayed-reward task, we have extended the inverse relationship by integrating it into the hyperbolic discounting framework, yielding the following linear model with e as the intercept^17,19,

E = kD + e (2)

We tested two monkeys with the delayed reward task. As shown in Fig. 2B, the average error rate linearly increased with longer delay periods for both reward sizes. This trend in average error rate was effectively captured by the modified hyperbolic discounting model (Eq. 2; dotted lines in Fig. 2B).

Effects of 5-HT₄R blockade on temporal discounting

To examine the effect of 5-HT₄R blockade on temporal discounting, we focused on the head of the dorsal caudate nucleus (dCDh) because this region is known to play a causal role in the processing of temporally discounted values¹⁷ and has a high density of 5-HT₄R (Fig. 1). Two monkeys received a local infusion of the 5-HT₄R antagonist GR125487 into the bilateral dCDh. The precise locations of the infusions were verified by overlaying CT images of the injection cannulae onto magnetic resonance (MR) images, and were further confirmed by post-mortem histology analysis (Fig. 3A). We confirmed the coverage of the target regions with the antagonist (Fig. 3B).

After 5-HT₄R blockade, both subjects showed a remarkable increase in the error rate during the tasks for each of the two reward sizes (Fig. 3C). A linear fit was applied to the error rates corresponding to each reward size, and the slope (discounting parameter k) was calculated for 5-HT₄R blockade and control conditions. We found that 5-HT₄R blockade increased the temporal discounting rate, which was approximately 150% of baseline, while the vehicle control induced no discernible changes (Fig. 3D). There was a significant difference between treatments (paired t-test, t₍₃₎ = 4.1, p = 0.026).

Additional behavioral metrics such as reaction times, error patterns, and total rewards earned remained consistent before and after the blockade (reaction time, two-way ANOVA for treatment × reward condition; main effect of treatment, F_{(1, 7)} = 4.18, p = 0.06; interaction, F_{(1, 7)} = 0.26, p = 0.96; error pattern, one-way ANOVA, treatment effect, F_{(1, 19)} = 1.82, p = 0.19; total rewards earned, one-way ANOVA, treatment effect, F_{(1, 19)} = 2.52, p = 0.13).

In the current study, we examined the impact of 5-HT₄R blockade in the dorsal caudate nucleus (dCDh) on temporal discounting in macaques. PET imaging results confirmed dense expression of 5-HT₄Rs in the dorsal striatum, including dCDh. Consistent with previous studies, the proportion of correct trials for delayed rewards was well described by a model with hyperbolic discounting. We found that 5-HT₄R blockade in dCDh significantly increased error rates in the delayed-reward task, indicating an increased rate of temporal discounting that determined how rapidly reward value declined with increased delay. These results, together with our previous findings, suggest that dCDh provides a critical contribution to the modulation of temporal discounting, at least in regards to regulating motivation for action, and probably also for decision making.

Previous studies suggested that serotonin levels are associated with impulsivity in decision making, particularly striatal information processing. For example, human imaging studies emphasize that serotonin controls the time scale of reward prediction by differentially regulating activities within the striatum^23,24. Neuronal activity in the striatum has been suggested to represent the discounted value of delayed rewards, which combines information about the amount of reward and the delay in delivery^16,17. In addition, local injections of muscimol and chemogenetic inactivation of dCDh significantly distorted linear error patterns without increasing errors, specifically disrupting the process integrating reward size and delay duration, thereby suggesting a causal contribution of dCDh on neuronal activity to compute the discounted values of delayed rewards. In contrast, the current study showed that infusion of 5-HT₄R antagonist into the dCDh enhances temporal discounting without disrupting linear relationships. This treatment did not significantly affect reaction times, error patterns, or total reward earned — behavioral indices of attention/motor preparation, motor impulsivity, and general motivation, respectively. These results strongly suggest that 5-HT₄R-mediated serotonin transmission in this region modulates neuronal activity and plays a crucial role in the computation of temporal discounting. Hence, our data provide new insights into the function of the serotonergic system in reward valuation and decision making, especially in the context of delay discounting.

