Reward-related Signals Research Articles

Cortico-striatal beta oscillations as a reward-related signal

The value associated with reward is sensitive to external factors, such as the time between the choice and reward delivery as classically manipulated in temporal discounting tasks. Subjective preference for two reward options is dependent on objective variables of reward magnitude and reward delay. Single neuron correlates of reward value have been observed in regions, including ventral striatum, orbital, and medial prefrontal cortex. Brain imaging studies show cortico-striatal-limbic network activity related to subjective preferences. To explore how oscillatory dynamics represent reward processing across brain regions, we measured local field potentials of rats performing a temporal discounting task. Our goal was to use a data-driven approach to identify an electrophysiological marker that correlates with reward preference. We found that reward-locked oscillations at beta frequencies signaled the magnitude of reward and decayed with longer temporal delays. Electrodes in orbitofrontal/medial prefrontal cortex, anterior insula, ventral striatum, and amygdala individually increased power and were functionally connected at beta frequencies during reward outcome. Beta power during reward outcome correlated with subjective value as defined by a computational model fit to the discounting behavior. These data suggest that cortico-striatal beta oscillations are a reward signal correlated, which may represent subjective value and hold potential to serve as a biomarker and potential therapeutic target.

Value-related learning in the olfactory bulb occurs through pathway-dependent perisomatic inhibition of mitral cells.

Associating values to environmental cues is a critical aspect of learning from experiences, allowing animals to predict and maximise future rewards. Value-related signals in the brain were once considered a property of higher sensory regions, but their wide distribution across many brain regions is increasingly recognised. Here, we investigate how reward-related signals begin to be incorporated, mechanistically, at the earliest stage of olfactory processing, namely, in the olfactory bulb. In head-fixed mice performing Go/No-Go discrimination of closely related olfactory mixtures, rewarded odours evoke widespread inhibition in one class of output neurons, that is, in mitral cells but not tufted cells. The temporal characteristics of this reward-related inhibition suggest it is odour-driven, but it is also context-dependent since it is absent during pseudo-conditioning and pharmacological silencing of the piriform cortex. Further, the reward-related modulation is present in the somata but not in the apical dendritic tuft of mitral cells, suggesting an involvement of circuit components located deep in the olfactory bulb. Depth-resolved imaging from granule cell dendritic gemmules suggests that granule cells that target mitral cells receive a reward-related extrinsic drive. Thus, our study supports the notion that value-related modulation of olfactory signals is a characteristic of olfactory processing in the primary olfactory area and narrows down the possible underlying mechanisms to deeper circuit components that contact mitral cells perisomatically.

Cognition-enhancing and cognition-impairing doses of psychostimulants exert opposing actions on frontostriatal neural coding of delay in working memory.

The prefrontal cortex (PFC) and extended frontostriatal circuitry play a critical role in executive cognitive processes that guide goal-directed behavior. Dysregulation of frontostriatal-dependent cognition is implicated in a variety of cognitive/behavioral disorders, including addiction and attention deficit hyperactivity disorder (ADHD). Psychostimulants exert dose-dependent and opposing actions on frontostriatal cognitive function. Specifically, low and clinically-relevant doses improve, while higher doses associated with abuse and addiction impair, frontostriatal-dependent cognitive function. Frontostriatal cognition is supported by the coordinated activity of neurons across this circuit. To date, the neural coding mechanisms that support the diverse cognitive actions of psychostimulants are unclear. This represents a significant deficit in our understanding of the neurobiology of frontostriatal cognition and limits the development of novel treatments for frontostriatal cognitive impairment. The current studies examined the effects of cognition-enhancing and cognition-impairing doses of methylphenidate (MPH) on the spiking activity of dorsomedial PFC (dmPFC) and dorsomedial striatal (dmSTR) neurons in 17 male rats engaged in a working memory task. Across this frontostriatal circuit, we observed opposing actions of low- and high-dose MPH on the population-based representation of delay: low-dose strengthened, while high-dose weakened, representation of this event. MPH elicited a more complex pattern of actions on reward-related signaling, that were highly dose-, region- and neuron-dependent. These observations provide novel insight into the neurophysiological mechanisms that support the cognitive actions of psychostimulants.

