Reward Modulation Research Articles

Exploring the role of orexins in the modulation of social reward

Abstract Rationale positive social interactions are essential for mental health, by offering emotional support, reducing stress levels, and promoting resilience against drugs of abuse effects. However, not all individuals perceive social interaction as rewarding. Objectives the goal of this study was to investigate whether the modulation of the orexin system can shift passive coping and non-social behavior (vulnerable) to active coping and social behavior (resilient). This knowledge is primordial for stress- and addiction-related disorders, and for other psychiatric disorders involving impairment in social interaction. Methods male C57/BL6N mice categorized into social and non-social groups, received injections of SB334867, a selective orexin 1 receptor (OX1R) antagonist, before the conditioning sessions with a male conspecific of the same weight and age. Results our results from the conditioned place preference test (CPP) show that SB334867 has no effect on social preference in non-social mice, but it reduces their stress levels and depression-like behavior. These effects appear to be due to a higher OX1R expression in the basolateral amygdala (BLA), a stress-related brain area, of non-social mice compared to their social counterparts. Conclusions these data suggest that the orexin system may be a target to alleviate stress and depression-like behavior in non-social individuals rather than to promote social reward.

K-PERM: Personalized Response Generation Using Dynamic Knowledge Retrieval and Persona-Adaptive Queries

Personalizing conversational agents can enhance the quality of conversations and increase user engagement. However, they often lack external knowledge to appropriately tend to a user’s persona. This is crucial for practical applications like mental health support, nutrition planning, culturally sensitive conversations, or reducing toxic behavior in conversational agents. To enhance the relevance and comprehensiveness of personalized responses, we propose using a two-step approach that involves (1) selectively integrating user personas and (2) contextualizing the response by supplementing information from a background knowledge source. We develop K-PERM (Knowledge-guided PErsonalization with Reward Modulation), a dynamic conversational agent that combines these elements. K-PERM achieves state-of-the- art performance on the popular FoCus dataset, containing real-world personalized conversations concerning global landmarks.We show that using responses from K-PERM can improve performance in state-of-the-art LLMs (GPT 3.5) by 10.5%, highlighting the impact of K-PERM for personalizing chatbots.

Transcranial Magnetic Stimulation for Reducing the Relative Reinforcing Value of Food in Adult Patients With Obesity Pursuing Metabolic and Bariatric Surgery: Protocol for a Pilot, Within-Participants, Sham-Controlled Trial.

Metabolic and bariatric surgery (MBS) is the most effective and durable obesity treatment. However, there is heterogeneity in weight outcomes, which is partially attributed to variability in appetite and eating regulation. Patients with a strong desire to eat in response to the reward of palatable foods are more likely to overeat and experience suboptimal outcomes. This subgroup, classified as at risk, may benefit from repetitive transcranial magnetic stimulation (rTMS), a noninvasive brain stimulation technique that shows promise for reducing cravings and consumption of addictive drugs and food; no study has evaluated how rTMS affects the reinforcing value of food and brain reward processing in the context of MBS. The goal of the Transcranial Magnetic Stimulation to Reduce the Relative Reinforcing Value of Food (RESTRAIN) study is to perform an initial rTMS test on the relative reinforcing value (RRV) of food (the reinforcing value of palatable food compared with money) among adult patients who are pursuing MBS and report high food reinforcement. Using a within-participants sham-controlled crossover design, we will compare the active and sham rTMS conditions on pre- to posttest changes in the RRV of food (primary objective) and the neural modulation of reward, measured via electroencephalography (EEG; secondary objective). We hypothesize that participants will show larger decreases in food reinforcement and increases in brain reward processing after active versus sham rTMS. Participants (n=10) will attend 2 study sessions separated by a washout period. They will be randomized to active rTMS on 1 day and sham rTMS on the other day using a counterbalanced schedule. For both sessions, participants will arrive fasted in the morning and consume a standardized breakfast before being assessed on the RRV of food and reward tasks via EEG before and after rTMS of the left dorsolateral prefrontal cortex. Recruitment and data collection began in December 2022. As of October 2023, overall, 52 patients have been screened; 36 (69%) screened eligible, and 17 (47%) were enrolled. Of these 17 patients, 3 (18%) were excluded before rTMS, 5 (29%) withdrew, 4 (24%) are in the process of completing the protocol, and 5 (29%) completed the protocol. The RESTRAIN study is the first to test whether rTMS can target neural reward circuits to reduce behavioral (RRV) and neural (EEG) measures of food reward in patients who are pursuing MBS. If successful, the results would provide a rationale for a fully powered trial to examine whether rTMS-related changes in food reinforcement translate into healthier eating patterns and improved MBS outcomes. If the results do not support our hypotheses, we will continue this line of research to evaluate whether additional rTMS sessions and pulses as well as different stimulation locations produce clinically meaningful changes in food reinforcement. ClinicalTrials.gov NCT05522803; https://clinicaltrials.gov/study/NCT05522803. DERR1-10.2196/50714.

