Temperament and arousal systems: A new synthesis of differential psychology and functional neurochemistry.

This paper critically reviews the unidimensional construct of General Arousal as utilised by models of temperament in differential psychology for example, to underlie 'Extraversion'. Evidence suggests that specialization within monoamine neurotransmitter systems contrasts with the attribution of a "general arousal" of the Ascending Reticular Activating System. Experimental findings show specialized roles of noradrenaline, dopamine, and serotonin systems in hypothetically mediating three complementary forms of arousal that are similar to three functional blocks described in classical models of behaviour within kinesiology, clinical neuropsychology, psychophysiology and temperament research. In spite of functional diversity of monoamine receptors, we suggest that their functionality can be classified using three universal aspects of actions related to expansion, to selection-integration and to maintenance of chosen behavioural alternatives. Monoamine systems also differentially regulate analytic vs. routine aspects of activities at cortical and striatal neural levels. A convergence between main temperament models in terms of traits related to described functional aspects of behavioural arousal also supports the idea of differentiation between these aspects analysed here in a functional perspective

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

Safety signals as instrumental reinforcers during free-operant avoidance.

Safety signals provide "relief" through predicting the absence of an aversive event. At issue is whether these signals also act as instrumental reinforcers. Four experiments were conducted using a free-operant lever-press avoidance paradigm in which each press avoided shock and was followed by the presentation of a 5-sec auditory safety signal. When given a choice between two levers in Experiment 1, both avoiding shock, rats preferentially responded on the lever that produced the safety signal as feedback, even when footshock was omitted. Following avoidance training with a single lever in Experiment 2, removal of the signal led to a decrease in avoidance responses and an increase in responses during the safety period normally denoted by the signal. These behavioral changes demonstrate the dual conditioned reinforcing and fear inhibiting properties of the safety signal. The associative processes that support the reinforcing properties of a safety signal were tested using a novel revaluation procedure. Prior experience of systemic morphine during safety signal presentations resulted in an increased rate of avoidance responses to produce the safety signal during a drug-free extinction test, a finding not seen with d-amphetamine in Experiment 3. Morphine revaluation of the safety signal was repeated in Experiment 4 followed by a drug-free extinction test in which responses did not produce the signal for the first 10 min of the session. Instrumental avoidance in the absence of the signal was shown to be insensitive to prior signal revaluation, suggesting that the signal reinforces free-operant avoidance behavior through a habit-like mechanism.This study was supported by a Wellcome Trust Programme grant to TWR, JW Dalley, BJ Everitt, AC Roberts and BJ Sahakian (089589/z/09/z). AF was supported by an MRC Case studentship and GU was supported by a Marie Curie Fellowship. The authors would also like to thank Dr Rudolf Cardinal for his helpful comments and critiques of the manuscript. The study was completed within the Behavioural and Clinical Neuroscience Institute, supported by a joint award from the MRC and the Wellcome Trust (G00001354).This is the final published version. It's also available from the publishers at http://learnmem.cshlp.org/content/21/9/488.long

Tryptophan Depletion Promotes Habitual over Goal-Directed Control of Appetitive Responding in Humans.

BACKGROUND: Optimal behavioral performance results from a balance between goal-directed and habitual systems of behavioral control, which are modulated by ascending monoaminergic projections. While the role of the dopaminergic system in behavioral control has been recently addressed, the extent to which changes in global serotonin neurotransmission could influence these 2 systems is still poorly understood. METHODS: We employed the dietary acute tryptophan depletion procedure to reduce serotonin neurotransmission in 18 healthy volunteers and 18 matched controls. We used a 3-stage instrumental learning paradigm that includes an initial instrumental learning stage, a subsequent outcome-devaluation test, and a slip-of-action stage, which directly tests the balance between hypothetical goal-directed and habitual systems. We also employed a separate response inhibition control test to assess the behavioral specificity of the results. RESULTS: Acute tryptophan depletion produced a shift of behavioral performance towards habitual responding as indexed by performance on the slip-of-action test. Moreover, greater habitual responding in the acute tryptophan depletion group was predicted by a steeper decline in plasma tryptophan levels. In contrast, acute tryptophan depletion left intact the ability to use discriminative stimuli to guide instrumental choice as indexed by the instrumental learning stage and did not impair inhibitory response control. CONCLUSIONS: The major implication of this study is that serotonin modulates the balance between goal-directed and stimulus-response habitual systems of behavioral control. Our findings thus imply that diminished serotonin neurotransmission shifts behavioral control towards habitual responding.This work was supported by a Wellcome Trust programme grant to T.W.R. (089589/z/09/z). The Behavioral and Clinical Neuroscience Institute is jointly funded by the MRC and the Wellcome Trust (G00001354).This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/ijnp/pyv01