How then does serotonin influence striatal neuronal activity through 5-HT₄Rs? In the dorsal striatum, 5-HT₄Rs are found primarily at postsynaptic sites²⁵. One possibility is the involvement of dopamine-mediated effects. Microanalysis studies in rats showed that administration of a systemic 5-HT₄R antagonist reduced the enhancement of both striatal dopamine release and nigral dopamine neuron impulse flow only under conditions in which nigrostriatal dopamine transmission was activated^26,27. Conversely, intrastriatal administration of 5-HT or 5-HT₄R agonists stimulates striatal dopamine release, which is blocked by 5-HT₄R antagonists^28,29. Given that dopamine neurons signal temporally discounted values³⁰, reduced 5-HT₄R stimulation may lead to decreased phasic dopamine signaling in the striatum, thereby resulting in steeper temporal discounting. Another possible explanation is an alteration in long-term plasticity, to which the 5-HT₄R is thought to contribute. It was shown that 5-HT₄Rs are densely localized in both axo-spinous and axo-dendritic sites of thalamostriatal synapses of projection neurons in the dorsal striatum, and that reduced 5-HT signaling attenuates activation of the 5-HT₄R subtype, thereby promoting spike-timing-dependent long-term depression (t-LTD) preferentially at thalamic afferents to striatal neurons³¹. Given that the thalamostriatal projections are critical for interrupting ongoing behavior and redirecting attention to salient stimuli^32,33, serotonin-dependent gating mechanisms of t-LTD may affect striatal information processing. Future studies including a combination of electrophysiological and pharmacological manipulations are needed to investigate the precise mechanisms linking these scenarios to steep delay discounting behavior.

Our findings also have some clinical relevance. PET imaging suggests that the 5-HT₄R is involved in a neurobiological mechanism underlying a risk for depression, with lower striatal 5-HT₄R binding being associated with increased risk⁹. Given the established association between steep delay discounting and depression, our findings on the modulatory role of 5-HTR in dCDh in temporal discounting may offer new perspectives on serotonergic mechanisms in depression, particularly regarding decision abnormalities and impulsivity. In addition, maladaptive plasticity due to decreased 5-HT signaling is implicated in the pathophysiology of depression³⁴ and OCD³⁵. As mentioned above, serotonergic signaling via 5-HT₄R plays a critical role in regulating input-specific synaptic plasticity in the dorsal striatum³¹. Given that 5-HT₄R is considered a promising target for the treatment of depression^10,36,37, further research to fill the gaps in knowledge on the molecular mechanisms at the cellular, information processing, and behavioral levels is important.

In summary, this study demonstrates the important role of 5-HT₄R in the dorsal head of the caudate nucleus in modulating temporal discounting in non-human primates. These findings contribute to our understanding of the serotonergic modulation of motivational regulation, and presumably decision making, and have potential implications for psychiatric disorders characterized by altered reward processing, such as depression.

Ethics statement

All experimental procedures involving animals were conducted in accordance with the Guide for the Care and Use of Nonhuman Primates in Neuroscience Research (The Japan Neuroscience Society; https://www.jnss.org/en/animal_primates), were approved by the Animal Ethics Committee of the National Institutes for Quantum Science and Technology (#09-1035), and were consistent with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines.

Subjects

A total of five adult male macaque monkeys (4 Rhesus [Macaca mulatta] and 1 Japanese [Macaca fuscata]; 5.1–8.6 kg; aged 7–12 years at the start of the experiment) were used in this study. Two monkeys (monkeys BI and RI) were also used in a previous study examining neuronal correlates and causality in temporal discounting¹⁷. The other three monkeys (monkey #153, #189, #235) were used for PET imaging. Food was available ad libitum, and motivation was controlled by restricting access to fluid to experimental sessions in which water was provided as a reward for task performance. Animals received water supplementation whenever necessary (e.g., when they were unable to obtain sufficient water through experimentation) and had free access to water whenever testing was interrupted for more than 1 week. For environmental enrichment, play objects and/or small food items (fruits, nuts, and vegetables) were provided daily in the home cages.

PET scans and analysis

Three monkeys (monkey #153, #189, #235) were used for PET measurements using the selective 5-HT₄R ligand [¹¹C]SB207145 as the tracer³⁸. PET scans were performed on conscious monkeys that were seated in a chair using a microPET Focus 220 scanner (Siemens Medical Solutions, USA). The injected amount of radioactivity and its molar activity at the time of injection were between 371.3 to 391.4 MBq and > 37 GBq/µmol, respectively. After transmission scans for correcting attenuation, a dynamic emission scan was performed for 90 minutes. Ligands were injected as a single bolus via the crural vein at the start of the scan. All emission data were reconstructed by means of filtered back projection using a Hanning filter. All PET images were coregistered to the individual’s MR images using PMOD image analysis software (PMOD Technologies, Switzerland) and then anatomically standardized to a standard MR template image (NIMH macaque template version 2.0)³⁹ using ANTs (picsl.upenn.edu/software/ants/)⁴⁰. Radioactive concentrations in tissue were obtained from volumes of interest (VOIs) placed on the putamen and cerebellum (as reference regions). Each VOI was defined on the NIMH macaque template version 2.0. Parametric maps of regional binding potentials relative to non-displaceable radioligands (BP_ND) of 5-HT₄R were constructed using an original multilinear reference tissue model¹⁸.