Ghrelin receptor antagonist JMV2959 blunts cocaine and oxycodone drug-seeking, but not self-administration, in male rats.

The drug overdose crisis has spawned serious health consequences, including the increased incidence of substance use disorders (SUDs), conditions manifested by escalating medical and psychological impairments. While medication management is a key adjunct in SUD treatment, this crisis has crystallized the need to develop additional therapeutics to facilitate extended recovery from SUDs. The "hunger hormone" ghrelin acts by binding to the growth hormone secretagogue receptor 1α (GHS1αR) to control homeostatic and hedonic aspects of food intake and has been implicated in the mechanisms underlying SUDs. Preclinical studies indicate that GHS1αR antagonists and inverse agonists suppress reward-related signaling associated with cocaine and opioids. In the present study, we found that the GHS1αR antagonist JMV2959 was efficacious to suppress both cue-reinforced cocaine and oxycodone drug-seeking, but not cocaine or oxycodone self-administration in male Sprague-Dawley rats. These data suggest a role of the ghrelin-GHS1αR axis in mediating overlapping reward-related aspects of cocaine and oxycodone and premises the possibility that a GHS1αR antagonist may be a valuable therapeutic strategy for relapse vulnerability in SUDs.

Reward-dependent Graded Suppression of Sensorimotor Beta-band Local Field Potentials During an Arm Reaching Task in NHP.

A better understanding of reward signaling in the sensorimotor cortices can aid in developing Reinforcement Learning-based Brain-Computer Interfaces (RLBCI) for restoration of movement functions with fewer implants. Brain-computer interfaces (BCIs) using local field potentials (LFPs) have recently achieved performance comparable to spike-BCIs [1]. With superior stability over time, LFPs may be the preferred signal for BCIs. We show that sensorimotor LFPs can provide reward level information (R1 - R3) like spikes[2]. We used a cued reward-level reaching task in which reward information was temporally dissociated from movement information. This allowed the study of reward- and movement-related modulations in LFPs. We recorded simultaneously from contralateral primary -somatosensory (S1), -motor (M1), and the dorsal premotor (PMd) cortices in a female Macaca Mulatta. We found that all three cortices' average beta band (14-30 Hz) amplitude showed robust modulation with reward levels during the cue presentation period. Such modulation was consistently observed after controlling for cue color, differences in behavioral variables, and electromyogram (EMG) activity. Statistical amplitude analysis showed that reward level could be extracted from the simple LFP feature of beta band amplitude, even before a reaching target appeared, and no specific reach plan could be developed. Clinical Relevance - The availability of reward-related signals in the sensorimotor cortical (S1, M1,and PMd) LFPs' prior to movement planning opens new avenues to build RLBCIs with fewer implants recording fewer sites among different cortices Reward and motivational representations derived from LFPs compared to spikes allow the development of long-term clinical applications given LFP's stability and ease of recording over long periods.

Task-level value affects trial-level reward processing

Despite disagreement about how anterior cingulate cortex (ACC) supports decision making, a recent hypothesis suggests that activity in this region is best understood in the context of a task or series of tasks. One important task-level variable is average reward because it is both a known driver of effortful behaviour and an important determiner of the tasks in which we choose to engage. Here we asked how average task value affects reward-related ACC activity. To answer this question, we measured a reward-related signal said to be generated in ACC called the reward positivity (RewP) while participants gambled in three tasks of differing average value. The RewP was reduced in the high-value task, an effect that was not explainable by either reward magnitude or outcome expectancy. This result suggests that ACC does not evaluate outcomes and cues in isolation, but in the context of the value of the current task.

Contextual influence of reinforcement learning performance of depression: evidence for a negativity bias?

