Laboratory of Molecular and Behavioural Neuroscience

Impulsivity biomarkers

winstanley_admin — Thu, 20 Nov 2008 00:02:01 +0000

One of the most well-characterised measures of impulsive action is that obtained from the five-choice serial reaction time task, where premature motor responses made before a cue light is illuminated are classified as impulsive. Drugs which target different neurotransmitter systems (5-HT, dopamine and noradrenaline) can exert similar effects on this form of motor impulsivity suggesting that these neurochemicals interact in their modulation of impulse control. This could happen at the receptor level, such that activation of 5-HT receptors located on dopaminergic neurons can modulate the dopaminergic contribution to impulsivity, but also at the molecular level in that activation of different receptors could activate similar intracellular signaling cascades. We have recently found that the noradrenergic drug yohimbine also increases premature (impulsive) responding on this task, in keeping with clinical reports that yohimbine increases motor impulsivity in healthy volunteers. This compound also increases phosphorylation (activation) of the transcription factor CREB and the kinase ERK 42/44, which is upstream of CREB, within a specific region of the frontal cortex. The hypothesis that activation of CREB may be involved in yohimbine’s effects on impulsivity is supported by our findings that increasing levels of CREB in this area of frontal cortex also increases impulsivity and potentiates the actions of yohimbine.

We now want to determine whether changes in CREB and ERK signaling are common to other pharmacological manipulations which affect impulsivity, and whether a causal relationship can be established between molecular activation and the behavioural effects of drug administration. This could lead to the generation of a molecular footprint for compounds capable of modulating impulsivity, regardless of their pharmacological properties. This novel research could provide valuable insight into the nature of impulsive behaviour and potentially indicate novel therapeutic targets for impulse control disorders. Such research incorporates qPCR and Western blotting techniques to track changes in levels of different proteins and gene products through a molecular signalling pathway.

Relevant publications

For more information, email info@winstanleylab.com with “Impulsivity Biomarkers” in the subject heading.

Modeling gambling behaviour

winstanley_admin — Wed, 19 Nov 2008 23:56:44 +0000

We are currently developing rodent analogues of a number of different tasks used to investigate gambling behaviour in healthy volunteers and clinical populations.

- The Rodent Iowa Gambling Task (rIGT)
- The Loss-Chase Game (L-CG)
- Slot Machines

The Loss-Chase Game (L-CG)

winstanley_admin — Wed, 19 Nov 2008 23:51:03 +0000

Loss-chasing describes the continual engagement in gambling behaviour to recover losses, and is associated with the transition from recreational to pathological gambling. We have recently developed a model of loss-chasing in rats. Testing takes place in five-hole operant chambers. Rats have a limited amount of time to earn food reward by making nosepoke responses in one of the response holes. Intermittently, these responses do not produce food reward but instead produce a light signal that the rat has lost time in which it might earn reward. Now, the rat must choose whether to chase this loss (and try to recover the time) or quit in order to move on. If the rat quits, it has to endure a 4s timeout period before being able to earn reward again. If the rat chooses to chase, it will either win or lose. If the rat wins, it can start earning reward again straight away, i.e. there will be no time penalty. However, if the rat loses, it will encounter a time penalty double the interval associated with a decision to quit. At the end of the chase time penalty, the animal chooses again whether to “chase” or “quit”. At this second decision point, the time penalties for both quitting and losing the chase are double what they were for chase 1 (i.e. 8s and 16s respectively) so that the time penalties mount up. The chase and quit options are signalled by illumination of other holes in the five-hole operant chamber. These lights flash on and off during the time-out “loss” periods associated with the choice of a particular hole. Loss periods are also signalled by distinct tones which makes the different stages of the task more discriminable to the rat.

Critically, the odds of winning any given chase are always 50:50, so the averaged time lost through chases is equal to the time lost through quits. In this way, chasing behaviour might reflect the loss-aversion often observed in human choice under uncertainty. Remarkably, we have found that, like human decision-makers, the majority of rats are very likely to chase losses following the first loss within a run of losing gambles (around 80%), and that this behaviour shows a steady reduction as the time penalties resulting from preceding unsuccessful decisions to chase mount up (around 60%). To further emphasise the similarities with the human behaviour, we have pilot data to indicate that serotonergic drugs can modulate a rats’ willingness to chase. This animal model could provide a novel technique for exploring the neurobiologial substrates of one of the central features of pathological gambling, and such research is currently ongoing.

Relevant publications

For more information, email info@winstanleylab.com with “Loss-chasing” in the subject heading.

If you would like a copy of our L-CG Med PC program code, please email info@winstanleylab.com with [Code Request] in the subject heading.

Intolerance to delay of gratification

winstanley_admin — Wed, 19 Nov 2008 23:43:33 +0000

One of the most successful and widely used models of impulsive decision-making which has been adapted for use with rodents is the delay-discounting paradigm. Both humans and animals find delay to reward delivery aversive i.e. the value of a reward can be discounted by the delay to its delivery. Although a large reward is normally valued more highly than a smaller reward, if the delay to the delivery of large reward is relatively long compared to the small reward, the subjective value of the small reward increases relative to the large reward and may surpass it. At this point, the individual may choose impulsively i.e. select a small immediate over a larger but delayed reward. Highly impulsive populations, such as those with ADHD, bipolar disorder, or substance abuse disorder, show steeper discounting curves i.e. shift their preference from large to small rewards even when the delay to the large reward is relatively short.

