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Cardinal, R. N.

Publications and source records attributed to Cardinal, R. N..

9 recordsLinked to original sources
bioRxiv2023

Common roles for serotonin in rats and humans for computations underlying flexible decision-making

Serotonin is critical for adapting behavior flexibly to meet changing environmental demands. Cognitive flexibility is important both for successful attainment of goals, as well as for social interactions, and is frequently impaired in neuropsychiatric disorders, including obsessive-compulsive disorder (OCD). However, a unifying mechanistic framework accounting for the role of serotonin in behavioral flexibility has remained elusive. Here, we demonstrate common effects of manipulating serotonin function across two species (rats and humans) on latent processes supporting choice behavior during probabilistic reversal learning using computational modelling. The findings support a role of serotonin in behavioral flexibility and plasticity, indicated, respectively, by increases or decreases in choice repetition ( stickiness) or reinforcement learning rates depending upon manipulations intended to increase or decrease serotonin function. More specifically, the rate at which expected value increased following reward and decreased following punishment (reward and punishment learning rates) was greatest after sub-chronic administration of the selective serotonin reuptake (SSRI) citalopram (5 mg/kg for 7 days followed by 10 mg/kg twice a day for 5 days) in rats. Conversely, humans given a single dose of an SSRI (20mg escitalopram), which can decrease post-synaptic serotonin signalling, and rats that received the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which destroys forebrain serotonergic neurons, exhibited decreased reward learning rates. A basic perseverative tendency ( stickiness), or choice repetition irrespective of the outcome produced, was likewise increased in rats after the 12-day SSRI regimen and decreased after single dose SSRI in humans and 5,7-DHT in rats. These common effects of serotonergic manipulations on rats and humans - identified via computational modelling - suggest an evolutionarily conserved role for serotonin in plasticity and behavioral flexibility and have clinical relevance transdiagnostically for neuropsychiatric disorders.

neuroscience↗
bioRxiv2021

Controlling one's world: identification of sub-regions of primate PFC underlying goal-directed behavior

Impaired detection of causal relationships between actions and their outcomes can lead to maladaptive behavior. However, causal roles of specific prefrontal cortex (PFC) sub-regions and the caudate nucleus in mediating such relationships in primates are unclear. We inactivated and over-activated five PFC sub-regions, reversibly and pharmacologically: areas 24 (perigenual anterior cingulate cortex), 32 (medial PFC), 11 (anterior orbitofrontal cortex, OFC), 14 (rostral ventromedial PFC/medial OFC) and 14-25 (caudal ventromedial PFC), and the anteromedial caudate, to examine their role in expressing learned action-outcome contingencies using a contingency degradation paradigm in marmosets. Area 24 or caudate inactivation impaired the response to contingency change, while area 11 inactivation enhanced it, and inactivation of areas 14, 32 or 14-25 had no effect. Over-activation of areas 11 and 24 impaired this response. These findings demonstrate distinct roles of PFC sub-regions in goal-directed behavior and illuminate the candidate neurobehavioral substrates of psychiatric disorders including obsessive-compulsive disorder.

neuroscience↗
bioRxiv2020

Effect of lysergic acid diethylamide (LSD) on reinforcement learning in humans

The non-selective serotonin 2A (5-HT2A) receptor agonist lysergic acid diethylamide (LSD) holds promise as a treatment for some psychiatric disorders. Psychedelic drugs such as LSD have been suggested to have therapeutic actions through their effects on learning. The behavioural effects of LSD in humans, however, remain largely unexplored. Here we examined how LSD affects probabilistic reversal learning in healthy humans. Healthy volunteers received intravenous LSD (75g in 10 mL saline) or placebo (10mL saline) in a within-subjects design and completed a probabilistic reversal learning task. Participants had to learn through trial and error which of three stimuli was rewarded most of the time, and these contingencies switched in a reversal phase. Computational models of reinforcement learning were fitted to the behavioural data to assess how LSD affected the updating ("learning rates") and deployment ("reinforcement sensitivity") of value representations during choice, as well as "stimulus stickiness", which assays choice repetition irrespective of reinforcement history. Conventional measures assessing sensitivity to immediate feedback ("win-stay" and "lose-shift" probabilities) were unaffected, whereas LSD increased the impact of the strength of initial learning on perseveration. Computational modelling revealed that the most pronounced effect of LSD was enhancement of the reward learning rate. The punishment learning rate was also elevated. Stimulus stickiness was decreased by LSD, reflecting heightened exploratory behaviour, while reinforcement sensitivity was unaffected. Increased reinforcement learning rates suggest LSD induced a state of heightened plasticity. These results indicate a potential mechanism through which revision of maladaptive associations could occur in the clinical application of LSD. Significance statementThe psychedelic ("mind-manifesting") drug LSD holds promise for the treatment of some psychiatric disorders. Theories have postulated its therapeutic potential centres on enhancing learning and flexible thinking. Here we provide substantiating empirical evidence by examining the computations underlying behaviour as healthy volunteers learned through trial and error under LSD. Viewing choice as based on representations of an actions value, LSD increased the speed at which value was updated following feedback, which was more pronounced following reward than punishment. Behaviour was also more exploratory under LSD, irrespective of the outcome of actions. These results indicate that LSD impacted a fundamental belief-updating process inherent in the brain which can be leveraged to revise maladaptive associations characteristic of a range of mental disorders.

neuroscience↗
bioRxiv2020

Individual differences in the engagement of habitual control over alcohol seeking predicts the development of compulsive alcoholseeking and drinking