Reward Modulates Visual Responses in the Superficial Superior Colliculus of Mice.

The processing of sensory input is constantly adapting to behavioral demands and internal states. The drive to obtain reward, e.g., searching for water when thirsty, is a strong behavioral demand and associating the reward with its source, a certain environment or action, is paramount for survival. Here, we show that water reward increases subsequent visual activity in the superficial layers of the superior colliculus (SC), which receive direct input from the retina and belong to the earliest stages of visual processing. We trained mice of either sex to perform a visual decision task and recorded the activity of neurons in the SC using two-photon calcium imaging and high-density electrophysiological recordings. Responses to visual stimuli in around 20% of visually responsive neurons in the superficial SC were affected by reward delivered in the previous trial. Reward mostly increased visual responses independent from modulations due to pupil size changes. The modulation of visual responses by reward could not be explained by movements like licking. It was specific to responses to the following visual stimulus, independent of slow fluctuations in neural activity and independent of how often the stimulus was previously rewarded. Electrophysiological recordings confirmed these results and revealed that reward affected the early phase of the visual response around 80 ms after stimulus onset. Modulation of visual responses by reward, but not pupil size, significantly improved the performance of a population decoder to detect visual stimuli, indicating the relevance of reward modulation for the visual performance of the animal.SIGNIFICANCE STATEMENT To learn which actions lead to food, water, or safety, it is necessary to integrate the receiving of reward with sensory stimuli related to the reward. Cortical stages of sensory processing have been shown to represent stimulus-reward associations. Here, we show, however, that reward influences neurons at a much earlier stage of sensory processing, the superior colliculus (SC), receiving direct input from the retina. Visual responses were increased shortly after the animal received the water reward, which led to an improved stimulus signal in the population of these visual neurons. Reward modulation of early visual responses may thus improve perception of visual environments predictive of reward.

The role of lateral habenula NMDA receptors in tramadol-induced conditioning.

The role of the lateral habenula (LHb) as a hub for receiving and relaying signals from the limbic system to serotonergic, dopaminergic, and norepinephrinergic regions in the brainstem makes this area a critical region in the control of reward and addiction. Behavioral evidence reveals the vital role of the LHb in negative symptoms during withdrawal. In this investigation, we study the role of the LHb N-Methyl D-Aspartate receptor (NMDAR) in the modulation of tramadol reward. Male adult Wistar rats were used in this study. The effect of intra-LHb micro-injection of NMDAR agonist (NMDA, 0.1, 0.5, 2 µg/rat) and antagonist (D-AP5, 0.1, 0.5, 1 µg/rat) was evaluated in conditioned place preference (CPP) paradigm. The obtained results showed that intra-LHb administration of NMDA induced place aversion dose-dependently, while blockade of NMDAR in the LHb using D-AP5 micro-injection led to an increased preference score in the CPP task. Co-administration of NMDA (0.5 µg/rat) with tramadol (4 mg/kg) reduced preference score, while co-administration of D-AP5 (0.5 µg/rat) with a non-effective dose of tramadol (1 mg/kg) potentiate the rewarding effect of tramadol. LHb receives inputs from the limbic system and projects to the monoaminergic nuclei in the brainstem. It has been declared that NMDAR is expressed in LHb, and as obtained data revealed, these receptors could modulate the rewarding effect of tramadol. Therefore, NMDA receptors in the LHb might be a new target for modulating tramadol abuse.