Surgery

Surgical procedure were carried out under general isoflurane anesthesia (1–2%) to implant a head fixation device (for all monkeys) and chambers for local injection of 5-HT₄R antagonist (for monkeys BI and RI). We implanted either a rectangular chamber (for monkey BI, 22 × 22 mm ID; KDS Ltd.) or two cylindrical chambers (for monkey RI, 19 mm ID; Crist Instrument Co., Inc.) angled 20° from vertical in the coronal plane targeting the bilateral caudate nucleus. Before surgery, MR images were obtained at 7 T under anesthesia (intravenous infusion of propofol, 0.2–0.6 mg/kg^/min) to determine the position of local injection. Using measurements made from the MR images, the centers of the chambers were placed to target the caudate near the anterior commissure.

Drug and pharmacological manipulation

For pharmacological manipulation, we used the potent and selective 5-HT₄R antagonist GR125487 (cat# 1658, Tocris)⁴¹. GR125487 was dissolved in 0.9% saline and the final volume was adjusted with saline. Two stainless steel injection cannulae were inserted into the caudate nucleus (O.D. 350 µm; BRC Inc., Japan), one in each hemisphere. Each cannula was connected to a 5-µl microsyringe (Hamilton, #7105KH) via polyethylene tubing. The cannulae were advanced through the guide tube by means of an oil-drive micromanipulator (Narishige Inc., Japan). GR125487 (0.5 µg/1 µL saline) was injected at a rate of 0.25 µL/min by auto-injector (Legato210, KD Scientific Inc.) to a total volume of 4 µL in each side. Soon after the injection was completed, the animal was allowed to start performing the tasks, which continued for 100 minutes. We performed at most one injection study per week. For the control, saline was injected at other times using the same parameters as used for the 5-HT₄R antagonist. At the end of each session, a CT scan was acquired to visualize the injection cannulae in relation to the chambers and skull. The CT images were overlaid on MR images using PMOD image analysis software to assist in identifying the injection sites (Fig. 3A). Based on previous reports^42,43, we plotted the injection sites as the estimated liquid diffusion areas, i.e., 4–5 mm in diameter from the cannula tip.

Behavioral tasks and testing procedures

For all behavioral training and testing, each monkey sat in a primate chair inside a sound-attenuated dark room. Visual stimuli were presented on a computer monitor in front of the monkey. Behavioral tasks and data acquisition were performed using a QNX-based Real-time Experimentation data acquisition system (REX; Laboratory of Sensorimotor Research, National Eye Institute) and commercially available software (Presentation, Neurobehavioral Systems). We used a delayed reward task, as previously described¹⁹. Before the behavioral experiments, all monkeys were trained to perform color discrimination trials on a cued multi-trial reward schedule task⁴⁴ for more than 3 months.

Two monkeys were trained and tested with the delayed reward task (Fig. 2A). In each of the trials, the monkey worked for one of six combinations of reward size and delay. Every trial had the same requirement for obtaining the reward: releasing the bar when a colored spot changed from red to green. Trials began when the monkey touched the bar at the front of the chair. A visual cue followed by a red spot (wait signal) sequentially appeared in the center of the monitor. After a variable interval, the red target then turned green (go signal). If the monkey released the bar between 0.2 and 1 s after this go signal, the trial was considered correct and the spot turned blue (correct signal). Either a small (one drop, ca. 0.1 mL) or large liquid reward (four drops) was delivered immediately (0.3 ± 0.1 s) or with an additional delay of either 3.3 ± 0.6 s, 6.9 ± 1.2 s or 10.5 ± 1.8 s after correct release of the bar. Each combination of reward size and delay (trial type) was chosen with equal probability and independently of the preceding reward condition. An inter-trial interval (ITI) of 1 s was enforced before allowing the next trial to begin. We used a fixed ITI instead of adjusted ITIs with post-reward delays (for example Blanchard et al., 2013)⁴⁵ because monkeys are insensitive to post-reward delays in our tasks (see Fig. 3 in Minamimoto et al., 2009). Anticipatory bar releases (before or no later than 0.2 s after the appearance of the go signal) and failures to release the bar within 1 s after the appearance of the go signal were counted as errors. In error trials, the trial was terminated immediately, all visual stimuli disappeared, and the trial was repeated following the ITI with the reward size/delay combination remaining the same as in the previous error trial. In the behavioral experiment, the visual cue indicated a unique combination of reward size and delay. Two sets of cues were used: a stripe set (for monkey RI) and an image set (for monkey BI) (Fig. 1A, bottom). Prior to the behavioral experiment, all monkeys were trained to perform color discrimination trials in a cued multi-trial reward schedule task for more than 3 months, followed by learning of each task for 1–3 months. We collected behavioral data with the delayed reward task for 5–25 daily testing sessions. Each session ended when the monkey would no longer initiate a new trial.

