Fronto-Sensory Circuits in Flexible Generalised Rule Learning

Learning complex rules guiding our everyday decisions requires explicit cognitive control and flexibility. However, we have little understanding of how flexible rule learning engages distributed neural circuits in the brain. One idea is that frontal cortical areas broadcast an attentional feedback signal that guides such learning. I will test the exact nature of this signal, at what circuit level it operates, and how altered feedback signals contribute to behavioural inflexibility in autism spectrum disorder (ASD). My proposed research will combine unimodal (tactile) and crossmodal (tactile-auditory) rule-learning and generalisation tasks in mice with state-of-the-art multi- area imaging of prefrontal brain areas and study their interactions with sensory cortices ('fronto-sensory circuits'). Task-related longitudinal functional measurements focusing on the orbitofrontal cortex will reveal mechanistic insights into the circuit-specific contributions of feedback signals guiding behavioural flexibility. As such framework emerges, key findings will be extended to identify core deficits in inflexible behaviour in syndromic ASD models - Rett, Shank3, and Fragile-X syndrome. We will develop novel genetic strategies (Beatrix) to identify mutant neurons within a mosaic brain and study their mechanistic contributions to inflexible behaviour. Overall, my findings will advance fundamental knowledge surrounding feedback- contingent learning and reveal novel cognitive biomarkers in preclinical models of ASD.