Mu Opioid Receptor–Expressing Neurons in the Dorsal Raphe Nucleus Are Involved in Reward Processing and Affective Behaviors

BackgroundMu opioid receptors (MORs) are key for reward processing, mostly studied in dopaminergic pathways. MORs are also expressed in the dorsal raphe nucleus (DRN), which is central for the modulation of reward and mood, but MOR function in the DRN remains underexplored. Here, we investigated whether MOR-expressing neurons of the DRN (DRN-MOR neurons) participate in reward and emotional responses. MethodsWe characterized DRN-MOR neurons anatomically using immunohistochemistry and functionally using fiber photometry in responses to morphine and rewarding/aversive stimuli. We tested the effect of opioid uncaging on the DRN on place conditioning. We examined the effect of DRN-MOR neuron optostimulation on positive reinforcement and mood-related behaviors. We mapped their projections and selected DRN-MOR neurons projecting to the lateral hypothalamus for a similar optogenetic experimentation. ResultsDRN-MOR neurons form a heterogeneous neuronal population essentially composed of GABAergic (gamma-aminobutyric acidergic) and glutamatergic neurons. Calcium activity of DRN-MOR neurons was inhibited by rewarding stimuli and morphine. Local photo-uncaging of oxymorphone in the DRN produced conditioned place preference. DRN-MOR neuron optostimulation triggered real-time place preference and was self-administered, promoted social preference, and reduced anxiety and passive coping. Finally, specific optostimulation of DRN-MOR neurons projecting to the lateral hypothalamus recapitulated the reinforcing effects of total DRN-MOR neuron stimulation. ConclusionsOur data show that DRN-MOR neurons respond to rewarding stimuli and that their optoactivation has reinforcing effects and promotes positive emotional responses, an activity which is partially mediated by their projections to the lateral hypothalamus. Our study also suggests a complex regulation of DRN activity by MOR opioids, involving mixed inhibition/activation mechanisms that fine-tune DRN function.

Sex-dependent divergence in the effects of GLP-1 agonist exendin-4 on alcohol reinforcement and reinstatement in C57BL/6J mice

RationaleAlcohol use disorder remains a leading cause of preventable deaths, and current treatments have limited efficacy. Glucagon-like peptide 1 (GLP-1) receptor agonists can reduce alcohol drinking in preclinical studies, but mechanisms are still not fully understood, and data in female subjects are scarce.ObjectivesTo assess whether the GLP-1 receptor agonist exendin-4 could decrease alcohol-seeking behavior in the absence of alcohol consumption or intoxication, to compare the potency and efficacy of exendin-4 in the reduction of alcohol seeking vs. alcohol taking, and to compare effects between male and female mice.MethodsMale and female C57BL/6J mice were trained to self-administer 20% alcohol under an FR 1 schedule of reinforcement. After extinction, systemic exendin-4 (saline, 1.8, and 3.2 μg/kg) was tested in cue-induced reinstatement of alcohol seeking. Effects of exendin-4 on alcohol self-administration were tested in a separate group.ResultsExendin-4 suppressed reinstatement of alcohol seeking to extinction levels, at both doses, in the male mice, but had no effect in the female mice. Both doses of exendin-4 also significantly decreased alcohol self-administration in male mice; females again showed less pronounced effects.ConclusionsIn male mice, exendin-4 appeared more effective at suppressing alcohol seeking in the absence of alcohol relative to alcohol self-administration, consistent with modulation of alcohol reward or inhibitory control, rather than satiety or aversive effects of alcohol. We saw marked sex differences with less effect of exendin-4 in female mice, and it will be important to include both sexes in further investigations into GLP-1 receptor agonists.