We use a delay-discounting task adapted for use in rats. We, and others, have shown that this form of impulsive decision-making can be influenced by dopaminergic manipulations, and that this behaviour is controlled by key nodes within the affective cortico-striatal loop. Furthermore, some evidence suggests that there may be competing circuits in the brain, one promoting impulsive choice (including the orbitofrontal cortex and subthalamic nucleus), the other self-control (including the nucleus accumbens and basolateral amygdala). We plan to perform asymmetrical disconnection experiments to determine whether such a hypothesis is true. We are also interested in understanding how using a cue to signal the duration of the delay decreases levels of impulsive decision-making, potentially due to recruitment of dopaminergic signalling in the orbitofrontal cortex.

Relevant publications

For more information, email info@winstanleylab.com with “Delay-Discounting” in the subject heading.

Environmental enrichment

winstanley_admin — Wed, 19 Nov 2008 23:40:17 +0000

Rats, like humans, are social creatures and their interactions with each other and with their environment can likewise influence or predict cognitive functions. It has been reported that people with extraverted personalities are more social and eager to explore new environments, and are also more impulsive in laboratory tests. This may reflect a lower level of basal arousal and an increased need for stimulation. Likewise male non-human primates who are more impulsive are more likely to reach the very top of the dominance hierarchy or to die trying due to dramatic risk-seeking behaviour (incredibly long leaps from tree to tree, initiating fights with older males etc.) If the same links can be made at the rodent level, this opens up new research possibilities as the neural, neurochemical and molecular basis of such individual differences could be empirically studied.

We are investigating whether housing animals in an enriched environment can exacerbate or inhibit impulsive tendencies, or affect the response to pharmacological challenges, as determined using different cognitive behavioural paradigms (five-choice serial reaction time task, delay-discounting, gambling models). We are also interested in exploring whether the kinds of behaviours which individual animals engage in within an enriched environment are predictive of their levels of impulsivity.

For more information, email info@winstanleylab.com with “Enrichment” in the subject heading.

Cognitive Effort

winstanley_admin — Wed, 19 Nov 2008 23:36:29 +0000

The application of mental effort to achieve a goal is an important element of decision-making behaviour. The onset of low mood or anhedonia may decrease our ability to apply ourselves even though our ability to succeed may be unimpaired. Understanding the biological basis of cognitive effort could offer valuable insight into how the brain allocates resources, and may suggest new ways to improve cognitive performance in those with psychiatric disorders such as depression and ADHD. In collaboration with Harriet de Wit at the University of Michigan, we are currently piloting a test of cognitive effort, where rats are given the opportunity to choose between an easy or difficult task. Successful responding on the difficult task results in more reward than success in the easy task, but will rats be willing to put in the extra mental effort to succeed? Please check back soon for more information.

For more information, email info@winstanleylab.com with “Cognitive Effort” in the subject heading.

Impulsivity and Addiction

admin — Fri, 14 Nov 2008 22:36:27 +0000

Increased impulsivity is believed to contribute to the maintenance of addiction and the relapse to drug-seeking, and has been linked to hypofunction within the orbitofrontal cortex (OFC). Little is known regarding the neurobiological mechanisms by which addictive drugs affect OFC function. Our data indicate that cocaine self-administration in rats induces the transcription factor ΔFosB in the OFC which alters the effects of cocaine on impulsivity. By combining self-administration with cognitive behavioural testing, we have recently been able to track the progressive decreases in motivation and impulse control associated with the development of habitual drug-taking. Unlike with human subjects, it is possible to determine whether impulsivity predicts increased drug intake or whether prolonged exposure to cocaine causes changes in impulse control. We observed that rats develop tolerance to such disruptive effects of cocaine self-administration, but show a deficit in impulse control which is unmasked during withdrawal from drug. Over-expression of ΔFosB within the OFC through viral-mediated gene transfer further impaired animals’ ability to regulate their drug intake and potentiated the increase in impulsivity observed during withdrawal. Blocking the effects of ΔFosB in the OFC may therefore inhibit aspects of drug-seeking behaviour and attenuate the withdrawal-induced elevation in impulsive responding, and future research will aim to test this hypothesis.

It is increasingly recognized that pathological gambling (PG) shares many features with substance abuse, and that pathological gamblers likewise become dependent on the “rush” obtained from gambling. PG may therefore be regarded as a behavioural addiction, implying that therapeutic interventions that alleviate craving for drug may also reduce the desire to gamble. The incidence of PG is also significantly higher in those with substance abuse disorder, and the co-occurrence of both conditions can have additive and detrimental effects on psychosocial functioning and the level of psychiatric distress experienced. Investigating the effects of drug addiction on risky decision-making would therefore provide valuable insight into PG and related disorders. We are planning to investigate these research questions using our new rodent models of gambling.

For more information, email info@winstanleylab.com with “Addiction” in the subject heading.