ROLE OF THE NUCLEUS ACCUMBENS AND ITS DOPAMINERGIC AND GLUTAMATERGIC AFFERENTS DURING DELAY DISCOUNTING

Effective decision making depends on an organism’s ability to assess available resources and choose the best available option. Organisms must also assess changes to reward value and update their behavior accordingly to keep selecting the best option. Value-based decision making depends on neural pathways including the nucleus accumbens (NAc) and its dopaminergic input from the ventral tegmental area (VTA). A glutamatergic afferent to the NAc core, the prelimbic cortex (PrL), may also be implicated in value-based decision-making, such as delay discounting. However, it is unknown how these dopaminergic and glutamatergic afferents to the NAc mediate value-based decision-making behavior. First, I used optogenetic techniques to examine the causal role of dopaminergic input to the NAc during delay discounting decision making tasks. This experiment revealed that dopamine release in the NAc core does not mediate delay discounting. The next set of experiments shifted focus to the PrL’s glutamatergic ennervation of the NAc. Electrophysiological recording of the PrL during our delay discounting task revealed that PrL neurons track the predicted and eventual outcome of preferred rewards, as the value of that reward shifts across blocks. Further, this tracking differentially encoded preferred rewards depending on rats’ inherent impulsivity, such that high impulsive rats demonstrated preferential encoding of the small/immediate option. In the next experiment, optogenetic stimulation of the PrL-NAc core pathway revealed that glutamate signaling in the NAc core was not sufficient to mediate delay discounting. Together, these experiments help to characterize of the neural circuits and mechanisms by which delay discounting behavior is processed within the brain, providing insight into the potential role of the NAc and its dopaminergic and glutamatergic afferents in mediating appropriate decisions.Doctor of Philosoph

Rapid dopamine signaling in the nucleus accumbens shell, but not core, encodes reward magnitude-based decision making

Effective decision making requires organisms to predict reward values and bias behavior toward the best available option. The mesolimbic dopamine system, including the nucleus accumbens (NAc) core and shell, is involved in this process. While studies support a differential role of the core and shell in subjective versus outcome based decision making, no studies have examined dopamine release to cues signaling the availability of different reward magnitudes. Here, electrochemical methods were used in rats to measure shell versus core dopamine release during a magnitude decision making task in which discrete cues signaled the availability of different reward sizes. Dopamine release in the shell (not core), preferentially tracks cues that predict the large preferred reward. Further, unique dopamine release dynamics are observed in the shell, but not core, upon lever press. These findings indicate a differential role of the core and shell in subjective, versus outcome-based, aspects of value-based decision-making.Master of Art

Reductions in Mesolimbic Dopamine Signaling and Aversion: Implications for Relapse and Learned Avoidance

The ability to adjust behavior appropriately following an aversive experience is essential for survival, yet variability in this process contributes to a wide range of disorders, including drug addiction. It is clear that proper approach and avoidance is regulated, in part, by the activity of the mesolimbic dopamine system. While the importance of this system as a critical modulator of reward learning has been extensively characterized, its involvement in directing aversion-related behaviors and learning is still poorly understood. Recent studies have revealed that aversive stimuli and their predictors cause rapid reductions in nucleus accumbens (NAc) dopamine concentrations. Furthermore, a normally appetitive stimulus that is made aversive through association with cocaine also decreases dopamine, and the magnitude of the expressed aversion predicts drug-taking. However, whether the presentation of a drug cue that reduces dopamine, and evokes a negative affective state, can motivate relapse is unknown. Here we demonstrate that the presentation of an aversive drug cue both reduces dopamine and causes cocaine-seeking. This finding is provocative because drug seeking in reinstatement designs is typically associated with increased dopamine signaling. Using a combination of fast scan cyclic voltammetry (FSCV) and in vivo electrophysiology we subsequently show that the presence of an aversive drug cue abolishes the dopaminergic encoding of other drug cues and alters NAc neuronal activity patterns. Importantly, a subpopulation of neurons that subsequently encode aspects of drug-seeking behavior increase their baseline firing rates during this aversive experience. We then examine the mechanistic regulation of dopamine signaling by aversive stimuli under more natural conditions. Using FSCV and site-specific behavioral pharmacology we demonstrate that blockade of ventral tegmental area kappa opioid receptors attenuates aversion-induced reductions in dopamine, and prevents proper avoidance learning caused by punishment. By maintaining D2 receptor occupancy within the NAc during punishment, we demonstrate the requirement of aversion-induced reductions in dopamine for aversive learning. Together, these studies inform an evolving model of striatal physiology. Our findings emphasize a role for both increases and decreases in dopamine signaling that modulate behavior by promoting the stimulus-specific activity of distinct striatal output pathways. The continued interrogation of this model may offer novel targets for therapeutic development aimed at treating neurodegenerative disease and drug addiction

Chronic Variable Stress Induces Avolition and Disrupts Corticoaccumbens Encoding of Approach Cues