Value-based decision-making impairment in depression is a complex phenomenon: while some studies did find evidence of blunted reward learning and reward-related signals in the brain, others indicate no effect. Here we test whether such reward sensitivity deficits are dependent on the overall value of the decision problem. We used a two-armed bandit task with two different contexts: one 'rich', one 'poor' where both options were associated with an overall positive, negative expected value, respectively. We tested patients (N = 30) undergoing a major depressive episode and age, gender and socio-economically matched controls (N = 26). Learning performance followed by a transfer phase, without feedback, were analyzed to distangle between a decision or a value-update process mechanism. Finally, we used computational model simulation and fitting to link behavioral patterns to learning biases. Control subjects showed similar learning performance in the 'rich' and the 'poor' contexts, while patients displayed reduced learning in the 'poor' context. Analysis of the transfer phase showed that the context-dependent impairment in patients generalized, suggesting that the effect of depression has to be traced to the outcome encoding. Computational model-based results showed that patients displayed a higher learning rate for negative compared to positive outcomes (the opposite was true in controls). Our results illustrate that reinforcement learning performances in depression depend on the value of the context. We show that depressive patients have a specific trouble in contexts with an overall negative state value, which in our task is consistent with a negativity bias at the learning rates level.

Cell-type-specific responses to associative learning in the primary motor cortex.

The primary motor cortex (M1) is known to be a critical site for movement initiation and motor learning. Surprisingly, it has also been shown to possess reward-related activity, presumably to facilitate reward-based learning of new movements. However, whether reward-related signals are represented among different cell types in M1, and whether their response properties change after cue-reward conditioning remains unclear. Here, we performed longitudinal in vivo two-photon Ca2+ imaging to monitor the activity of different neuronal cell types in M1 while mice engaged in a classical conditioning task. Our results demonstrate that most of the major neuronal cell types in M1 showed robust but differential responses to both the conditioned cue stimulus (CS) and reward, and their response properties undergo cell-type-specific modifications after associative learning. PV-INs' responses became more reliable to the CS, while VIP-INs' responses became more reliable to reward. Pyramidal neurons only showed robust responses to novel reward, and they habituated to it after associative learning. Lastly, SOM-INs' responses emerged and became more reliable to both the CS and reward after conditioning. These observations suggest that cue- and reward-related signals are preferentially represented among different neuronal cell types in M1, and the distinct modifications they undergo during associative learning could be essential in triggering different aspects of local circuit reorganization in M1 during reward-based motor skill learning.

Mid-lateral cerebellar complex spikes encode multiple independent reward-related signals during reinforcement learning

Although the cerebellum has been implicated in simple reward-based learning recently, the role of complex spikes (CS) and simple spikes (SS), their interaction and their relationship to complex reinforcement learning and decision making is still unclear. Here we show that in a context where a non-human primate learned to make novel visuomotor associations, classifying CS responses based on their SS properties revealed distinct cell-type specific encoding of the probability of failure after the stimulus onset and the non-human primate’s decision. In a different context, CS from the same cerebellar area also responded in a cell-type and learning independent manner to the stimulus that signaled the beginning of the trial. Both types of CS signals were independent of changes in any motor kinematics and were unlikely to instruct the concurrent SS activity through an error based mechanism, suggesting the presence of context dependent, flexible, multiple independent channels of neural encoding by CS and SS. This diversity in neural information encoding in the mid-lateral cerebellum, depending on the context and learning state, is well suited to promote exploration and acquisition of wide range of cognitive behaviors that entail flexible stimulus-action-reward relationships but not necessarily motor learning.

Neurobiological Basis of Reinforcement-Based Decision-Making in Adults With ADHD Treated With Lisdexamfetamine Dimesylate

Background: The objective of this study was to examine changes in the activation of the brain reward system following treatment with lisdexamfetamine (LDX) vs. placebo (PL) as a function of clinical improvement in attention deficit/hyperactivity disorder (ADHD) symptoms. Methods: Twenty adults with ADHD were included in a randomized cross-over study. Participants underwent two functional magnetic resonance imaging (fMRI) scans, after receiving 3 to 5 weeks of treatment with both LDX and PL. During scanning, participants performed the passive-avoidance learning task to assess reward-related learning using computational variables (e.g., estimated value and prediction error). Pre-treatment to post-treatment symptom change was assessed via the ADHD Rating Scale (ADHD-RS). The imaging contrasts were Object Choose or Object Refuse during the object choice component of the task, modulated by expected value (reward vs. nonreward cue), and Reward vs. Punishment during feedback, modulated by prediction error (expected vs. actual outcome). To address the primary objective, we performed group-level mass univariate analyses between pre-treatment to post-treatment percent change of the ADHD-RS total scores and the four contrast images under the choice and feedback conditions, with significance set at a whole-brain voxel-wise threshold of p < .05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels. Results: Improvement in ADHD symptoms was accompanied by significant increases of brain activation during the Object Refuse, Reward and Punishment contrasts in a widespread network including left caudate and putamen, and right orbitofrontal cortex (i.e., reward-related signaling) and left middle frontal, superior frontal, and precentral gyri (i.e., executive control). Conclusions: These findings are the first to show that the increase in responsiveness of systems engaged in reward processing with LDX treatment is positively related to symptom improvement. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD.