Contributions of transient and sustained reward to memory formation.

Reward benefits to memory formation have been robustly linked to dopaminergic activity. Despite the established characterization of dopaminergic mechanisms as operating at multiple timescales, potentially supporting distinct functional outcomes, the temporal dynamics by which reward might modulate memory encoding are just beginning to be investigated. In the present study, we leveraged a mixed block/event experimental design to disentangle transient and sustained reward influences on task engagement and subsequent recognition memory in an adapted monetary-incentive-encoding (MIE) paradigm. Across three behavioral experiments, transient and sustained reward modulation of item and context memory was probed, at both 24-h and ~ 15-min retention intervals, to investigate the importance of overnight consolidation. In general, we observed that transient reward was associated with enhanced item memory encoding, while sustained reward modulated response speed but did not appear to benefit subsequent recognition accuracy. Notably, reward effects on item memory performance and response speed were somewhat inconsistent across the three experiments, with suggestions that RT speeding might also be related to time on task, and we did not observe reward modulation of context memory performance or amplification of reward benefits to memory by overnight consolidation. Taken together, the observed pattern of behavior is consistent with potentially distinct roles for transient and sustained reward in memory encoding and cognitive performance and suggests that further investigation of the temporal dynamics of dopaminergic contributions to memory formation will advance the understanding of motivated memory.

Value-driven modulation of visual perception by visual and auditory reward cues: The role of performance-contingent delivery of reward.

Perception is modulated by reward value, an effect elicited not only by stimuli that are predictive of performance-contingent delivery of reward (PC) but also by stimuli that were previously rewarded (PR). PC and PR cues may engage different mechanisms relying on goal-driven versus stimulus-driven prioritization of high value stimuli, respectively. However, these two modes of reward modulation have not been systematically compared against each other. This study employed a behavioral paradigm where participants' visual orientation discrimination was tested in the presence of task-irrelevant visual or auditory reward cues. In the first phase (PC), correct performance led to a high or low monetary reward dependent on the identity of visual or auditory cues. In the subsequent phase (PR), visual or auditory cues were not followed by reward delivery anymore. We hypothesized that PC cues have a stronger modulatory effect on visual discrimination and pupil responses compared to PR cues. We found an overall larger task-evoked pupil dilation in PC compared to PR phase. Whereas PC and PR cues both increased the accuracy of visual discrimination, value-driven acceleration of reaction times (RTs) and pupillary responses only occurred for PC cues. The modulation of pupil size by high reward PC cues was strongly correlated with the modulation of a combined measure of speed and accuracy. These results indicate that although value-driven modulation of perception can occur even when reward delivery is halted, stronger goal-driven control elicited by PC reward cues additionally results in a more efficient balance between accuracy and speed of perceptual choices.

A Regional and Projection-Specific Role of RGSz1 in the Ventrolateral Periaqueductal Grey in the Modulation of Morphine Reward.

