Reward-seeking Behavior Research Articles

T62. A COMPUTATIONAL ANALYSIS OF MOTIVATIONAL DEFICITS IN SCHIZOPHRENIA SPECTRUM DISORDERS

BackgroundWe have found that measures of reinforcement learning (RL) performance correlate with negative symptoms severity in adult schizophrenia patients as well as in adolescents and young adults seeking psychiatric services. Most of these tasks assess reinforcement learning in stable environments, however. In unstable, or volatile environments, adaptive learning and decision making depend on the ability to use one’s own uncertainty to modulate attention to feedback. In stable RL environments, parameters called learning rates (signified by ⍺) capture the impact of prediction errors on changes in association strength with each subject having a single learning rate for a given kind of prediction error (positive and negative, e.g.). In volatile environments, learning rates might be more appropriately modeled as dynamic, modulated by uncertainty. Furthermore, uncertainty is known to guide what is called “the explore/exploit trade-off” – the threshold for choosing more informative options potentially at the expense of options with higher expected value.MethodsWe have examined the contribution of uncertainty processing to the emergence of negative symptoms in people along the schizophrenia spectrum, in several ways. First, in conjunction with fMRI, we administered 26 patients with schizophrenia (PSZ) and 23 healthy volunteers (HV) a 3-choice version of a probabilistic reversal learning task that required participants to resolve uncertainty and determine the new best option after sudden, sporadic contingency shifts. Second, we assessed the role of uncertainty in driving decision making under ambiguity, using two distinct tasks in cohorts of schizophrenia patients and healthy volunteers. Motivational symptoms were assessed in PSZ using the Scale for the Assessment of Negative Symptoms (SANS), from which we computed scores for Avolition/Role-Functioning, Anhedonia/Asociality, and an Avolition/Anhedonia/Asociality (AAA) factor.ResultsIn the context of the 3-choice version of a probabilistic reversal learning task, we found that SZ patients with more severe anhedonia and avolition show a reduced ability to dynamically modulate learning rates in a volatile environment. A follow-up psychophysiological interaction analysis revealed decreased dmPFC-VS connectivity concurrent with learning rate modulation, most prominently in individuals with the most severe motivational deficits. Finally, in the context of decision making under ambiguity, we have found that SZ patients with more severe anhedonia and avolition, as measured by the SANS, show a reduced tendency to explore contingences in the service of reducing uncertainty. Furthermore, we found that mean negative symptom scores correlated negatively with change in information weight, a model-based measure of directed exploration.DiscussionThese results indicate that multiple potential mechanisms underlie motivational deficits in schizophrenia spectrum disorders, including processes related to the ability to flexibly modulate learning and decision making according to one’s level of certainty about contingencies in the environment. That is, beyond deficits in reward-seeking behavior, a reduced ability to use uncertainty to modulate learning rates and a reduced tendency to engage in information-seeking behavior may make substantial contributions to negative symptoms in people with psychotic illness and people at risk for psychotic illness. The ability to dynamically value actions in terms of both prospective reward and information is likely to contribute deficits in motivation across diagnoses.

Astrocytic equilibrative nucleoside transporter type 1 upregulations in the dorsomedial and dorsolateral striatum distinctly coordinate goal-directed and habitual ethanol-seeking behaviours in mice.

