MRC Transition Support Award CSF Sanjay Manohar

The fellowship aimed to answer four main questions: 1. Do dopamine agonists affect different types of motivation differentially? 2. Can anticholinergic drugs modulate motivation in healthy volunteers? 3. Are motivational changes following ventromedial prefrontal damage explainable as reduced context-sensitivity?

Question 1 constituted 3 experiments, which were completed and published. We established that

- dynamic effects of motivation can be captured by online corrective feedback during a movement (Manohar et al. Neuropsychologia 2018), - dopamine has opposing effects on two types of motivation (Grogan, Sandhu, Hu & Manohar, eLife 2020),

- we can predict impulse control disorders using pupillometry (Drew, Muhammed, Baig, ... Manohar*, Husain* et al. Brain 2020), - dopamine improved cognitive fluency (Ang*, Manohar* et al. Curr Biol 2018)

- dopamine also has opposing effects on different aspects of working memory (Fallon, Kienast, ... Manohar & Husain , J. Psychopharmacol. 2019),

- the effect on working memory influences control over actions (Fallon, Drew, Muhammed, Manohar & Husain, Cortex 2018), and

- I developed the first physiological model of working memory that also accounts for action control (Manohar et al. Neurosci Biobeh Rev. 2019). The surprising new principle here is that neural patterns change their meaning over seconds, calling for re-evaluation of much single-neuron data. This has been cited in 4 major reviews, led to invited talks (Zurich, Brown, UCL) and formed the basis for my Leverhulme grant.

This work has led to my being awarded the Thomas Willis Intermediate Career Researcher award. The second two questions are left unanswered by this data:

1. Acetylcholine is a critical regulator of striatal dopamine release. Can cholinergic drugs modulate disorders of motivation?

2. Dopamine release may be controlled by medial prefrontal cortex. Do apathy and impulsivity arise after lesions to different subregions within this area?

The transition award will permit me to answer these questions. Data collection and recruitment have already begun. I aim to have these two key publications out by the time of applying for a Senior Fellowship in 2022.