Opioid analgesics exert their therapeutic and adverse effects by activating μ opioid receptors (MOPR); however, functional responses to MOPR activation are modulated by distinct signal transduction complexes within the brain. The ventrolateral periaqueductal gray (vlPAG) plays a critical role in modulation of nociception and analgesia, but the exact intracellular pathways associated with opioid responses in this region are not fully understood. We previously showed that knockout of the signal transduction modulator Regulator of G protein Signaling z1 (RGSz1) enhanced analgesic responses to opioids, whereas it decreased the rewarding efficacy of morphine. Here, we applied viral mediated gene transfer methodology and delivered adeno-associated virus (AAV) expressing Cre recombinase to the vlPAG of RGSz1fl\fl mice to demonstrate that downregulation of RGSz1 in this region decreases sensitivity to morphine in the place preference paradigm, under pain-free as well as neuropathic pain states. We also used retrograde viral vectors along with flippase-dependent Cre vectors to conditionally downregulate RGSz1 in vlPAG projections to the ventral tegmental area (VTA) and show that downregulation of RGSz1 prevents the development of place conditioning to low morphine doses. Consistent with the role for RGSz1 as a negative modulator of MOPR activity, RGSz1KO enhances opioid-induced cAMP inhibition in periaqueductal gray (PAG) membranes. Furthermore, using a new generation of bioluminescence resonance energy transfer (BRET) sensors, we demonstrate that RGSz1 modulates Gαz but not other Gαi family subunits and selectively impedes MOPR-mediated Gαz signaling events invoked by morphine and other opioids. Our work highlights a regional and circuit-specific role of the G protein-signaling modulator RGSz1 in morphine reward, providing insights on midbrain intracellular pathways that control addiction-related behaviors. SIGNIFICANCE STATEMENT: This study used advanced genetic mouse models to highlight the role of the signal transduction modulator named RGSz1 in responses to clinically used opioid analgesics. We show that RGSz1 controls the rewarding efficacy of opioids by actions in ventrolateral periaqueductal gray projections to the ventral tegmental area, a key component of the midbrain dopamine pathway. These studies highlight novel mechanisms by which pain-modulating structures control the rewarding efficacy of opioids.

A role for the circadian transcription factor NPAS2 in the progressive loss of non-rapid eye movement sleep and increased arousal during fentanyl withdrawal in male mice.

Synthetic opioids like fentanyl are contributing to the rise in rates of opioid use disorder and drug overdose deaths. Sleep dysfunction and circadian rhythm disruption may worsen during opioid withdrawal and persist during abstinence. Severe and persistent sleep and circadian alterations are putative factors in opioid craving and relapse. However, very little is known about the impact of fentanyl on sleep architecture and sleep-wake cycles, particularly opioid withdrawal. Further, circadian rhythms regulate sleep-wake cycles, and the circadian transcription factor, neuronal PAS domain 2 (NPAS2) is involved in the modulation of sleep architecture and drug reward. Here, we investigate the role of NPAS2 in fentanyl-induced sleep alterations. To determine the effect of fentanyl administration and withdrawal on sleep architecture, and the role of NPAS2 as a factor in fentanyl-induced sleep changes. Electroencephalography (EEG) and electromyography (EMG) was used to measure non-rapid eye movement sleep (NREMS) and rapid eye movement sleep (REMS) at baseline and following acute and chronic fentanyl administration in wild-type and NPAS2-deficient male mice. Acute and chronic administration of fentanyl led to increased wake and arousal in both wild-type and NPAS2-deficient mice, an effect that was more pronounced in NPAS2-deficient mice. Chronic fentanyl administration led to decreased NREMS, which persisted during withdrawal, progressively decreasing from day 1 to 4 of withdrawal. The impact of fentanyl on NREMS and arousal was more pronounced in NPAS2-deficient mice. Chronic fentanyl disrupts NREMS, leading to a progressive loss of NREMS during subsequent days of withdrawal. Loss of NPAS2 exacerbates the impact of fentanyl on sleep and wake, revealing a potential role for the circadian transcription factor in opioid-induced sleep changes.

Flexible Glassy Carbon Multielectrode Array for In Vivo Multisite Detection of Tonic and Phasic Dopamine Concentrations.

Dopamine (DA) plays a central role in the modulation of various physiological brain functions, including learning, motivation, reward, and movement control. The DA dynamic occurs over multiple timescales, including fast phasic release, as a result of neuronal firing and slow tonic release, which regulates the phasic firing. Real-time measurements of tonic and phasic DA concentrations in the living brain can shed light on the mechanism of DA dynamics underlying behavioral and psychiatric disorders and on the action of pharmacological treatments targeting DA. Current state-of-the-art in vivo DA detection technologies are limited in either spatial or temporal resolution, channel count, longitudinal stability, and ability to measure both phasic and tonic dynamics. We present here an implantable glassy carbon (GC) multielectrode array on a SU-8 flexible substrate for integrated multichannel phasic and tonic measurements of DA concentrations. The GC MEA demonstrated in vivo multichannel fast-scan cyclic voltammetry (FSCV) detection of electrically stimulated phasic DA release simultaneously at different locations of the mouse dorsal striatum. Tonic DA measurement was enabled by coating GC electrodes with poly(3,4-ethylenedioxythiophene)/carbon nanotube (PEDOT/CNT) and using optimized square-wave voltammetry (SWV). Implanted PEDOT/CNT-coated MEAs achieved stable detection of tonic DA concentrations for up to 3 weeks in the mouse dorsal striatum. This is the first demonstration of implantable flexible MEA capable of multisite electrochemical sensing of both tonic and phasic DA dynamics in vivo with chronic stability.