Two distinct dorsal striatum regions, dorsomedial striatum (DMS) and dorsolateral striatum (DLS), are attributed to conditioned goal-directed and habitual reward-seeking behaviours, respectively. Previously, our study shows that the ethanol-sensitive adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), regulates ethanol-drinking behaviours. Although ENT1 is expressed in both neurons and astrocytes, astrocytic ENT1 is thought to regulate adenosine levels in response to ethanol. However, the role of DMS and DLS astrocytic ENT1 in goal-directed and habitual ethanol-seeking is not well known. Here, we identified whether the upregulation of astrocytic ENT1 in the DMS and DLS differentially regulates operant seeking behaviours towards the 10% sucrose (10S); 10% ethanol and 10% sucrose (10E10S); and 10% ethanol (10E) in mice. Using 4days of random interval (RI), mice exhibited habitual seeking for 10S, but goal-directed seeking towards 10E10S. Using the same mice conditioned with 10E10S, we examined 10E-seeking behaviour on a fixed ratio (FR) for 6days and RI for 8days. On the other hand, during FR and the first 4days of RI schedules, mice showed goal-directed seeking for 10E, whereas mice exhibited habitual seeking for 10E during the last 4days of RI schedule. Interestingly, DMS astrocytic ENT1 upregulation promotes shift from habitual to goal-directed reward-seeking behaviours. By contrast, DLS astrocytic ENT1 upregulation showed no effects on behavioural shift. Taken together, our findings demonstrate that DMS astrocytic ENT1 contributes to reward-seeking behaviours.

Activation of Astrocytes in the Dorsomedial Striatum Facilitates Transition From Habitual to Goal-Directed Reward-Seeking Behavior

BackgroundHabitual reward-seeking behavior is a hallmark of addictive behavior. The role of the dorsomedial striatum (DMS) in regulating goal-directed reward-seeking behavior has been long appreciated. However, it remains unclear how the astrocytic activities in the DMS differentially affect the behavioral shift. MethodsTo investigate the astrocytic activity-driven neuronal synaptic events and behavioral consequences, we chemogenetically activated astrocytes in the DMS using GFAP promoter–driven expression of hM3Dq, the excitatory DREADDs (designer receptors exclusively activated by designer drugs). First, we confirmed the chemogenetically induced cellular activity in the DMS astrocytes using calcium imaging. Then, we recorded electrophysiological changes in the synaptic activity of the two types of medium spiny neurons (MSNs): direct and indirect pathway MSNs. To evaluate the behavioral consequences, we trained mice in nose-poking operant chambers that developed either habitual or goal-directed reward-seeking behaviors. ResultsThe activation of DMS astrocytes reduced the frequency of spontaneous excitatory postsynaptic currents in the direct pathway MSNs, whereas it increased the amplitude of the spontaneous excitatory postsynaptic currents and decreased the frequency of spontaneous inhibitory postsynaptic currents in the indirect pathway MSNs. Interestingly, astrocyte-induced DMS neuronal activities are regulated by adenosine metabolism, receptor signaling, and transport. Importantly, mice lacking an astrocytic adenosine transporter, ENT1 (equilibrative nucleoside transporter 1; Slc29a1), show no transition from habitual to goal-directed reward-seeking behaviors upon astrocyte activation, while restoring ENT1 expression in the DMS facilitated this transition. ConclusionsOur findings reveal that DMS astrocyte activation differentially regulates MSNs’ activity and facilitates shifting from habitual to goal-directed reward-seeking behavior.

Sex Differences in Reward- and Punishment-Guided Actions

Men and women show differences in prevalence, symptomology, and treatment responsivity in most brain disorders. Here we use rodent models to explore sex differences in reward-seeking and punishment-avoidance behaviors, which are critical to the pathophysiology of psychiatric illnesses that also show sex differences, such as anxiety, major depressive, substance use, and attention-deficit hyperactivity disorders.

Paranigral VTA Nociceptin Neurons Constrain Motivation for Reward

Nociceptin and the nociceptin opioid peptide (NOP) receptor are widely distributed throughout the brain and have been proposed to have an endogenous role in regulating motivational state; however, how this regulation may occur remains unresolved. NOP receptors are broadly expressed in ventral tegmental area (VTA) dopamine neurons and their activation inhibits dopamine neuron activity, yet the behavioral consequences of this neuropeptide system’s impact in the VTA are unknown. Here we dissected the role of a VTA nociceptin peptide circuit that constrains reward-seeking behavior.