Neuronal Activity in the Premotor Cortex of Monkeys Reflects Both Cue Salience and Motivation for Action Generation and Inhibition.

Reward prospect weighs on motor decision processes, enhancing the selection of appropriate actions and the inhibition of others. While many studies have investigated the neuronal basis of reward representations and of cortical control of actions, the neuronal correlates of the influences of reward prospect on motor decisions are less clear. We recorded from the dorsal premotor cortex (PMd) of 2 male macaque monkeys performing a modified version of the Stop-signal (countermanding) task. This task challenges motor decisions by requiring responding to a frequent Go stimulus, but to suppress this response when a rare Stop signal is presented during the reaction time. We unbalanced the motivation to respond or to suppress the response by presenting a cue informing on three different rewards schedules: in one case, Go trials were rewarded more than Stop trials; in another case, Stop trials were rewarded more than Go trials; in the last case, both types of trials were rewarded equally. Monkeys adopted different strategies according to reward information provided by the cue: the higher the reward for Stop trials, the higher their ability to suppress the response and the slower their response to Go stimuli. PMd neuronal activity evolved in time and correlated with the behavior: PMd signaled first the cue salience, representing the chance to earn the highest reward at stake, then reflected the shaping of the motor choice by the motivation to move or to stop. These findings represent a neuronal correlate of the influence of reward information on motor decision.SIGNIFICANCE STATEMENT The motivation to obtain rewards drives how animals act over their environment. To explore the involvement of motor cortices in motivated behaviors, we recorded high-resolution neuronal activity in the premotor cortex of monkeys performing a task that manipulated the motivation to generate/withhold a movement through different cued reward probabilities. Our results show the presence of neuronal signals dynamically reflecting the salience of the cue, in the time immediately following its presentation, and a motivation-related activity in performing (or cancelling) a motor program, while the behavioral response approached. The encoding of multiple reward-related signals in this region leads to consider an important role of premotor areas in the reward circuitry supporting action.

Dopamine release, diffusion and uptake: A computational model for synaptic and volume transmission.

Computational modeling of dopamine transmission is challenged by complex underlying mechanisms. Here we present a new computational model that (I) simultaneously regards release, diffusion and uptake of dopamine, (II) considers multiple terminal release events and (III) comprises both synaptic and volume transmission by incorporating the geometry of the synaptic cleft. We were able to validate our model in that it simulates concentration values comparable to physiological values observed in empirical studies. Further, although synaptic dopamine diffuses into extra-synaptic space, our model reflects a very localized signal occurring on the synaptic level, i.e. synaptic dopamine release is negligibly recognized by neighboring synapses. Moreover, increasing evidence suggests that cognitive performance can be predicted by signal variability of neuroimaging data (e.g. BOLD). Signal variability in target areas of dopaminergic neurons (striatum, cortex) may arise from dopamine concentration variability. On that account we compared spatio-temporal variability in a simulation mimicking normal dopamine transmission in striatum to scenarios of enhanced dopamine release and dopamine uptake inhibition. We found different variability characteristics between the three settings, which may in part account for differences in empirical observations. From a clinical perspective, differences in striatal dopaminergic signaling contribute to differential learning and reward processing, with relevant implications for addictive- and compulsive-like behavior. Specifically, dopaminergic tone is assumed to impact on phasic dopamine and hence on the integration of reward-related signals. However, in humans DA tone is classically assessed using PET, which is an indirect measure of endogenous DA availability and suffers from temporal and spatial resolution issues. We discuss how this can lead to discrepancies with observations from other methods such as microdialysis and show how computational modeling can help to refine our understanding of DA transmission.

