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Neuromodulation of flexible foraging

Reference	BB/X008487/1
Principal Investigator / Supervisor	Professor Mark Walton
Co-Investigators / Co-Supervisors	Dr Thomas Akam, Professor Alex Kacelnik, Professor Trevor Sharp
Institution	University of Oxford
Department	Experimental Psychology
Funding type	Research
Value (£)	623,171
Status	Current
Type	Research Grant
Start date	01/04/2023
End date	31/03/2026
Duration	36 months

Abstract

Dopamine has long been linked with regulating adaptive decisions, yet there is little consensus as to how it achieves this. There are several reasons for this impasse. First, laboratory studies have typically focused on simple decision making scenarios where animals choose between simultaneously presented options. By contrast, decisions in naturalistic settings often involve determining how long to harvest reward in one location and when to move to an alternative, which requires dynamic comparison of the gain in the current patch against the average reward rate in the environment. Second, while the focus of much research has built on the canonical finding that transient dopamine reflects reward prediction errors, dopamine also simultaneously represents reward information at slower timescales, which could provide crucial additional information to balance adaptive decisions. Third, dopamine does not act in isolation but interacts with other neurotransmitters such as serotonin (5-HT), also implicated in flexible foraging. Here, we will take advantage of exciting methodological advances, which permit minimally-invasive measurement and manipulation of neuromodulators in freely-behaving mice, and will test the hypothesis that dopamine, operating over different timescales and in concert with other neurotransmitters, provides key signals for efficient foraging. To do this, we will first measure fluctuations in striatal dopamine receptor binding in mice engaged in a patch leaving foraging task using fibre photometry and regress these signals against behaviour and model-derived estimates of task variables. Second, to test the causal contribution of these signals, we will use optogenetics to manipulate transient and sustained dopamine release during patch foraging. Finally, we will examine whether serotonin interacts with dopamine to regulate foraging by examining the effects of optogenetic stimulation of 5-HT neurons on patch leaving and striatal dopamine signals.

Summary

'Should I stay or should I go?' is a type of decision that we all repeatedly face. How animals solve this type of dilemma has been of interest across a wide range of disciplines, including psychology, economics, artificial intelligence and behavioural ecology. Strikingly, a well-established efficient solution to the problem emerged from studying animal foraging behaviour: an animal should only continue to persist with its current strategy if it yields greater returns than the average of the opportunities available elsewhere in the environment. This framework, called the Marginal Value Theorem (MVT), has proven remarkably effective in explaining stay-or-leave decisions across a wide variety of settings and animal species, from foraging for food in invertebrates to searching for information in humans. Nonetheless, it is not clear how the brain keeps track of the key variables to enable this to happen efficiently. In neuroscience, it is generally accepted that brain chemicals such as dopamine and serotonin play essential roles in coordinating adaptive behaviour. For example, disrupting these chemicals, either experimentally using pharmacological agents, through natural processes in healthy ageing, or as a consequence of psychiatric or neurological disease, can change how quickly animals adapt to changes in their environment. Importantly, our understanding of these chemicals' roles comes mainly from simple decision making tasks where animals make repeated choices between options and update their behaviour based on trial-and-error experience. Therefore, a major gap in our knowledge is the roles these chemicals play in guiding more naturalistic dynamic foraging decisions. Intriguingly, some of our team's recent work has demonstrated that dopamine can simultaneously signal two different variables that could be important for such foraging decisions: (1) transient fluctuations in dopamine (lasting <1 second) that track the difference between the expected and obtainedreward, believed to be an essential teaching signal for learning reward values, and (2) sustained changes in dopamine (lasting multiple seconds and longer) that track the average potential gains in the environment. Moreover, recent methodological advances have revolutionised our ability to monitor moment-by-moment changes in brain chemicals as well as to manipulate them with sub-second precision. These two developments set the stage for us to address for the first time what role dopamine, in concert with serotonin, plays in implementing efficient dynamic stay-or-leave decision making. First, we will measure dopamine levels in the brains of mice performing a foraging task using an optical technique called fibre photometry. By manipulating (i) how often they get rewards in the patch they are foraging in and (ii) how long it will take them to reach an alternative foraging site, we can determine how moment-by-moment changes in dopamine correlate with their decisions to stay or leave and how these align with predictions from models. Second, we will test whether these changes in dopamine play a causal role in animals' choices to stay or leave. To do this, we will use a technique called optogenetics to selectively turn on or off neurons that express dopamine as the mice perform the foraging task. Third, we will investigate whether another brain chemical, serotonin, influences stay-or-leave foraging decisions by modulating dopamine release. To do this, we will use new combinations of techniques to manipulate serotonin while simultaneously monitoring dopamine as mice perform the foraging task, using the same techniques as described above. We will test our hypothesis that boosting serotonin promotes persistence by modulating dopamine release in response to rewards. Together, this will provide important insights into how dopamine interacts with serotonin to enable efficient flexibility in naturalistic environments.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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