ULTRASOUND-MEDIATED FOCAL SEROTONIN DELIVERY CAUSALLY MODULATES MOTIVATION IN PRIMATES

Serotonin fundamentally shapes brain function and behaviour. Previous findings have demonstrated serotonin’s role in tracking environmental statistics, whereas others have implicated serotonin in changes of behavioural strategy, such as between impulsivity and persistence or exploration and exploitation.
We recently showed that the dorsal raphe nucleus (DRN) – the principal serotonergic centre of the brain – plays a critical role in controlling changes in motivation state by tracking the average value of the environment. However, to fully disentangle the cognitive function of serotonin, causal methods are required that are both spatially precise and translatable across species.
In this study, we introduce transcranial ultrasound (TUS)-mediated neuromodulator delivery as a tool to probe brain circuits at the mesoscale and to investigate their effects on behaviour and cognition. Using TUS-mediated BBB-opening, we non-invasively and transiently deliver serotonin to the perigenual ACC (pgACC) of macaques, enabling causal interrogation of serotonin’s role in motivation and decision making. At the brain level, we show that focal serotonergic manipulation alters brain chemistry (MRS) and functional connectivity (rs-fMRI); while at the behavioural level, it biases animals towards a low motivation state by reducing sensitivity to environmental value. Together, these findings establish a translatable paradigm for spatially precise neuropharmacological manipulation of behaviour in awake, behaving primates, with direct relevance for understanding and targeting circuit-level dysfunction in disorders of motivation.