Stanley Bogdan Floresco

Professor

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Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2019)
Contributions of nucleus accumbens circuitry to aspects of aversively-motivated behaviors (2018)

The nucleus accumbens is a heterogeneous brain structure involved in the integration of limbic and cortical input and the coordination of motor output during behavior. Made up primarily of two major subregions, the nucleus accumbens core (NAcC) and shell (NAcS), this region has been suggested to contribute to dissociable aspects of appetitive behavior on the basis of differential functions localized within these subregions. Briefly, the NAcC may promote states of behavioral action during reward-seeking, while the NAcS may refine such behavior by actively inhibiting inappropriate or irrelevant actions. In Chapter 1, we discuss relevant research related to the dissociability of the NAcC and NAcS at the circuit and behavioral levels. In Chapters 2, 3, and 4, we examine the contribution of these two NAc subregions, as well as associated cortical and limbic structures, to Pavlovian and instrumental suppression. Results suggested that the NAcC acted to promote behavioral indices of reward-seeking vigor, while the NAcS was necessary for the appropriate instantiation and expression of conditioned suppression. In Chapter 5, we probed the relevance of these NAc subregions to the performance of a novel active/passive avoidance behavior. On this task, rats had to dynamically promote or inhibit their responding, guided by discrete cues, to avoid a painful stimulus. While both NAc subregions were necessary for promoting behavior during active avoidance trials, only the NAcS was required for inhibiting responding during presentations of the passive avoidance stimulus. A control study suggested that neither NAc subregion was necessary for unconditioned responding to foot-shock, indicating that the previous results could not be explained by changes in pain sensitivity. We also probed the role of monoaminergic transmission to motivational conflict and active/passive avoidance by systemically administering d-amphetamine (AMPH) to a subset of animals in Chapter 3 and 4. These results suggested that AMPH promoted punishment induced inhibition of behavior during motivational conflict, but had the opposite effect during passive avoidance trials, inducing pressing despite punishment. Chapter 5 discusses these results in the framework of a dichotomy between response-promotion and response-inhibition, relating these findings to extant literature in the appetitive and aversive domains.

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Prefrontal cortical GABAergic regulation of cognition : implications for schizophrenia & other psychiatric disorders (2018)

Deficient GABA signalling in the frontal lobes has been posited as a pathophysiological mechanism underlying symptoms and cognitive impairments in schizophrenia and other psychiatric disorders. Yet, there has been a lack of basic research assessing how decreased prefrontal cortex (PFC) GABAergic transmission impacts cognition. The experiments described here were aimed at elucidating how PFC GABA signalling regulates working memory and attention, two core cognitive processes altered in psychiatric conditions. In the first experiment, pharmacological reduction of PFC GABAA receptor transmission led to delay-independent deficits in working memory, suggesting that PFC GABA signalling may be particularly important for working memory encoding, while PFC NMDA glutamatergic transmission appears to be necessary for working memory maintenance. Given that attention strongly influences encoding, the next experiment identified separable attentional processes modulated by PFC GABAergic transmission. In addition to disrupting attention, PFC GABA dysfunction may contribute to working memory deficits by impairing filtering of distracting information. In the third study, PFC GABAergic regulation of resistance to proactive interference from past information was examined in a massed-trials variant of the reference/working radial maze task. While PFC GABAA antagonism did not increase proactive interference effects, strong impairments in working and reference memory were found across the test session. PFC inactivation did not affect performance, indicating that disinhibition of the PFC may interfere with activity of other circuitry responsible for mnemonic or cognitive functions. To investigate this, expression of c-Fos, a marker of neuronal activation, was throughout the brain following PFC GABAA antagonism in the final studies. Reduced PFC GABA function was associated with widespread increases in neuronal activation in PFC efferent regions in animals at rest. Intriguingly, enhanced neuronal activation following PFC disinhibition was only observed in the hippocampus and rhomboid thalamic nucleus of animals trained on the task, suggesting that plasticity in the PFC-thalamic-hippocampal circuit associated with learning may alter the effects of diminished PFC GABA function on neuronal activation. Collectively, the work described identifies component aspects of cognition affected by deficiencies of PFC GABA, and suggests that diminished or dysfunctional PFC GABA signalling could play a role in cognitive deficits observed in neuropsychiatric disorders.

