A Genetic Locus Mediating Attentional Processing

Attention is required for most higher-order cognitive functions, but despite extensive and careful study, central unifying principles have been challenging to elicit. To provide a new perspective, we took a forward genetics approach to identify genes with large contributions to attentional performance. We studied 200 genetically diverse mice on measures of pre-attentive processing and through genetic mapping identified a small locus on chromosome 13 (95%CI: 92.22– 94.09 Mb), driving substantial variation (19%) in this trait. Further characterization of the locus revealed a causative gene, Homer1a, a synaptic protein, whose down-regulation specifically in prefrontal excitatory cells during a developmental critical period (<p14) led to significant improvements in multiple measures of attentional performance in the adult. Subsequent molecular and physiological studies revealed that prefrontal Homer1 down-regulation is associated with GABAergic receptor up-regulation in those same cells and an overall inhibitory tone in prefrontal cortex. This inhibitory tone was relieved during task performance, where large increases in locus-coeruleus (LC) to prefrontal cortex (PFC) coupling led to sustained elevations in PFC activity, specifically prior to cue-onset, predicting short-latency correct responses. Notably high-Homer1a, low-attentional performers, exhibited constantly elevated LC-PFC correlations and PFC response magnitudes both at baseline and during task. Thus, rather than overall increases in neural activity, a scalable dynamic range of LC-PFC coupling and of pre-cue PFC responses supported attentional performance. We thus identify a gene with outsized contributions to attentional performance - Homer1 - and link this with prefrontal inhibitory tone as an important component of dynamic task-dependent neuromodulation during attention.