Orbitofrontal, dorsal striatum, and habenula functional connectivity in psychiatric patients with substance use problems

Substance abuse is commonly defined as the persistence of drug use despite negative consequences. Recent preclinical work has shown that higher input from the orbitofrontal cortex (OFC) to the dorsal striatum was associated with compulsive reward-seeking behavior despite negative effects. It remains unknown whether drug use is associated with the connectivity between the OFC and dorsal striatum in humans. We studied the resting state functional connectivity (RSFC) between the OFC, dorsal striatum, and habenula (and the whole brain in a separate analysis) in psychiatric inpatients with high (PU, problem users) and low (LU, low users) substance use. We matched PU and LU for psychiatric comorbidities. We found that PU showed higher RSFC between the left OFC and the left dorsal striatum than LU. RSFC between the habenula and both OFC and dorsal striatum was also higher in PU, which suggests the habenula may be a part of the same circuit. Finally, higher RSFC between the OFC and insula was also observed in PU. Our data shows that OFC, habenula, dorsal striatum, and insula may play an important role in PU. Furthermore, we postulate that the habenula may link the mesolimbic and cortico-striatal systems, which are altered in PU.

Amygdala-Midbrain Connections Modulate Appetitive and Aversive Learning

The central amygdala (CeA) orchestrates adaptive responses to emotional events. While CeA substrates for defensive behaviors have been studied extensively, CeA circuits for appetitive behaviors and their relationship to threat-responsive circuits remain poorly defined. Here, we demonstrate that the CeA sends robust inhibitory projections to the lateral substantia nigra (SNL) that contribute to appetitive and aversive learning in mice. CeA→SNL neural responses to appetitive and aversive stimuli were modulated by expectation and magnitude consistent with a population-level salience signal, which was required for Pavlovian conditioned reward-seeking and defensive behaviors. CeA→SNL terminal activation elicited reinforcement when linked to voluntary actions but failed to support Pavlovian associations that rely on incentive value signals. Consistent with a disinhibitory mechanism, CeA inputs preferentially target SNL GABA neurons, and CeA→SNL and SNL dopamine neurons respond similarly to salient stimuli. Collectively, our results suggest that amygdala-nigra interactions represent a previously unappreciated mechanism for influencing emotional behaviors.

Off-Target Influences of Arch-Mediated Axon Terminal Inhibition on Network Activity and Behavior.

Archaerhodopsin (ArchT)-mediated photoinhibition of axon terminals is commonly used to test the involvement of specific long-range neural projections in behavior. Although sustained activation of this opsin in axon terminals has the unintended consequence of enhancing spontaneous vesicle release, it is unclear whether this desynchronized signaling is consequential for ArchT’s behavioral effects. Here, we compare axon terminal and cell body photoinhibition of nucleus accumbens (NAc) afferents to test the utility of these approaches for uncovering pathway-specific contributions of neural circuits to behavior. First, in brain slice recordings we confirmed that ArchT photoinhibition of glutamatergic axons reduces evoked synaptic currents and increases spontaneous transmitter release. A further consequence was increased interneuron activity, which served to broadly suppress glutamate input via presynaptic GABAB receptors. In vivo, axon terminal photoinhibition increased feeding and reward-seeking behavior irrespective of the afferent pathway targeted. These behavioral effects are comparable to those obtained with broad inhibition of NAc neurons. In contrast, cell body inhibition of excitatory NAc afferents revealed a pathway-specific contribution of thalamic input to feeding behavior and amygdala input to reward-seeking under extinction conditions. These findings underscore the off-target behavioral consequences of ArchT-mediated axon terminal inhibition while highlighting cell body inhibition as a valuable alternative for pathway-specific optogenetic silencing.