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Dopaminergic mechanisms guiding probabilistic choice (2014)

Dopamine, acting via different modes of transmission, is involved in making cost-benefit decisions involving reward uncertainty. Phasic and tonic dopamine contribute to different behavioral strategies by influencing the connectivity and strength of inputs within the cortico-limbic-striatal circuit. Chapter 1 introduces the construct of risk-based decision-making and approaches to studying it before delving into how tonic and phasic dopamine are involved in encoding reward uncertainty and reward prediction error. This chapter also describes the nucleus accumbens (NAc) as a corticolimbic interface innervated by dopamine and the lateral habenula (LHb) as a modulator of dopamine and source of negative reward prediction error. Chapter 2 examines how receptor-selective dopaminergic drugs infused into the NAc influence risk-based decision-making. The D₂ receptor, mainly influenced by tonic dopamine, was not involved in risky choice. Stimulation of the D₁ receptor, presumably by phasic dopamine, optimized decision-making while blockade of this receptor made animals risk-averse. Chapter 3 demonstrates that the LHb is critical for expressing subjective choice preferences. Inactivation of the LHb induced indifference in animals trained on probabilistic and delay discounting tasks. LHb inactivation on a simpler reward magnitude discrimination task and inactivation of closely adjacent areas were without effect, highlighting both the behavioral and anatomical specificity of this effect. Chapter 4 reveals that temporally and behaviorally specific phasic dopamine changes are critical for probabilistic choice biases. Ventral tegmental area stimulation following a risky loss increased risky choice while stimulation of the LHb, or intermediary rostromedial tegmental area, following a risky win decreased risky choice. Chapter 5 integrates these findings with previous literature and proposes ideas for how phasic and tonic dopamine acting in the cortico-limbic-striatal circuit are used to bias choices involving reward uncertainty.

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The contribution of prefrontal-subcortical circuitry to risk-based decision making (2012)

The ability to make decisions about different risks and rewards appears to recruit a neural circuit that includes the prefrontal cortex (PFC), the amygdala and the ventral striatum. The present thesis used a combination of behavioural, statistical, anatomical, and pharmacological techniques to elucidate the nature of risk-based decision making and the underlying neural circuits and neuromodulatory systems that contribute to this form of behaviour. Chapter 2 examined probabilistic discounting as a model of risk-based decision making. Statistical modeling revealed substantial individual variability in discounting of large, probabilistic rewards in well-trained animals which develops over the course of training. These discounting patterns were not influenced by luckiness in receiving reward early in training. Rather, patterns of risky vs. safe choices were influenced by both 1) recent luck in forced choice outcomes early in training and 2) outcomes of free choice trials in the animal’s recent reinforcement history. Chapter 3 revealed that the prelimbic region of the rat medial PFC makes a selective contribution to probabilistic discounting by keeping track of changes in reward probability in order to update value representations, whereas the insular and dorsal anterior cingulate subregions have no influence on risky choice. While it makes no contribution to choice outcome, the OFC region aids decision latency. Chapter 4 describes a series of asymmetrical disconnections which revealed that separate neural circuits mediate different aspects of risk-based decision making. Amygdala projections to the nucleus accumbens bias behaviour towards large, risky reward options whereas top-down projections from the medial PFC to the amygdala regulate this bias and promote adjustments in choice towards smaller, but potentially more valuable, options. Chapter 5 revealed that the contribution of medial PFC activity to probabilistic discounting is further modulated by a fine balance of D1 and D2 receptor activity. The general discussion in Chapter 6 integrates these findings into a broader perspective on the neural basis of decision making about probabilistic rewards, while focusing on the PFC and its interactions with other neural systems to guide decision making.

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Master's Student Supervision (2010 - 2018)
Modulation of probabilistic discounting and probabilistic reversal learning by dopamine within the medial orbitofrontal cortex (2017)

Weighing the value of a reward against its likelihood of delivery is a necessary component of adaptive decision-making. The medial subregion of the orbitofrontal cortex (OFC) plays a key role in this form of cognition, as inactivation of this subregion in rats alters behaviour during risk/reward decision-making and a probabilistic assay of cognitive flexibility. The medial OFC receives dopaminergic input from midbrain neurons, yet whether dopamine (DA) modulates medial OFC function has been virtually unexplored. Here, we assessed how D₁ and D₂ receptors in the medial OFC may modulate adaptive decision-making in the face of probabilistic outcomes. One series of experiments assessed probabilistic reversal learning, while another set of studies assessed risk/reward decision-making using a probabilistic discounting task. Separate groups of well-trained rats, received intra-medial OFC microinfusions of selective D₁ or D₂ antagonists prior to task performance. Our results indicate that blocking D₁ receptors in the medial OFC impaired while blockade of D₂ receptors facilitated the number of reversals completed. This may be due to an impairment in probabilistic reinforcement learning, as effects were mediated by changes in errors during the initial discrimination of the task. One function for DA within the medial OFC might therefore be to inform about responses that yield a higher probability of reward over less profitable options to maintain adaptive choice. During risk/reward decision-making, blocking D₁ receptors reduced risky choice driven by an increase in negative feedback sensitivity. Blockade of D₂ receptors increased risky choice, mediated instead by an increase in reward sensitivity. This implicates medial OFC DA in dampening the win-stay/lose-shift strategy to limit the use of immediate reward feedback in situations where rats have prior knowledge about reward profitability. These findings highlight a novel role for medial OFC DA in guiding behavior in situations of reward uncertainty. Medial OFC D₁ and D₂ receptors play dissociable and opposing roles in different forms of reward-related action selection. Elucidating how DA within different nodes of mesocorticolimbic circuitry biases behavior in these situations will expand our understanding of the mechanisms regulating optimal and aberrant decision-making.