Beyond the Motor Cortex: Theta Burst Stimulation of the Anterior Midcingulate Cortex

BackgroundWhile the facilitatory and inhibitory effects of intermittent theta burst stimulation (iTBS) and continuous TBS (cTBS) protocols have been well documented on motor physiology, the action of TBS protocols on prefrontal functioning remain unclear. Here we asked whether iTBS or cTBS can differentially modulate reward-related signaling in the anterior midcingulate cortex (aMCC). MethodsAcross 2 experiments, we used a robot-assisted transcranial magnetic stimulation system, combined with electroencephalogram recordings, to investigate the aftereffects of prefrontal iTBS and cTBS on the reward positivity, an electrophysiological signal believed to index sensitivity of the aMCC to rewards. Twenty adults (age, 18–28 years) participated in experiment 1 in which we used a scalp landmark for TBS targeting, and 14 adults (age, 18–28 years) participated in experiment 2, in which we aimed to increase TBS effectiveness by utilizing cortical thickness maps to select individualized dorsal lateral prefrontal cortex targets. ResultsWe demonstrated that prefrontal iTBS suppressed reward-related signaling in the aMCC (reduction in reward positivity) and caused a decrease in postfeedback switch choices. cTBS displayed no effect. We replicated and strengthened this effect on the reward positivity by targeting dorsal lateral prefrontal cortex regions displaying maximal cortical thickness. ConclusionsWhile these results are inconsistent with reported TBS effects on motor cortex, the present findings offer a novel transcranial magnetic stimulation targeting approach and normative insights into the magnitude and time course of TBS-induced changes in aMCC excitability. By modulating how the aMCC links value to goal-directed behavior, this research opens an exciting new era of investigative possibilities in the understanding of aMCC function and treatment of aMCC dysfunction.

Reduced frontostriatal response to expected value and reward prediction error in remitted monozygotic twins with mood disorders and their unaffected high-risk co-twins.

Depressive episodes experienced in unipolar (UD) and bipolar (BD) disorders are characterized by anhedonia and have been associated with abnormalities in reward processes related to reward valuation and error prediction. It remains however unclear whether these deficits are associated with familial vulnerability to mood disorders. In a functional magnetic resonance imaging study, we evaluated differences in the expected value (EV) and reward prediction error (RPE) signals in ventral striatum (VS) and prefrontal cortex between three groups of monozygotic twins: affected twins in remission for either UD or BD (n = 53), their high-risk unaffected co-twins (n = 34), and low-risk twins with no family history of mood disorders (n = 25). Compared to low-risk twins, affected twins showed lower EV signal bilaterally in the frontal poles and lower RPE signal bilaterally in the VS, left frontal pole and superior frontal gyrus. The high-risk group did not show a significant change in the EV or RPE signals in frontostriatal regions, yet both reward signals were consistently lower compared with low-risk twins in all regions where the affected twins showed significant reductions. Our findings strengthen the notion that reduced valuation of expected rewards and reduced error-dependent reward learning may underpin core symptom of depression such as loss of interest in rewarding activities. The trend reduction in reward-related signals in unaffected co-twins warrants further investigation of this effect in larger samples and prospective follow-up to confirm possible association with increased familial vulnerability to mood disorders.

Encoding of eye movements explains reward-related activity in cerebellar simple spikes.

The cerebellum exhibits both motor and reward-related signals. However, it remains unclear whether reward is processed independently from the motor command or might reflect the motor consequences of the reward drive. To test how reward-related signals interact with sensorimotor processing in the cerebellum, we recorded Purkinje cell simple spike activity in the cerebellar floccular complex while monkeys were engaged in smooth pursuit eye movement tasks. The color of the target signaled the size of the reward the monkeys would receive at the end of the target motion. When the tracking task presented a single target, both pursuit and neural activity were only slightly modulated by the reward size. The reward modulations in single cells were rarely large enough to be detected. These modulations were only significant in the population analysis when we averaged across many neurons. In two-target tasks where the monkey learned to select based on the size of the reward outcome, both behavior and neural activity adapted rapidly. In both the single- and two-target tasks, the size of the reward-related modulation matched the size of the effect of reward on behavior. Thus, unlike cortical activity in eye movement structures, the reward-related signals could not be dissociated from the motor command. These results suggest that reward information is integrated with the eye movement command upstream of the Purkinje cells in the floccular complex. Thus reward-related modulations of the simple spikes are akin to modulations found in motor behavior and not to the central processing of the reward value.NEW & NOTEWORTHY Disentangling sensorimotor and reward signals is only possible if these signals do not completely overlap. We recorded activity in the floccular complex of the cerebellum while monkeys performed tasks designed to separate representations of reward from those of movement. Activity modulation by reward could be accounted for by the coding of eye movement parameters, suggesting that reward information is already integrated into motor commands upstream of the floccular complex.