Excessive drinking is an important behavioural characteristic of alcohol addiction, but not the only one. Individuals addicted to alcohol crave alcoholic beverages, spend time seeking alcohol despite negative consequences, and eventually drink to intoxication. With prolonged use, control over alcohol seeking devolves to anterior dorsolateral striatum, dopamine-dependent mechanisms implicated in habit learning and individuals in whom alcohol-seeking relies more on these mechanisms are more likely to persist in seeking alcohol despite the risk of punishment. Here, we tested the hypothesis that the development of habitual alcohol-seeking predicts the development of compulsive seeking and that, once developed, it is associated with compulsive alcohol drinking. Male alcohol-preferring rats were pre-exposed intermittently to a two-bottle choice procedure, and trained on a seeking-taking chained schedule of alcohol reinforcement until some individuals developed punishment-resistant seeking behaviour. The associative basis of their seeking responses was probed with an outcome-devaluation procedure, early or late in training. After seeking behaviour was well established, subjects that had developed greater resistance to outcome-devaluation (were more habitual) were more likely to show punishment-resistant (compulsive) alcohol seeking. These individuals also drank more alcohol, despite quinine adulteration, even though having similar alcohol preference and intake before and during instrumental training. They were also less sensitive to changes in the contingency between seeking responses and alcohol outcome, providing further evidence of recruitment of the habit system. We therefore provide direct behavioural evidence that compulsive alcohol seeking emerges alongside compulsive drinking in individuals that have preferentially engaged the habit system.

neuroscience↗
bioRxiv2020

Serotonin depletion impairs both Pavlovian and instrumental reversal learning in healthy humans

Serotonin is implicated in aversive processing and updating responses to changing environmental circumstances. Optimising behaviour to maximise reward and minimise punishment may require shifting strategies upon encountering new situations. Likewise, emotional reactions to threats are critical for survival yet must be modified as danger shifts from one source to another. Whilst numerous psychiatric disorders are characterised by behavioural and emotional inflexibility, few studies have examined the contribution of serotonin in humans. We modelled both processes in two independent experiments (N = 97), using instrumental and aversive Pavlovian reversal learning paradigms, respectively. Upon depleting the serotonin precursor tryptophan - in a double-blind randomised placebo-controlled design - healthy volunteers showed impairments in updating both behaviour and emotion to reflect changing contingencies. Reversal deficits in each domain, furthermore, were correlated with the extent of tryptophan depletion. These results translate findings in experimental animals to humans and have implications for the neurochemical basis of cognitive inflexibility.

neuroscience↗
bioRxiv2020

Effect of tryptophan depletion on conditioned threat memory expression: role of intolerance of uncertainty

BackgroundResponding emotionally to danger is critical for survival. Normal functioning also requires flexible alteration of emotional responses when a threat becomes safe. Aberrant threat and safety learning occurs in many psychiatric disorders including post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and schizophrenia, where emotional responses can persist pathologically. Whilst there is evidence that threat and safety learning can be modulated by the serotonin systems, there have been few studies in humans. We addressed a critical clinically relevant question: How does pharmacological lowering of serotonin affect the retention of conditioned threat memory? MethodsForty-seven healthy participants underwent threat conditioning on Day 1 followed by an extinction session. Emotional responding was assessed by the skin conductance response (SCR). On Day 2, we employed acute dietary tryptophan depletion to lower serotonin temporarily, in a double-blind placebo-controlled randomized between-groups design. We then tested for the return of conditioned threat memory spontaneous recovery). We also measured self-reported intolerance of uncertainty, known to modulate threat memory expression. ResultsThe expression of emotional memory was attenuated in participants who had undergone tryptophan depletion. Individuals who were more intolerant of uncertainty showed even greater attenuation of emotion following depletion. ConclusionsThese results support the view that serotonin is involved in predicting aversive outcomes and refine our understanding of the role of serotonin in the persistence of emotional responsivity, with implications for individual differences in vulnerability to psychopathology.

neuroscience↗
bioRxiv2019

Serotonin depletion amplifies distinct human social emotions as a function of individual differences in personality

Serotonin is involved in a wide range of mental capacities essential for navigating the social world, including emotion and impulse control. Much recent work on serotonin and social functioning has focused on decision-making. Here we investigated the influence of serotonin on human emotional reactions to social conflict. We used a novel computerised task that required mentally simulating social situations involving unjust harm and found that depleting the serotonin precursor tryptophan - in a double-blind randomised placebo-controlled design - enhanced emotional responses to the scenarios in a large sample of healthy volunteers (n = 73), and interacted with individual differences in trait personality to produce distinctive human emotions. Whereas guilt was preferentially elevated in highly empathic participants, annoyance was potentiated in those high in trait psychopathy, with medium to large effect sizes. Our findings show how individual differences in personality, when combined with fluctuations of serotonin, may produce diverse emotional phenotypes. This has implications for understanding vulnerability to psychopathology, determining who may be more sensitive to serotonin-modulating treatments, and casts new light on the functions of serotonin in emotional processing.

neuroscience↗
bioRxiv2018

Action-outcome knowledge dissociates from behavior in obsessive-compulsive disorder following contingency degradation

Goal-directed and habitual systems orchestrate action control. In disorders of compulsivity, their interplay seems disrupted and actions persist despite being inappropriate and without relationship to the overall goal. We manipulated action-outcome contingency to test whether actions are goal-directed or habitual in obsessive-compulsive disorder (OCD), the prototypical disorder of compulsivity, in which prominent theories have suggested that dysfunctional beliefs underlie the necessity for compulsive actions.\n\nOCD patients responded more than controls when an action was causally less related to obtaining an outcome, indicating excessive habitual responding. Patients showed intact explicit action-outcome knowledge but this was not translated normally into behavior; the relationship between causality judgment and responding was blunted. OCD patients actions were dissociated from explicit action-outcome knowledge, providing experimental support for the ego-dystonic nature of OCD and suggesting that habitual action is not sustained by dysfunctional belief.

neuroscience↗