Is decision-making impairment an endophenotype of Anorexia Nervosa?

IntroductionPatients with anorexia nervosa (AN) show impaired decision-making ability, but it is still unclear if this is a trait marker, i.e. a stable endophenotype of AN, or a state parameter, i.e. being explained by present symptoms and associated comorbidity.ObjectivesWe aimed to determine whether decision-making impairment is an endophenotype of AN. We hypothesized that decision-making alteration would not respect the criteria of an endophenotype, and that these alterations would have a relationship with illness severity.MethodsNinety-one patients with acute AN (A-AN), 90 unaffected relatives (UR), 23 patients remitted from AN (R-AN) and 204 healthy controls (HC) underwent the Iowa Gambling Task (IGT) and psychometric assessments. Prospective Valence Learning model (PVL) was employed to distinguish the cognitive dimensions underlying the decision-making process. Performance at the IGT was compared between the four groups and then analysed according to clinical and psychometric variables.ResultsPatients with A-AN scored worse than UR and HC at the IGT (p<.01). PVL-feedback sensitivity parameter was lower in patients with R-AN and A-AN than in the two other groups (p<.01) and PVL-loss aversion parameter was lower in A-AN than in UR and R-AN (p<.01). Decision-making style, in particular learning and loss aversion parameters, accounted for a significant part of variance of psychopathology in patients with AN (p<.01).ConclusionsImpaired decision-making represents a state-associated, cognitive hallmark of AN. The aggravation of reward modulation along with illness progression may explain the persistence of symptoms despite their consequences on health. Reversal of decision-making impairment should not be limited by inherited vulnerability.DisclosureNo significant relationships.

Sex-specific role for serotonin 5-HT2A receptor in modulation of opioid-induced antinociception and reward in mice

Opioids are among the most effective analgesics and the mainstay of pain management. However, concerns about safety and abuse liability have challenged their widespread use by the medical community. Opioid-sparing therapies include drugs that in combination with opioids have the ability to enhance analgesia while decreasing opioid requirement as well as their side effects. Sex differences in antinociceptive responses to opioids have received increasing attention in recent years. However, the molecular mechanisms underlying sex differences related to opioid-sparing adjuncts remain largely unexplored. Using warm water tail-withdrawal as a mouse model of acute thermal nociception, our data suggest that adjunctive administration of the serotonin 5-HT2A receptor (5-HT2AR) antagonist volinanserin dose-dependently enhanced potency of the opioid analgesic oxycodone in male, but not female, mice. This antinociceptive-like response induced by oxycodone was also augmented in 5-HT2AR knockout (5-HT2AR−/−) male, but not female mice; an effect that was reversed by Cre-loxP-mediated selective expression of 5-HT2AR in dorsal root ganglion (DRG) neurons of 5-HT2AR−/− littermates. Pharmacological inhibition with volinanserin or genetic deletion in 5-HT2AR−/− animals potentiated the ability of oxycodone to reduce DRG excitability in male mice. Adjunctive volinanserin did not affect oxycodone-induced conditioned place preference (CPP), whereas it reduced oxycodone-induced locomotor sensitization in male and female mice. Together, these results suggest that adjunctive volinanserin augments opioid-induced antinociception, but not abuse-related behavior, through a sex-specific signaling crosstalk mechanism that requires 5-HT2AR expression in mouse DRG neurons. Ultimately, our results may pave the way for the clinical evaluation of volinanserin as a potential sex-specific opioid adjuvant.

