Nicotinic regulation of local and long-range input balance drives top-down attentional circuit maturation

Cognitive function depends on frontal cortex development; however, the mechanisms driving this process are poorly understood. Here, we identify that dynamic regulation of the nicotinic cholinergic system is a key driver of attentional circuit maturation associated with top-down frontal neurons projecting to visual cortex. The top-down neurons receive robust cholinergic inputs, but their nicotinic tone decreases following adolescence by increasing expression of a nicotinic brake, Lynxl. Lynxl shifts a balance between local and long-range inputs onto top-down frontal neurons following adolescence and promotes the establishment of attentional behavior in adulthood. This key maturational process is disrupted in a mouse model of fragile X syndrome but was rescued by a suppression of nicotinic tone through the introduction of Lynxl in top-down projections. Nicotinic signaling may serve as a target to rebalance local/long-range balance and treat cognitive deficits in neurodevelopmental disorders.

Automated summary

This study reveals that dynamic regulation of the nicotinic cholinergic system plays a key role in the maturation of attentional circuit, particularly in the development of top-down frontal neurons. Following adolescence, the decrease in nicotinic tone by upregulation of Lynxl promotes the establishment of attentional behavior in adulthood. Disruption of this key maturational process is observed in a mouse model of fragile X syndrome, but can be rescued by suppressing nicotinic tone through the introduction of Lynxl in top-down projections.