Disorders in the ability to process, evaluate, and interact with rewards are hallmarks of a range of mental illnesses. Such disorders are multi-faceted and arise from altered activity throughout diffuse brain regions. Chronic variable stress (CVS) is an oft-used tool for modeling reward-related disorders in preclinical research because it impairs the function of multiple brain regions and causes a range of severe hedonic and motivational deficits. While much research has focused on the former, the latter is poorly characterized. A panel of behavioral tests was used to characterize the effect of CVS exposure on different facets of reward related behaviors in Sprague-Dawley rats. In a subset of animals, in vivo electrophysiology was used to assess the impact of CVS on reward encoding in a primary reward processing region, the nucleus accumbens (NAc). Behavioral deficits occurred in motivational, rather than hedonic, domains, and stress altered the encoding of primary rewards in the Shell subregion of the NAc, an area responsible for encoding value. The prelimbic region of the prefrontal cortex (PL) is known to be sensitive to stress and responsive to reward-predictive cues. The extent to which this area encodes the incentive value of cues has not been characterized. Pavlovian autoshaping is a behavior in which trained animals transfer the incentive value of a primary reward to an associated cue. In vivo electrophysiological recordings of single units in the PL of Sprague-Dawley rats demonstrated that this region was attuned to incentivized cues in the autoshaping paradigm. A projection pathway from the PL targeting the NAc Core (NAcC) subregion has a significant role in promoting motivated approach. However, little is known about how activity in this pathway (1.) changes during associative learning to encode incentivized cues or (2.) may be altered by stress. An intersectional fiber photometry approach used in male Sprague Dawley rats engaged in autoshaping demonstrated that the rapid acquisition of conditioned approach was associated with cue-induced PL-NAcC activity. Prior stress reduced both cue-directed behavior and associated cortical activity. These results support the interpretation that stress disrupts reward processing by altering the attribution of incentive to associated cues

The Neural Encoding of Reward in the Striatal-Pallidal Circuitry

Humans and animals are constantly exposed to external stimuli. The ability to process reward value of a stimulus is critical to guiding appropriate behavior and essential for survival. These processes are regulated by neuronal activity and neurochemical signaling in the reward circuitry, particularly in the nucleus accumbens (NAc). The NAc receives dopaminergic inputs from the midbrain ventral tegmental area (VTA) and sends GABAergic projections to the ventral pallidum (VP). Electrophysiological studies have characterized phasic neuronal responses in the NAc that differential encode appetitive and aversive taste stimuli. Exposure to an appetitive taste stimulus evoked predominantly phasic inhibitory responses in the NAc whereas a majority of responses to an aversive taste was excitation. The work presented here focused on investigating how activity in the NAc modulate reward encoding in downstream VP, and the role of dopamine signaling in regulating neuronal responses to reward in the NAc. Using electrophysiological recording techniques, we present evidence of neural encoding of reward information in the VP. VP neurons responded to appetitive and aversive taste stimuli with primarily inhibitory and excitatory responses, respectively. Furthermore, devaluation of the appetitive stimulus resulted from cocaine-induced taste aversion conditioning revealed that the encoding of sucrose shifted from inhibition to excitation, resembling that of an aversion response. These data suggest that the VP, similar to the NAc, also encode reward information neuronally. In a subsequent study, the influence of NAc on VP reward encoding was tested by pharmacologically manipulating activity in the NAc while monitoring the neuronal activity in the VP. We demonstrate that by inhibiting activity in the NAc with a GABAergic agonist, the neural encoding to sucrose in the VP was augmented, followed by increased sucrose consumption. These findings support the notion that at least some aspect of reward information processed in VP is modulated by NAc activity. In the final study, we show that chemogenetically suppressing activity of VTA dopamine neurons inverted the response profile to sucrose from inhibition to excitation in the NAc. This elimination of inhibitory reward encoding in the NAc was accompanied by a dampened motivational state, demonstrated by subjects terminating leverpress behavior for sucrose reward quicker in a progressive ratio test on day that dopamine signaling was chemogenetically suppressed but not in control condition. Taken together, results from these studies provide insights into how reward information is represented by physiological events in the reward circuitry. We demonstrate that neuronal responses in both the NAc and the VP encode reward and correlate strongly to reward-driven motivated behavior. Furthermore, we used a chemogenetic approach to show that suppressed NAc dopamine signaling models a low motivational state that is represented by altered neuronal responses in the NAc. This endeavor to better understand the neural representation of reward may help us better understand the physiology of both normal and diseased motivational and affective states

Ramping single unit activity in the medial prefrontal cortex and ventral striatum reflects the onset of waiting but not imminent impulsive actions.