The Novel μ-Opioid Receptor Antagonist GSK1521498 Decreases Both Alcohol Seeking and Drinking: Evidence from a New Preclinical Model of Alcohol Seeking.

Distinct environmental and conditioned stimuli influencing ethanol-associated appetitive and consummatory behaviors may jointly contribute to alcohol addiction. To develop an effective translational animal model that illuminates this interaction, daily seeking responses, maintained by alcohol-associated conditioned stimuli (CSs), need to be dissociated from alcohol drinking behavior. For this, we established a procedure whereby alcohol seeking maintained by alcohol-associated CSs is followed by a period during which rats have the opportunity to drink alcohol. This cue-controlled alcohol-seeking procedure was used to compare the effects of naltrexone and GSK1521498, a novel selective μ-opioid receptor antagonist, on both voluntary alcohol-intake and alcohol-seeking behaviors. Rederived alcohol-preferring, alcohol-nonpreferring, and high-alcohol-drinking replicate 1 line of rats (Indiana University) first received 18 sessions of 24 h home cage access to 10% alcohol and water under a 2-bottle choice procedure. They were trained subsequently to respond instrumentally for access to 15% alcohol under a second-order schedule of reinforcement, in which a prolonged period of alcohol-seeking behavior was maintained by contingent presentations of an alcohol-associated CS acting as a conditioned reinforcer. This seeking period was terminated by 20 min of free alcohol drinking access that achieved significant blood alcohol concentrations. The influence of pretreatment with either naltrexone (0.1-1-3 mg/kg) or GSK1521498 (0.1-1-3 mg/kg) before instrumental sessions was measured on both seeking and drinking behaviors, as well as on drinking in the 2-bottle choice procedure. Naltrexone and GSK1521498 dose-dependently reduced both cue-controlled alcohol seeking and alcohol intake in the instrumental context as well as alcohol intake in the choice procedure. However, GSK1521498 showed significantly greater effectiveness than naltrexone, supporting its potential use for promoting abstinence and preventing relapse in alcohol addiction

Alcohol-Preferring Rats Show Goal Oriented Behaviour to Food Incentives but Are Neither Sign-Trackers Nor Impulsive.

Drug addiction is often associated with impulsivity and altered behavioural responses to both primary and conditioned rewards. Here we investigated whether selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) rats show differential levels of impulsivity and conditioned behavioural responses to food incentives. P and NP rats were assessed for impulsivity in the 5-choice serial reaction time task (5-CSRTT), a widely used translational task in humans and other animals, as well as Pavlovian conditioned approach to measure sign- and goal-tracking behaviour. Drug-naïve P and NP rats showed similar levels of impulsivity on the 5-CSRTT, assessed by the number of premature, anticipatory responses, even when the waiting interval to respond was increased. However, unlike NP rats, P rats were faster to enter the food magazine and spent more time in this area. In addition, P rats showed higher levels of goal-tracking responses than NP rats, as measured by the number of magazine nose-pokes during the presentation of a food conditioned stimulus. By contrast, NP showed higher levels of sign-tracking behaviour than P rats. Following a 4-week exposure to intermittent alcohol we confirmed that P rats had a marked preference for, and consumed more alcohol than, NP rats, but were not more impulsive when re-tested in the 5-CSRTT. These findings indicate that high alcohol preferring and drinking P rats are neither intrinsically impulsive nor do they exhibit impulsivity after exposure to alcohol. However, P rats do show increased goal-directed behaviour to food incentives and this may be associated with their strong preference for alcohol.There are errors in the Funding section. The correct funding information is as follows: The present study was funded by the Wellcome Trust and the Medical Research Council Programme (MRC Ref: G1002231 awarded to BJE, JWD, TWR, Wellcome Trust Ref: 093875/Z/10/Z), and the R24 Alcohol Research Resource Award grant (R24 AA015512) from NIAAA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It first appeared from PLoS via http://dx.doi.org/10.1371/journal.pone.013101