Testosterone reactivity is associated with reduced neural response to reward in early adolescence

The marked increase in adolescent reward-seeking behavior has important implications for adaptive and maladaptive development. Reward-seeking is linked to increased testosterone and increased neural responses to reward cues. How acute testosterone changes modulate neural reward systems remains unclear. Based on previous work, adolescents, particularly males, showing an increase in endogenous testosterone reactivity were hypothesized to show increased neural response to reward in ventromedial prefrontal cortex, ventral striatum, and posterior cingulate cortex. Sixty-one healthy adolescents aged 10–13 (38 female, mean age = 12.01 [SD = 1.00]) completed a reward-cue processing task during fMRI. Saliva samples to be assayed for testosterone were collected immediately before and after scanning. Acute testosterone changes were not associated with variation in behavioral performance. Within ventromedial prefrontal and posterior cingulate cortices, increased acute testosterone change was associated with reduced discrimination between rewarded and un-rewarded trials. Results suggest that increasing levels of testosterone may result in reduced attention to/salience of task irrelevant information. In contrast to previous studies that found a positive association between testosterone and neural response to reward, the reward information in the current paradigm was irrelevant to success in task performance. These results are consistent with theoretical conceptualization of testosterone’s role in reproduction, which involves a shift in salience to short-term relative to long-term goals. These data further emphasized the need to consider context in the study of hormones; specific behaviors will be up- or down-regulated by a hormone based on the fit of the behavior with the broader contextual goal being orchestrated by the hormone.

Endocannabinoid LTD in Accumbal D1 Neurons Mediates Reward-Seeking Behavior.

SummaryThe nucleus accumbens (NAc) plays a key role in drug-related behavior and natural reward learning. Synaptic plasticity in dopamine D1 and D2 receptor medium spiny neurons (MSNs) of the NAc and the endogenous cannabinoid (eCB) system have been implicated in reward seeking. However, the precise molecular and physiological basis of reward-seeking behavior remains unknown. We found that the specific deletion of metabotropic glutamate receptor 5 (mGluR5) in D1-expressing MSNs (D1miRmGluR5 mice) abolishes eCB-mediated long-term depression (LTD) and prevents the expression of drug (cocaine and ethanol), natural reward (saccharin), and brain-stimulation-seeking behavior. In vivo enhancement of 2-arachidonoylglycerol (2-AG) eCB signaling within the NAc core restores both eCB-LTD and reward-seeking behavior in D1miRmGluR5 mice. The data suggest a model where the eCB and glutamatergic systems of the NAc act in concert to mediate reward-seeking responses.

Acute administration of perampanel, an AMPA receptor antagonist, reduces cognitive impairments after traumatic brain injury in rats

Traumatic brain injury (TBI) is a major cause of death and physical as well as cognitive disability for which an effective treatment option remains to be identified. Evidence in preclinical models has indicated that antagonists of the α-amino-3-hydroxy-5-methyl-4-isozazole propionate (AMPA) receptor exert neuroprotective effects after mechanical injury in vitro and in vivo. In particular, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate (perampanel), a selective AMPA receptor antagonist with good bioavailability, was recently shown to therapeutically protect against the sequelae of TBI in the rodent controlled cortical impact model. However, this model induces a largely focal injury and is less representative of diffuse injury components that occur in TBI resulting from acceleration/deceleration forces. Here, we investigated the neuroprotective effects of perampanel in the rodent lateral fluid percussion injury model (LFPI), which produces both focal and diffuse injury. Pre- or post-injury administration of perampanel in male adult rats attenuated the injury-induced increase in the pro-apoptotic bax/bcl-xL ratio in the hippocampus; reduced impairments in learning and memory, assessed by the Morris water maze test; and reduced impairments in reward-seeking behavior, assessed by a female encounter test. Although additional studies are needed to determine the sex-related differences in the neuroprotective effects, these results provide support for the therapeutic potential of perampanel in TBI.

