Dopamine mechanisms underlying bidirectional effects of cue salience on Pavlovian learning

Animals learn to use cues in the environment to predict the occurrence of rewarding events (e.g. the presence of food). However, natural environments are highly complex and some cues are more attention-grabbing (or salient) than others, and it is not clear how animals select which cues they should learn about. The actions of the chemical messenger dopamine, in a brain region called the nucleus accumbens (NAc), is essential for learning about the relationship between individual cues and the presence of reward. The role of NAc dopamine in this type of learning has been well-studied and we have several good theoretical models that link NAc dopamine and learning to explain how these associations are formed. Although these models take into account how salient cues are, we have recently found that the relationship between cue salience and learning of this type is more complex than is currently appreciated. Specifically, we have found that a particular type of genetically-altered mouse is much more sensitive to the salience of a cue than normal mice: they learn faster than normal mice when a cue is highly salient, but slower when it is less salient. Additionally, the genetic alteration that these mice carry implicates dopamine in another brain region - the cortex - in mediating this enhanced sensitivity. This is surprising, as the cortex is not normally thought to be involved in this type of learning. Therefore, this research will investigate what it is about specific cues that make them more or less salient, whether the relationship between NAc dopamine and learning is different in the genetically-altered mice, and whether the cortex is responsible for causing these differences. To do this, we will take advantage of two newly-developed and powerful techniques. Firstly, we are able to use fast-scan cyclic voltammetry to record NAc dopamine at a very fine timescale whilst animals learn which cues predict reward. This means that an animal's behaviour at a given moment in time can be directly related to its NAc dopamine, something which is essential for developing good theoretical models about the link between these factors. Secondly, we will use virally-mediated gene transfer to selectively remedy the genetic alteration found in the mice in either the cortex or NAc, to see whether doing so returns the mice's behaviour to normal. This will allow us to test which brain regions cause the behavioural difference that we see in the genetically-altered mice.

Understanding how animals select which cues to learn about is fundamental to lots of types of behaviours. Understanding how differences between cues shape this process is essential to developing good theoretical models of learning. This research will provide new information about this relatively-neglected process, and will investigate the role that dopamine in the NAc and cortex plays. These studies will contribute to our understanding of how different brain regions work together as a whole, something which is critical to fully understand what might go wrong in brain disorders.

Dopamine, particularly its phasic release in the nucleus accumbens (NAc), plays a key role in several aspects of reward processing, most notably the encoding of reward prediction errors during associative learning. Theoretical models of associative learning include a parameter to account for the influence of unconditioned cue salience: the more perceptually salient (attention-grabbing) a stimulus, the faster associations form with it. However, in spite of its clear importance, the precise factors that determine cue salience, and how these are represented in brain circuits, remains underexplored. We have found striking bidirectional effects of cue identity - and, by inference, cue salience - on Pavlovian associative learning in transgenic mice with altered cortical dopamine function. These data indicate that the role of unconditioned salience in associative learning is more complex than currently appreciated, and implicate cortical-striatal dopamine circuitry as a potential mediator of this interactive effect.

Here, we use these transgenic mice as a model to investigate the impact of unconditioned cue salience on associative learning and the underlying neural circuitry. We will first conduct a behavioural study to dissect which cue properties contribute to its unconditioned salience. We will then use fast-scan cyclic voltammetry (FCV) to investigate whether genotype differences in NAc dopamine, either at baseline (to unconditioned cues and/or unpredicted reward delivery) or during Pavlovian learning, underlie the differential sensitivity of the transgenic mice to unconditioned cue salience. Finally, we will investigate which brain regions are causally responsible for the observed genotype differences in behaviour, by using viral vectors to selectively restore gene function in NAc or frontal cortex. This cutting-edge approach will extend the role of NAc, and possible cortical, dopamine in reward learning to include effects on unconditioned cue salience.

As outlined in the 'Academic Beneficiaries' section, one of the main people to benefit from this research will be the post-doctoral researcher. As well as receiving training in cutting-edge techniques available in only a few laboratories worldwide, he/she will gain experience of taking a project from start to finish and will develop their technical and research skills. This is of significant value, given the shortage of experienced scientists with in vivo expertise in both academia and industry. The post-doctoral researcher will be embedded with the active and diverse neuroscience community within Oxford, who have joint lab meetings and many seminars and lectures. As part of this, they will have the opportunity to present their research in an informal and friendly environment in preparation for conferences presentations.
Whilst this grant does not directly fund any students, part of the research could be undertaken by MSc or, in the case of the non-regulated procedures, undergraduate students. This will give them hands-on experience of research, as well as direct experience of the process of undertaking animal research. All of the applicants have significant contact with, and supervisory experience of, MSc and undergraduate students.
As outlined elsewhere, we anticipate that scientists in the pharmaceutical industry and clinical scientists will benefit from the research, both via the training of researchers with knowledge of cutting-edge in vivo techniques and from the results of the research.

In the course of our research we have found that the idea that genetic factors can influence an individual's ability to learn is of significant interest to the general public. The proposed research is therefore likely to provide opportunities to engage with the public to promote the public understanding of science.