Specific effect of a dopamine partial agonist on counterfactual learning: evidence from Gilles de la Tourette syndrome.

The dopamine partial agonist aripiprazole is increasingly used to treat pathologies for which other antipsychotics are indicated because it displays fewer side effects, such as sedation and depression-like symptoms, than other dopamine receptor antagonists. Previously, we showed that aripiprazole may protect motivational function by preserving reinforcement-related signals used to sustain reward-maximization. However, the effect of aripiprazole on more cognitive facets of human reinforcement learning, such as learning from the forgone outcomes of alternative courses of action (i.e., counterfactual learning), is unknown. To test the influence of aripiprazole on counterfactual learning, we administered a reinforcement learning task that involves both direct learning from obtained outcomes and indirect learning from forgone outcomes to two groups of Gilles de la Tourette (GTS) patients, one consisting of patients who were completely unmedicated and the other consisting of patients who were receiving aripiprazole monotherapy, and to healthy subjects. We found that whereas learning performance improved in the presence of counterfactual feedback in both healthy controls and unmedicated GTS patients, this was not the case in aripiprazole-medicated GTS patients. Our results suggest that whereas aripiprazole preserves direct learning of action-outcome associations, it may impair more complex inferential processes, such as counterfactual learning from forgone outcomes, in GTS patients treated with this medication

The control of tonic pain by active relief learning.

Tonic pain after injury characterises a behavioural state that prioritises recovery. Although generally suppressing cognition and attention, tonic pain needs to allow effective relief learning to reduce the cause of the pain. Here, we describe a central learning circuit that supports learning of relief and concurrently suppresses the level of ongoing pain. We used computational modelling of behavioural, physiological and neuroimaging data in two experiments in which subjects learned to terminate tonic pain in static and dynamic escape-learning paradigms. In both studies, we show that active relief-seeking involves a reinforcement learning process manifest by error signals observed in the dorsal putamen. Critically, this system uses an uncertainty ('associability') signal detected in pregenual anterior cingulate cortex that both controls the relief learning rate, and endogenously and parametrically modulates the level of tonic pain. The results define a self-organising learning circuit that reduces ongoing pain when learning about potential relief

Reply to: Systematic Overestimation of Reflection Impulsivity in the Information Sampling Task

To the Editor: Impulsivity, a psychological construct comprising both motor and cognitive factors, is thought to underlie important interindividual differences in health and disease (1). In particular, reflection impulsivity, which refers to the tendency to gather and evaluate information before decision making (2), has been implicated in many psychiatric and neurological disorders (3, 4, 5). One of the standard tasks for measuring reflection impulsivity in healthy and clinical populations is the Information Sampling Task (IST), designed by Clark et al. (3) and included in the widely used Cambridge Neuropsychological Test Automated Battery (CANTAB) (6). In this CANTAB version of the IST, participants sample a variable amount of information about an uncertain outcome before making a decision. The amount of information sampled before the decision gives a measure of participants’ reflection impulsivity. In this correspondence, we show that the calculation of the IST’s main outcome measure, P(correct), is based on incorrect statistical inference, resulting in systematic overestimation of participants’ reflection impulsivity and potentially inflated type II error rates. This might affect the results of numerous recent psychopharmacological, neuropsychological, and psychiatric publications that have used the IST (4, 5, 7).This work was supported by a Strategic Research Initiative Grant (to CM) from the University of Melbourne, Australia, and the National Health and Medical Research Council of Australia (Grant No. APP1021973 to MY