Recruitment and disruption of ventral pallidal cue encoding during alcohol seeking.

A critical area of inquiry in the neurobiology of alcohol abuse is the mechanism by which cues gain the ability to elicit alcohol use. Previously, we found that cue-evoked activity in rat ventral pallidum robustly encodes the value of sucrose cues trained under both Pavlovian and instrumental contingencies, despite a stronger relationship between cue-evoked activity and behavioral latency after instrumental training (Richard etal., 2018, Elife, 7, e33107). Here, we assessed: (a) ventral pallidal representations of Pavlovian versus instrumental cues trained with alcohol reward, and (b) the impact of non-associative alcohol exposure on ventral pallidal representations of sucrose cues. Decoding of cue identity based on ventral pallidum firing was blunted for the Pavlovian alcohol cue in comparison to both the instrumental cue trained with alcohol and either cue type trained with sucrose. Further, non-associative alcohol exposure had opposing effects on ventral pallidal encoding of sucrose cues trained on instrumental versus Pavlovian associations, enhancing decoding accuracy for an instrumental discriminative stimulus and reducing decoding accuracy for a Pavlovian conditioned stimulus. These findings suggest that alcohol exposure can drive biased engagement of specific reward-related signals in the ventral pallidum.

Reinforcement Learning Recruits Somata and Apical Dendrites across Layers of Primary Sensory Cortex

SUMMARYThe mammalian brain can form associations between behaviorally relevant stimuli in an animal’s environment. While such learning is thought to primarily involve high-order association cortex, even primary sensory areas receive long-range connections carrying information that could contribute to high-level representations. Here, we imaged layer 1 apical dendrites in the barrel cortex of mice performing a whisker-based operant behavior. In addition to sensory-motor events, calcium signals in apical dendrites of layers 2/3 and 5 neurons and in layer 2/3 somata track the delivery of rewards, both choice related and randomly administered. Reward-related tuft-wide dendritic spikes emerge gradually with training and are task specific. Learning recruits cells whose intrinsic activity coincides with the time of reinforcement. Layer 4 largely lacked reward-related signals, suggesting a source other than the primary thalamus. Our results demonstrate that a sensory cortex can acquire a set of associations outside its immediate sensory modality and linked to salient behavioral events.

Minimal Circuit Model of Reward Prediction Error Computations and Effects of Nicotinic Modulations.

Dopamine (DA) neurons in the ventral tegmental area (VTA) are thought to encode reward prediction errors (RPE) by comparing actual and expected rewards. In recent years, much work has been done to identify how the brain uses and computes this signal. While several lines of evidence suggest the interplay of the DA and the inhibitory interneurons in the VTA implements the RPE computation, it still remains unclear how the DA neurons learn key quantities, for example the amplitude and the timing of primary rewards during conditioning tasks. Furthermore, endogenous acetylcholine and exogenous nicotine, also likely affect these computations by acting on both VTA DA and GABA (γ -aminobutyric acid) neurons via nicotinic-acetylcholine receptors (nAChRs). To explore the potential circuit-level mechanisms for RPE computations during classical-conditioning tasks, we developed a minimal computational model of the VTA circuitry. The model was designed to account for several reward-related properties of VTA afferents and recent findings on VTA GABA neuron dynamics during conditioning. With our minimal model, we showed that the RPE can be learned by a two-speed process computing reward timing and magnitude. By including models of nAChR-mediated currents in the VTA DA-GABA circuit, we showed that nicotine should reduce the acetylcholine action on the VTA GABA neurons by receptor desensitization and potentially boost DA responses to reward-related signals in a non-trivial manner. Together, our results delineate the mechanisms by which RPE are computed in the brain, and suggest a hypothesis on nicotine-mediated effects on reward-related perception and decision-making.