Impulsive-compulsive disorders in Parkinson's Disease: influence on individual and social decision-making processes

Parkinson's Disease (PD) has been considered for a long time as a neurodegenerative disorder affecting mainly motor functions, because of the involvement of basal ganglia. Recent research has shown that these brain structures have a crucial role even in higher level cognitive and social functions, as executive ones, impulse control and decision-making. A research of the peer-reviewed scientific literature was conducted in order to identify articles on the dysfunctions in individual and social decision-making in PD. This work provides the reader with a literature review on individual and social decision-making processes in PD, highlighting how the existence of impulse control disorders and the associated reward-seeking behaviors might elucidate the social symptoms of PD, both in terms of abnormal risk proneness and/or reward salience.

Opposite Consequences of Tonic and Phasic Increases in Accumbal Dopamine on Alcohol-Seeking Behavior

SummaryDespite many years of work on dopaminergic mechanisms of alcohol addiction, much of the evidence remains mostly correlative in nature. Fortunately, recent technological advances have provided the opportunity to explore the causal role of alterations in neurotransmission within circuits involved in addictive behaviors. Here, we address this critical gap in our knowledge by integrating an optogenetic approach and an operant alcohol self-administration paradigm to assess directly how accumbal dopamine (DA) release dynamics influences the appetitive (seeking) component of alcohol-drinking behavior. We show that appetitive reward-seeking behavior in rats trained to self-administer alcohol can be shaped causally by ventral tegmental area-nucleus accumbens (VTA-NAc) DA neurotransmission. Our findings reveal that phasic patterns of DA release within this circuit enhance a discrete measure of alcohol seeking, whereas tonic patterns of stimulation inhibit this behavior. Moreover, we provide mechanistic evidence that tonic-phasic interplay within the VTA-NAc DA circuit underlies these seemingly paradoxical effects.

Optogenetic Activation of the Basolateral Amygdala Promotes Both Appetitive Conditioning and the Instrumental Pursuit of Reward Cues.

Reward-associated stimuli can both evoke conditioned responses and acquire reinforcing properties in their own right, becoming avidly pursued. Such conditioned stimuli (CS) can guide reward-seeking behavior in adaptive (e.g., locating food) and maladaptive (e.g., binge eating) ways. The basolateral amygdala (BLA) regulates conditioned responses evoked by appetitive CS, but less is known about how the BLA contributes to the instrumental pursuit of CS. Here we studied the influence of BLA neuron activity on both behavioral effects. Water-restricted male rats learned to associate a light-tone cue (CS) with water delivery into a port. During these Pavlovian conditioning sessions, we paired CS presentations with photo-stimulation of channelrhodopsin-2 (ChR2)-expressing BLA neurons. BLA photo-stimulation potentiated CS-evoked port entries during conditioning, indicating enhanced conditioned approach and appetitive conditioning. Next, new rats received Pavlovian conditioning without photo-stimulation. These rats then received instrumental conditioning sessions where they could press an inactive lever or an active lever that produced CS presentation, without water delivery. Rats pressed more on the active versus inactive lever, and pairing CS presentation with BLA-ChR2 photo-stimulation intensified responding for the CS. This suggests that BLA-ChR2 photo-stimulation enhanced CS incentive value. In a separate experiment, rats did not reliably self-administer BLA-ChR2 stimulations, suggesting that BLA neurons do not carry a primary reward signal. Last, intra-BLA infusions of d-amphetamine also intensified lever-pressing for the CS. The findings suggest that BLA-mediated activity facilitates CS control over behavior by enhancing both appetitive Pavlovian conditioning and instrumental pursuit of CS.SIGNIFICANCE STATEMENT Cues paired with rewards can guide animals to valuable resources such as food. Cues can also promote dysfunctional reward-seeking behavior, as in overeating. Reward-paired cues influence reward seeking through two major mechanisms. First, reward-paired cues evoke conditioned anticipatory behaviors to prepare for impending rewards. Second, reward-paired cues are powerful motivators and they can evoke pursuit in their own right. Here we show that increasing neural activity in the basolateral amygdala enhances both conditioned anticipatory behaviors and pursuit of reward-paired cues. The basolateral amygdala therefore facilitates cue-induced control over behavior by both increasing anticipation of impending rewards and making reward cues more attractive.