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Optogenetic dissection of temporal dynamics of amygdala-striatal interplay during risk/reward decision making (2017)

Assessing costs and benefits associated with different options that vary in terms of rewardmagnitude and uncertainty is an adaptive behaviour which allows us to select an optimal courseof action. Previous studies using reversible pharmacological inactivations have shown that thebasolateral amygdala (BLA) to nucleus accumbens (NAc) pathway plays a key role in promotingchoice towards larger, riskier rewards. Neural activity in the BLA and NAc show distinct, phasicchanges in firing prior to action initiation and following action outcomes. Yet, how temporally precise patterns of activity within BLA-NAc circuitry influence choice behaviour is unclear. Weassessed how optogenetic silencing of BLA projection terminals in the NAc altered actionselection during probabilistic decision making. Rats that received intra-BLA infusions of anAAV encoding for the inhibitory opsin eArchT were well-trained on a probabilistic discountingtask, where they chose between a smaller/certain reward and a larger/riskier reward, with theprobability of obtaining the larger reward changing from 50% to 12.5% across two separateblocks of trials. During testing, discrete 4-7 second pulses of light were delivered via fiber opticferrules into the NAc to suppress activity within BLA terminals during specific task events;during the period prior to choice or during the outcome immediately following a choice.Silencing activity of BLA inputs to the NAc prior to choice reduced selection of the morepreferred option, suggesting that at this time, activity within this pathway biases choice towardsmore preferred rewards. Silencing during reward omissions increased risky choice during thelow-probability block, indicating that activity in this circuit after non-rewarded actions serves tomodify subsequent choice behaviour. In contrast, silencing during rewarded outcomes did notreliably affect choice behaviour. Collectively these data demonstrate how patterns of activity in BLA-NAc circuitry convey different types of information that guide optimal action-selection insituations involving reward uncertainty.

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A dissociable role for dopamine receptors in the basolateral amygdala in risk/reward decision making (2015)

Different aspects of cost/benefit decision making involving uncertain rewards are facilitated by distributed corticolimbic circuits linking different regions of the prefrontal cortex, ventral striatum and the basolateral amygdala (BLA). Dopamine (DA) also plays an integral role in promoting choice of larger, uncertain rewards, as manipulations of DA transmission the PFC or nucleus accumbens alters risky choice. However, considerably less is known about how DA activity within the BLA regulates risk-based decision making. The present study assessed the effects of DA receptor modulation within the BLA on risk-based decision making, utilizing a probabilistic discounting task. Rats were trained to choose between a small/certain lever (1 sugar pellet) and a large/risky lever (4 sugar pellets) delivered in a probabilistic manner. The odds of obtaining the larger reward decreased in a systematic manner across 4 blocks of trials (100%, 50%, 25%, & 12.5%) during a daily session. Animals received counterbalanced intra-BLA microinfusions of the D1 receptor antagonist SCH23390, D2 antagonist eticlopride, the D1 agonist SKF81297 or D2 agonist quinpirole. Blockade of D1 receptors in the BLA caused rats to discount the larger/uncertain reward significantly more when compared to their performance after saline infusions, resulting in a reduction in risky choice most prominently during blocks where delivery of the larger reward was uncertain. Further, stimulation of the D1 receptor produced an optimization effect on choice behavior, increasing risky choice when it is more advantageous and decreasing risky choice when it is not advantageous. D1 receptors in the BLA seem to have an important role in facilitating optimal decision making and promoting choice of larger uncertain rewards. D2 receptor blockade showed a significant reduction in reward sensitivity, while stimulation of the D2 receptor did not affect choice behavior. More generally, these findings highlight a key contribution by mesoamygdala DA in regulating certain aspects of cost/benefit decision making, particularly the D1 receptor which may be the primary mechanism through which DA exerts its effect the BLA. These findings may have important implications to understanding mechanisms underlying disruptions in decision making and reward processes in psychiatric disorders linked to dysfunction of the DA system and the amygdala.