Histology

For histologic examination, monkeys were immobilized with ketamine (10 mg/kg, i.m.) and xylazine (0.5 mg/kg, i.m.), deeply anesthetized with an overdose of thiopental sodium (50 mg/kg, i.v.), and then transcardially perfused with saline at 4°C, followed by 4% paraformaldehyde in 0.1 M PBS at a pH of 7.4. The brain was removed from the skull, postfixed in the same fresh fixative overnight, saturated with 30% sucrose in phosphate buffer at 4°C, and then cut serially into 50-µm-thick sections on a freezing microtome. The sections were then mounted on gelatin-coated glass slides, air dried, and coverslipped. A series of sections were Nissl stained with 1% cresyl violet. Images of sections were digitally captured using a whole slide scanner (NanoZoomer S60, Hamamatsu Photonics, Japan).

Data analysis

All data and statistical analyses were performed using the R statistical computing environment (R Development Core Team, 2004). The average error rate for each trial type was calculated for each daily session, with error rates for each trial type being defined as the number of error trials divided by the total number of trials of that given type. We did not distinguish between the two types of errors (early or late release) and used their sum except for in the error pattern analysis. We performed repeated-measures ANOVAs to determine the effect of treatment × trial type or treatment × delay duration on error rate, RT, and error pattern across monkeys. Post hoc comparisons were performed using Tukey’s HSD test, and the a priori statistical significance was set at p = 0.05.

We used a linear model (Eq. 2) to estimate the rate of temporal discounting, as previously described^14,19. We independently fitted a linear model to the data for each reward size using sum-of-squares minimization without weighting. We estimated the effect of 5-HT₄R blockade and vehicle injections on the discounting parameter by making comparisons with the baseline condition.

Acknowledgements
We thank R. Yoshida, R. Suma, T. Sugii, R. Yamaguchi, Y. Matsuda, and J. Kamei for their technical assistance. This study was supported by MEXT/JSPS KAKENHI Grant Numbers JP22K07339 (to YH), and JP18H04037 and JP20H05955 (to TM). A monkey used in this study was provided by the National Bio-Resource Project: “Japanese Monkeys” of MEXT, Japan.

Author contributions

Conceptualization and study design: Y.H., T.M. Investigation: Y.H., Y.N. Statistics: Y.H., K.M. Funding acquisition: Y.H., T.M. Writing—original draft: Y.H., T.M. Writing—review and editing: Y.H., H.I., Y.N., M.K., M.H., T.M.

Data availability statement
All the data underlying figures are available in the GitHub repository:　https://github.com/minamimoto-lab/2024-5HT4R-Data　

Competing interests
The authors declare no competing interests.

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Effects of 5-HT 4 receptor antagonist in the caudate nucleus on the performance of macaques in a delayed reward task

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Results

Mapping 5-HT₄R in the striatum of monkeys

Assessing temporal discounting using the delayed reward task

Effects of 5-HT₄R blockade on temporal discounting

Discussion

Materials and Methods

Ethics statement

Subjects

PET scans and analysis

Surgery

Drug and pharmacological manipulation

Behavioral tasks and testing procedures

Histology

Data analysis

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1

Effects of 5-HT 4 receptor antagonist in the caudate nucleus on the performance of macaques in a delayed reward task

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Results

Mapping 5-HT4R in the striatum of monkeys

Assessing temporal discounting using the delayed reward task

Effects of 5-HT4R blockade on temporal discounting

Discussion

Materials and Methods

Ethics statement

Subjects

PET scans and analysis

Surgery

Drug and pharmacological manipulation

Behavioral tasks and testing procedures

Histology

Data analysis

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1

Mapping 5-HT₄R in the striatum of monkeys

Effects of 5-HT₄R blockade on temporal discounting