The medial prefrontal cortex (mPFC) and ventral striatum (VS), including the nucleus accumbens, are key forebrain regions involved in regulating behaviour for future rewards. Dysfunction of these regions can result in impulsivity, characterized by actions that are mistimed and executed without due consideration of their consequences. Here we recorded the activity of single neurons in the mPFC and VS of 16 rats during performance on a five-choice serial reaction time task of sustained visual attention and impulsivity. Impulsive responses were assessed by the number of premature responses made before target stimuli were presented. We found that the majority of cells signalled trial outcome after an action was made (both rewarded and unrewarded). Positive and negative ramping activity was a feature of population activity in the mPFC and VS (49.5 and 50.4% of cells, respectively). This delay-related activity increased at the same rate and reached the same maximum (or minimum) for trials terminated by either correct or premature responses. However, on premature trials, the ramping activity started earlier and coincided with shorter latencies to begin waiting. For all trial types the pattern of ramping activity was unchanged when the pre-stimulus delay period was made variable. Thus, premature responses may result from a failure in the timing of the initiation of a waiting process, combined with a reduced reliance on external sensory cues, rather than a primary failure in delay activity. Our findings further show that the neural locus of this aberrant timing signal may emanate from structures outside the mPFC and VS.This research was funded in part by a Medical Research Council grant to J.W.D. (G0701500) and by a joint award from the Medical Research Council (G1000183) and Wellcome Trust (093875/Z/10/Z) in support of the Behavioural and Clinical Neuroscience Institute at Cambridge University. N.A.D. was funded by the University of Cambridge School of Clinical Medicine MB/PhD Program. The authors would like to thank Alan Lyon and David Theobald for assistance with histology, Tim Harris and the Applied Physics and Instrumentation Group at HHMI Janelia Farm for providing electrodes, Ken Harris and the Klustateam at UCL for providing software for spike detection and sorting, and Tahl Holtzman for technical assistance with training in surgical procedures.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/ejn.1289

The role of cellular and chemical signaling within the nucleus accumbens in value-based decision making behaviors

A critical component of an organism's survival is the ability to secure the necessary resources including food, shelter and mates. In order to make appropriate decisions to do so, animals must weigh the costs and benefits of different courses of action and choose the best available option. Importantly, these costs and benefits are rarely static, and organisms must attend to these changes in order to act appropriately. Multiple lines of research have identified that value-based decision making is mediated by a distributed network of brain nuclei including the nucleus accumbens (NAc) and its innervation from dopamine neurons located in the midbrain. However, the precise way in which this circuitry mediates value-based decision making remains unclear. The first set of experiments detailed in this dissertation used electrophysiological recording techniques to measure neural activity within the NAc during a risky decision making paradigm. These experiments revealed that a subset of NAc neurons tracked the different options available to the animal, displaying selective activity for risk versus safe options. Further, behavioral preferences to take a risk or play it safe were correlated with neural encoding of reward omissions. In the second set of experiments electrochemical procedures were used to evaluate the patterns of dopamine release that signal reward value as animals attend to changes in their environment and adjust their behavior accordingly. In these experiments, animals learned that cues predicted the availability of a smaller immediate reward or larger rewards delivered after varying delays. NAc dopamine concentration signaled the predicted value of the future outcome, and shifted as the relative value of the rewards changed. The final set of experiments evaluated possible causal links between phasic dopamine release and decision making using optogenetic methods. Animals displayed goal-directed behavior to receive optical stimulation of dopamine terminals, and adjusted their behavior as the intensity of stimulation changed. Further, stimulation of phasic dopamine release was sufficient to shift certain value-based decisions. Together, these experiments provide novel characterizations of the neural circuits and mechanisms by which value-based decisions are processed within the brain, providing insight into the potential role of the NAc and mesolimbic dopamine system in mediating appropriate decisions.Doctor of Philosoph

Sign Tracking and Goal Tracking Are Characterized by Distinct Patterns of Nucleus Accumbens Activity

During Pavlovian conditioning, if a cue (e.g., lever extension) predicts reward delivery in a different location (e.g., a food magazine), some individuals will come to approach and interact with the cue, a behavior known as sign tracking (ST), and others will approach the site of reward, a behavior known as goal tracking (GT). In rats, the acquisition of ST versus GT behavior is associated with distinct profiles of dopamine release in the nucleus accumbens (NAc), but it is unknown whether it is associated with different patterns of accumbens neural activity. Therefore, we recorded from individual neurons in the NAc core during the acquisition, maintenance, and extinction of ST and GT behavior. Even though NAc dopamine is specifically important for the acquisition and expression of ST, we found that cue-evoked excitatory responses encode the vigor of both ST and GT behavior. In contrast, among sign trackers only, there was a prominent decrease in reward-related activity over the course of training, which may reflect the decreasing reward prediction error encoded by phasic dopamine. Finally, both behavior and cue-evoked activity were relatively resistant to extinction in sign trackers, as compared with goal trackers, although a subset of neurons in both groups retained their cue-evoked responses. Overall, the results point to the convergence of multiple forms of reward learning in the NAc