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The role of corticotropin-releasing factor in mediating the effect of acute stress on effort-based decision-making (2015)

The acute stress response is an adaptive response to threats in the environment, activating numerous coordinating systems to return the organism to homeostasis. Episodes of acute stress can have differential impacts on learning and memory functioning depending on myriad factors including the context, duration or timing of the stress. The manner in which acute stress influences higher-level cognitive function, including decision-making, however, is relatively less known. Decision-making involves weighing the alternative costs and benefits in order to optimize choice behavior. Increasing the amount of effort required in order to obtain a reward is one type of cost that can alter the subjective value of objectively larger rewards. Using an operant chamber assay, rats were required to choose between a low effort/low reward lever (LR; 2 pellets), and a high effort/high reward lever (HR; 4 pellets), with the effort requirement increasing over trial blocks (2, 5, 10, and 20 presses). Normally rats will choose the HR lever more often when the effort cost is low, reducing their preference for this option as the amount of effort increases. Previous research in our lab revealed that one hour of restraint stress reduces choice of the HR option in this task, which was not mimicked by systemic corticosterone (CORT) injection and not blocked by the dopamine (DA) antagonist, flupenthixol (Shafei et al.2012). The goal of the current study is to elucidate the neurochemical mechanisms underlying the ability of acute stress to reorganize effort-related decision-making preferences and to clarify the regional specificity of this action. Initial experiments found that corticotropin-releasing factor (CRF), which initiates the hypothalamic-pituitary-adrenal (HPA) axis, is primarily involved in mediating the effect of acute stress, as prior CRF antagonism (alpha-helical CRF; 30 μg) ameliorated the effect of one hour of acute restraint stress and central CRF infusion (3 μg) mimicked the effect of acute restraint stress on HR preference. The effect of CRF was not due to altering the subjective value of objectively larger rewards, as prior CRF administration (3 μg) had no effect on choice behavior when there were no costs associated with reward, however, this manipulation did reduce the motivation to work for reward, indicating that CRF acts in the effort-based decision-making task by reducing the drive to work for reward. Subsequent experiments aimed to investigate the regional specificity of CRF action in reorganizing effort-related preference behavior. With this in mind, we targeted the ventral tegmental area (VTA), as previous experiments revealed that CRF is released in the VTA in response to stress (Wang et al.,2005), and intra-VTA CRF reduces motivation to work for reward (Wanat et al.,2013). Intra-VTA, but not intra-nucleus accumbens (NAc) core, CRF infusion (0.5 μg) mimicked the effect of central CRF and acute restraint stress on HR preference, signifying the importance of this region in mediating the behavioral effect of acute stress on effort choice. Taken together, these experiments highlight the importance of CRF in mediating the effect of effort-based decision-making and indicate that CRF transmission may influence the motivational impairments and abnormal decision-making associated with human depression.

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Effort-based decision making is sensitive to the effects of acute stress (2011)

Acute stress can either exert beneficial or detrimental effects on different forms of cognition, and these effects may be mediated in part by enhanced glucocorticoid and dopaminergic activity. Recent studies in humans have shown that acute stress disrupts certain aspects of cost/benefit decision making. In the following series of experiments, we assessed the effects of acute restraint stress on different forms of cost/benefit decision making, and some of the hormonal and neurochemical mechanisms that may underlie these effects. Effort-based decision making was assessed with a discounting task where rats chose between a low effort/reward lever (1 press=2 pellets), or a high effort/reward lever that delivered 4 pellets, with the effort requirement increasing over 4 blocks of discrete trials (2, 5, 10, and 20 presses). A single exposure to 1 hour stress decreased preference for the high effort/reward and increased response latencies. Control experiments revealed that these effects did not appear to be mediated by general decreases in motivation or reduced preference for larger rewards. A separate group of rats were trained on delay discounting task where they chose between a small/immediate reward (1 pellet) or a larger, 4 pellet reward delivered after a delay (0, 15, 30, 45 sec). In contrast to effort discounting, acute stress did not affect choice of larger, delayed rewards. The role of glucocorticoids in regulating effort-based decision making was assessed via the systemic administration of exogenous corticosterone (1 or 3 mg/kg). These treatments failed to mimic the effects of stress on effort discounting. In a final experiment, dopamine receptor blockade with flupenthixol (0.25 mg/kg) prior to restraint to did not attenuate the stress-induced effects on effort-related choice. However, this treatment abolished the stress-induced increase in response latencies. These data suggest that acute stress interferes somewhat selectively with cost/benefit evaluations concerning rewards of different magnitudes and the relative effort costs associated with obtaining them. These effects do not appear to be mediated by enhanced glucocorticoid activity, whereas dopaminergic activation may contribute to increased latencies induced by stress. These findings may provide insight on impairments in decision making and anergia associated with stress-related disorders such as depression.