Contribution of the prefrontal cortex and basolateral amygdala to behavioral decision-making under reward/punishment conflict.

Control of reward-seeking behavior under conditions of punishment is an important function for survival. We designed a task in which rats could choose to either press a lever and obtain a food pellet accompanied by a footshock or refrain from pressing the lever to avoid footshock, in response to tone presentation. In the task, footshock intensity steadily increased, and the task was terminated when the lever press probability reached < 25% (last intensity). Rats were trained until the last intensity was stable. Subsequently, we investigated the effects of the pharmacological inactivation of the ventromedial prefrontal cortex (vmPFC), lateral orbitofrontal cortex (lOFC), and basolateral amygdala (BLA) on task performance. Bilateral inactivation of the vmPFC, lOFC, and BLA did not alter lever press responses at the early stage of the task. The number of lever presses increased following vmPFC and BLA inactivation but decreased following lOFC inactivation during the later stage of the task. The last intensity was elevated by vmPFC or BLA inactivation but lowered by lOFC inactivation. Disconnection of the vmPFC-BLA pathway induced behavioral alterations that were similar to vmPFC or BLA inactivation. Inactivation of any regions did not alter footshock sensitivity and anxiety levels. Our results demonstrate a strong role of the vmPFC and BLA and their interactions in reward restraint to avoid punishment and a prominent role of the lOFC in reward-seeking under reward/punishment conflict situations.

Impulsivity Relates to Relative Preservation of Mesolimbic Connectivity in Patients with Parkinson Disease.

The relationship between Parkinson Disease (PD) pathology, dopamine replacement therapy (DRT), and impulse control disorder (ICD) development is still incompletely understood. Given the sensorimotor-lateral substantia nigra (SN) selective degeneration associated with PD, we posit that a relative sparing of the limbic-medial SN in the context of DRT drives impulsive, reward-seeking behavior in PD patients with recent history of severe impulsivity. Impulsive and control participants were selected from a consecutive list of PD patients receiving pre-operative deep brain stimulation (DBS) planning scans including 3T structural MRI and 64 direction diffusion tensor imaging (DTI). Using previously identified substantia nigra (SN) subsegment network connectivity profiles to develop classification targets, split-hemisphere target-based SN segmentation with probabilistic tractography was performed. The relative subsegment volumes and strength of connectivity between the SN and the limbic, associative, and motor network targets were compared. Our results show that there is greater probability of connectivity between the SN and limbic network targets relative to motor and associative network targets in PD patients with recent history of severe impulsivity as compared to PD patients without impulsivity (P=0.0075). We did not observe relative volumetric subsegment differences across groups. Firstly, our results suggest that fine-grained, atlas-derived classification targets may be used in PD to parcellate and classify functionally distinct subsegments of the SN, with the apparent preservation of previously reported topographical limbic-medial SN, associative-ventral SN, and sensorimotor-lateral SN orientation. We suggest that relative, as opposed to absolute, degeneration amongst SN-associated dopaminergic networks relates to the impulsivity phenotype in PD.