Effect of traumatic brain injury on nicotine-induced modulation of dopamine release in the striatum and nucleus accumbens shell.

BackgroundTraumatic brain injury is associated with substantial alterations in reward processing, but underlying mechanisms are controversial.ObjectiveA better understanding of alterations in dopamine (DA) release patterns from the dorsal striatum and nucleus accumbens shell (NAc) may provide insights into posttraumatic reward pathology.Materials and MethodsThe patterns of DA release with or without exposure to nicotine in brain slices with striatum and NAc, isolated from Sprague-Dawley rats with 6 psi fluid percussion (FPI) or sham injury were analysis by using fast-scan cyclic voltammetry. Tonic and phasic DA releases were assessed using single pulse and 10 pulses at 25 Hz, respectively. DA release relative to stimulation intensity, frequency, number of pulses, and paired-pulse facilitation was evaluated to determine release probability and response to bursting.ResultsThere was a profound suppression in tonic DA release after nicotine desensitization after FPI, and the input/output curve for the DA release based on stimulation intensity was shifted to the right. FPI was associated with a significant decrease in frequency-dependent DA release augmentation, DA release induced by high frequency stimulation trains, and DA release in response to paired-pulse facilitation. The effect of nicotine desensitization was similar in FPI and sham-injured animals, although significantly smaller after FPI. Nicotine desensitization–induced differences between phasic and tonic release concentrations that contrasted with the reward-related signals then became less prominent in NAc after FPI.ConclusionsTBI blunts DA release from mesolimbic reward centers, and more intense stimuli are required to produce context-dependent DA release sufficient to have a physiological effect.ImplicationsThe nicotine desensitization-related suppression in tonic DA release was profound with right-ward shift of the input/output curve for DA release after FPI. FPI was associated with a significant decrease in frequency-dependent DA release augmentation, DA release induced by high frequency stimulation trains, and DA release in response to paired-pulse facilitation. Nicotine desensitization–induced differences between phasic and tonic release concentrations that contrasted with the reward-related signals then became less prominent in NAc after FPI. TBI thus blunts DA release from mesolimbic reward centers, and more intense stimuli are required to produce context-dependent DA release sufficient to have a physiological effect.

Lateral septum stimulation disinhibits dopaminergic neurons in the antero-ventral region of the ventral tegmental area: Role of GABA-A alpha 1 receptors

The mechanisms commanding the activity of dopaminergic neurons of the ventral tegmental area (VTA) and the location of these neurons are relevant for the coding and expression of motivated behavior associated to reward-related signals. Anatomical evidence shows that several brain regions modulate VTA dopaminergic neurons activity via multiple mechanisms. However, there is still scarce knowledge of how the lateral septum (LS) modulates VTA activity. We performed in-vivo dual-probe microdialysis to measure VTA dopamine, glutamate and GABA extracellular levels after LS stimulation in the presence or absence of GABAergic antagonists. Anterograde tracing and immunohistochemical analysis was used to reveal the anatomical relationship between LS and VTA. LS stimulation significantly increased dopamine and GABA, but not glutamate, VTA extracellular levels. Intra VTA infusion of bicuculline, GABA-A receptor antagonist, inhibited the increase of dopamine but not of GABA VTA levels induced by LS stimulation. Intra VTA infusion of indiplon, selective positive allosteric modulator of GABA-A receptors containing alpha1 subunit, significantly increases VTA dopamine extracellular levels induced by LS. Combined c-Fos and tyrosine hydroxylase immunohistochemistry, revealed that LS stimulation increases the activity of dopaminergic neurons in the antero-ventral region of the VTA. Consistently, anterograde tracing with biotinylated dextran amine revealed the existence of fibers arising from the LS to the antero-ventral region of the VTA. Taken together, our results suggest that LS modulates dopaminergic activity in the antero-ventral region of VTA by inhibiting GABAergic interneurons bearing GABA-A receptors containing alpha1 subunit.