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Amphetamine sensitization disrupts certain aspects of associative learning about natural rewards (2010)

Repeated exposure to psychostimulant drugs induces numerous behavioral, and neuronal changes, which in animals is thought to model certain neural adaptations that may contribute to drug addiction. Chronic AMPH has repeatedly been shown to alter the acquisition and expression of associations between a conditioned stimulus (CS) and natural rewards. Although repeated psychostimulant exposure can interfere with associative learning about natural food rewards, the manner in which these treatments affect acquisition and expression of these associations remains unclear. The current study investigated how repeated AMPH exposure (5 x 2 mg/kg over 10 days) affects learning, extinction and cue-induced reinstatement of instrumental responding of food-seeking behavior. Rats were trained over 7 days to press one of two levers for food and a tone/light CS. During subsequent extinction conducted over 3-6 days, responding delivered neither food nor the CS. On reinstatement tests, active lever presses produced the CS, but not food. Rats received repeated AMPH or saline prior to training (exp. 1A), after instrumental training (exp. 1B), or after training and extinction (exp. 1C). In experiment 1A, cue-induced reinstatement was blunted significantly in AMPH-treated rats. In contrast, AMPH-treatment after initial training (experiment 1B) significantly retarded extinction relative to controls, but did not affect cue-induced reinstatement. In experiment 1C, AMPH exposed rats displayed enhanced cue-induced reinstatement. Experiment 2 was conducted to clarify the results of experiment 1A. Rats were trained to nosepoke for food following a CS, and were then tested in the presence of two novel levers, responding on one delivered the food-associated CS. AMPH treatment impaired the acquisition of a new response with conditioned reinforcement. These findings suggest that repeated AMPH exposure prior to formation of response-CS associations selectively disrupts the ability of food-related stimuli to influence instrumental responding. Exposure after initial associative learning impedes extinction. AMPH administration after training and extinction enhance responding. Collectively, these findings suggest that AMPH sensitization can perturb certain aspects of amygdala-mediated associative learning related to natural, food rewards, and this impairment seems to reflect a weakened CS-reward association as opposed to a reduced preference for the food.

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Dissociable roles for nucleus accumbens core and shell in regulating risk-based decision making (2010)

Decision making under conditions of risk and uncertainty constitutes a fundamental aspect of society. Few routine cost/benefit decisions are independent of any consideration of risk and uncertainty, from investing and financial matters to simple assessments of time management and resource allocation. Neuropsychological studies with brain-damaged patients gave initial insights into the cortical contributions to risk-based decision making. Subsequent imaging work has allowed for an understanding of the neural functioning of patients afflicted by disorders which impair risk-based decision making and has also implicated various subcortical structures, including the nucleus accumbens, in these types of decisions. Recent research in humans has shown that nucleus accumbens activation precedes risk-taking or risk-seeking on a financial decision making task. Additionally, animal research has determined that lesions of the nucleus accumbens bias choice away from larger but riskier rewards. The current experiments expand upon these findings by demonstrating that inactivation of a subregion of the accumbens, the shell, is responsible for this bias while the other subregion, the core, mediates the speed at which these decision are made. The effects of accumbens inactivation on risky choice appeared to be due to a reduced tendency to choose the riskier option following trials where rats chose risky and received reward (i.e., reduced win-stay performance), suggesting reduced reward sensitivity. Additionally, this set of experiments demonstrates that instead of inducing risk-aversive tendencies, inactivation of the nucleus accumbens interferes with general value judgments. Specifically, accumbens inactivation induces a slight reduction in preference for the larger reward when the risk/uncertainty component is eliminated. Additionally, inactivation only shifts choice preference away from the more valuable option when it is larger and probabilistic. These data suggest that in addition to effort- and delay-based decision making, the nucleus accumbens also mediates risk-based decision making. In addition to decisions under risk, the nucleus accumbens also seems to play a smaller, yet significant role in judgments of overall value and utility.

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