Reward Rapidly Enhances Visual Perception

Rewards exert a deep influence on our cognition and behavior. Here, we used a paradigm in which reward information was provided at either encoding or retrieval of a brief, masked stimulus to show that reward can also rapidly modulate perceptual encoding of visual information. Experiment 1 (n = 30 adults) showed that participants’ response accuracy was enhanced when a to-be-encoded grating signaled high reward relative to low reward, but only when the grating was presented very briefly and participants reported that they were not consciously aware of it. Experiment 2 (n = 29 adults) showed that there was no difference in participants’ response accuracy when reward information was instead provided at the stage of retrieval, ruling out an explanation of the reward-modulation effect in terms of differences in motivated retrieval. Taken together, our findings provide behavioral evidence consistent with a rapid reward modulation of visual perception, which may not require consciousness.

An endogenous opioid circuit determines state-dependent reward consumption.

µ-Opioid peptide receptor (MOPR) stimulation alters respiration, analgesia and reward behaviour, and can induce substance abuse and overdose1-3. Despite its evident importance, the endogenous mechanisms for MOPR regulation of consummatory behaviour have remained unknown4. Here we report that endogenous MOPR regulation of reward consumption in mice acts through a specific dorsal raphe to nucleus accumbens projection. MOPR-mediated inhibition of raphe terminals is necessary and sufficient to determine consummatory response, while select enkephalin-containing nucleus accumbens ensembles are engaged prior to reward consumption, suggesting that local enkephalin release is the source of the endogenous MOPR ligand. Selective modulation of nucleus accumbens enkephalin neurons and CRISPR-Cas9-mediated disruption of enkephalin substantiate this finding. These results isolate a fundamental endogenous opioid circuit for state-dependent consumptive behaviour and suggest alternative mechanisms for opiate modulation of reward.

Deliberative Decision-Making in Macaques Removes Reward-Driven Response Vigor.

Most of our daily decisions are governed by one of two systems: an impulsive system driving instantaneous decisions and a deliberative system driving thoughtful ones. The impulsive system reacts to immediately available concrete rewards. In contrast, the deliberative system reacts to more delayed rewards and/or punishments, which imposes consideration of longer-term choice consequences. Contingency management for addiction treatment is hypothesized to engage deliberative processes. Ultimately, in both decision-making situations, an action is needed to enact the decision. Whether those actions differ in implementation is an open question whose answer could inform as to whether distinct neural systems are engaged. To explore whether there is evidence of separate mechanisms between deliberated and immediate choices, we trained monkeys to perform a decision-making task where they made a choice on a touch screen between two visual cues predicting different amounts of reward. In immediate choice (IC) trials, the cues appeared at the final response locations where subjects could immediately touch the chosen cue. In deliberated choice (DC) trials, compound cues appeared orthogonally to the response locations. After a delay, allowing for decision formation, an identifying cue component was displaced to the randomly assigned response locations, permitting subjects to reach for the chosen cue. Both trial types showed an effect of cue value on cue selection time. However, only IC trials showed an effect of the competing cue on response vigor (measured by movement duration) and a reach trajectory that deviated in the direction of the competing cue, suggesting a decision reexamination process. Reward modulation of response vigor implicates dopaminergic mechanisms. In DC trials, reach trajectories revealed a commitment to the chosen choice target, and reach vigor was not modulated by the value of the competing cue. Our results suggest that choice–action dynamics are shaped by competing offers only during instantaneous, impulsive choice. After a deliberated decision, choice–action dynamics are unaffected by the alternative offer cue, demonstrating a commitment to the choice. The potential relevance to contingency management is discussed.

Targeting Endocannabinoid Signaling in the Lateral Habenula as an Intervention to Prevent Mental Illnesses Following Early Life Stress: A Perspective.