Cocaine- and amphetamine-regulated transcript peptide promotes reward seeking behavior in socially isolated rats

Reward deficit, expressed as anhedonia, is one of the major symptoms associated with neuropsychiatric disorders, but the underlying maladaptations have not been understood. Herein, we test the hypothesis that the neuropeptide cocaine- and amphetamine-regulated transcript (CART) may participate in the process. The study is justified since the peptide is a major player in inducing satiety and also processing of reward. The rats were socially isolated to induce reward deficit and conditioned to self-stimulate via an electrode in lateral hypothalamus (LH)-medial forebrain bundle (MFB) region. Compared to group–housed control rats, the socially isolated animals showed decreased lever press activity and elevated ICSS threshold indicating anhedonia-like condition. However, the effects of social isolation were alleviated by CART administered via intracerebroventricular route. The changes in the expression of CART protein and mRNA were screened using immunofluorescence and qRT-PCR methods, respectively. Socially isolated rats showed reduction in the expression of CART in the LH, nucleus accumbens shell (AcbSh) and posterior ventral tegmental area (pVTA) and CART mRNA in the Acb and LH. Double immunostaining with antibodies against CART and synaptophysin revealed significant loss of colabeled elements in LH, AcbSh and pVTA. We suggest that down-regulation of endogenous CARTergic system in the LH-pVTA-AcbSh reward circuitry may be causal to motivational anhedonia like phenotype seen in neuropsychiatric conditions.

Vulnerability to relapse under stress: insights from affective neuroscience.

In this review article, we aim at analysing the role of stress in addiction and relapse. In order to do so, we first offer a summary of the findings from affective neuroscience trying to understand compulsive reward-seeking behaviours. These behaviours are characterised by an imbalance between the considerable amount of effort an individual is willing to mobilise to obtain a reward and the comparatively little pleasure that is felt once the reward is obtained and consumed. We illustrate how the neuropsychological mechanisms underlying these behaviours might play an important role in substance addiction and in particular for stress-induced relapse. We then review evidence suggesting that a personalised health approach would be particularly beneficial in order to better understand the role of stress in addiction and relapse in humans. More specifically, observing individual differences during distinct forms of learning (Pavlovian, habitual and goal-directed learning) might represent a very promising way to identify risk profiles for compulsive reward-seeking behaviours, addiction, and vulnerabilities to relapse under stress.

Pain modulates neural responses to reward in the medial prefrontal cortex.

Pain has been found to promote reward‐seeking behaviors, which might be a consequence of modulated brain activities in the reward neural circuitry in a painful state. The present study investigated how pain affected reward processing and reward‐related neural activities using fMRI technique. A total of 50 healthy participants were recruited and used for data analyses, with half being treated with topical capsaicin cream and the other half with hand cream (treatment: pain or control). The participants were asked to perform a card‐guessing game when their brain activities responding to feedbacks (outcome: win or loss) were recorded. Behavioral results showed that participants in pain group overestimated their correct choices in the card‐guess game. Whole‐brain fMRI analysis revealed that the main effect of outcome (win vs. loss) activated a typical network of the reward neural circuitry, including the medial prefrontal cortex (mPFC) and the bilateral nucleus accumbens (NAcc). Importantly, the region of interest analysis revealed a significant interaction of treatment and outcome in the mPFC, with increased mPFC neural activity responding to win outcome in pain condition. Moreover, the functional connectivity between the mPFC and the NAcc was decreased in pain condition. We conclude that the pain‐induced modulation of the mPFC activity could result in alterations of both the emotional response to and the cognitive evaluation of reward.

Median raphe controls acquisition of negative experience in the mouse.

Adverse events need to be quickly evaluated and memorized, yet how these processes are coordinated is poorly understood. We discovered a large population of excitatory neurons in mouse median raphe region (MRR) expressing vesicular glutamate transporter 2 (vGluT2) that received inputs from several negative experience-related brain centers, projected to the main aversion centers, and activated the septohippocampal system pivotal for learning of adverse events. These neurons were selectively activated by aversive but not rewarding stimuli. Their stimulation induced place aversion, aggression, depression-related anhedonia, and suppression of reward-seeking behavior and memory acquisition-promoting hippocampal theta oscillations. By contrast, their suppression impaired both contextual and cued fear memory formation. These results suggest that MRR vGluT2 neurons are crucial for the acquisition of negative experiences and may play a central role in depression-related mood disorders.