Adverse events and childhood trauma increase the susceptibility towards developing psychiatric disorders (substance use disorder, anxiety, depression, etc.) in adulthood. Although there are treatment strategies that have utility in combating these psychiatric disorders, little attention is placed on how to therapeutically intervene in children exposed to early life stress (ELS) to prevent the development of later psychopathology. The lateral habenula (LHb) has been a topic of extensive investigation in mental health disorders due to its prominent role in emotion and mood regulation through modulation of brain reward and motivational neural circuits. Importantly, rodent models of ELS have been shown to promote LHb dysfunction. Moreover, one of the potential mechanisms contributing to LHb neuronal and synaptic dysfunction involves endocannabinoid (eCB) signaling, which has been observed to critically regulate emotion/mood and motivation. Many pre-clinical studies targeting eCB signaling suggest that this neuromodulatory system could be exploited as an intervention therapy to halt maladaptive processes that promote dysfunction in reward and motivational neural circuits involving the LHb. In this perspective article, we report what is currently known about the role of eCB signaling in LHb function and discuss our opinions on new research directions to determine whether the eCB system is a potentially attractive therapeutic intervention for the prevention and/or treatment of ELS-associated psychiatric illnesses.

Furthering GPR171 as a novel pain target by assessing its abuse liability

Previous work from our lab showed a small-molecule ligand for the G protein-coupled receptor, GPR171, is capable of modulating morphine antinociception in mice. This suggests possible clinical use as a combination therapeutic with opioids, but side effects, such as reward modulation, must be assessed. Here we investigated this ligand, MS15203, further by asking whether it alters morphine reward. To investigate this question, we used in vivo conditioned place preference and ex vivo immunohistochemistry. For conditioned place preference (CPP), animals were injected with MS15203 alone or in combination with morphine on Days 2-9 and placed in an isolated compartment of a three-chamber CPP apparatus. On Day 1 and 10 animals were allowed to roam freely through the entirety of apparatus, time spent in each chamber was quantified using motion tracking software. CPP results show MS15203 alone does not cause aversion or preference for the drug-paired chamber. MS15203 when combined with morphine decreases time spent in the drug-paired chamber compared to morphine alone, but is not significant. To test whether MS15203 alters dopamine neuron function, neuronal activity was assessed within the ventral tegmental area of animals treated with MS15203 alone or with morphine. Thirty minutes following injection of the drugs, animals were transcardially perfused and brains were sliced coronally (50 µm). Slices of ventral tegmental area (VTA) were stained for cfos and tyrosine hydroxylase, and colocalization of the two antibodies were subsequently visualized and quantified. IHC results corroborate in vivo CPP results by showing similar cfos activation in the VTA for controls and MS15203 groups. Taken together, these results further the potential of GPR171 as an opioid antinociceptive enhancer that does not increase the abuse liabilities of opioids. NARSAD Young Investigator Award Brain and Behavior Research Foundation, 2017 – 2019.

High-frequency neuromodulation improves obsessive-compulsive behavior.

Nearly one billion people worldwide suffer from obsessive-compulsive behaviors1,2, yet our mechanistic understanding of these behaviors is incomplete, and effective therapeutics are unavailable. An emerging perspective characterizes obsessive-compulsive behaviors as maladaptive habit learning3,4, which may be associated with abnormal beta-gamma neurophysiology of the orbitofrontal-striatal circuitry during reward processing5,6. We target the orbitofrontal cortex with alternating current, personalized to the intrinsic beta-gamma frequency of the reward network, and show rapid, reversible, frequency-specific modulation of reward- but not punishment-guided choice behavior and learning, driven by increased exploration in the setting of an actor-critic architecture. Next, we demonstrate that chronic application of the procedure over 5 days robustly attenuates obsessive-compulsive behavior in a non-clinical population for 3 months, with the largest benefits for individuals with more severe symptoms. Finally, we show that convergent mechanisms underlie modulation of reward learning and reduction of obsessive-compulsive symptoms. The results contribute to neurophysiological theories of reward, learning and obsessive-compulsive behavior, suggest a unifying functional role of rhythms in the beta-gamma range, and set the groundwork for the development of personalized circuit-based therapeutics for related disorders.