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

Abstract

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, Lynx1. Lynx1 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 Lynx1 in top-down projections. Nicotinic signaling may serve as a target to rebalance local/long-range balance and treat cognitive deficits in neurodevelopmental disorders.

Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons

“…The effects of lynxes on nicotinic receptor function have so far been determined by heterologous expression systems ( 39, 61 ), knockout studies ( 61, 81 ), exogenous application of recombinant water-soluble lynx proteins ( 86, 87 ), and more recently viral overexpression in the brain ( 42, 88 ). Our results are highlight complex endogenous regulation of optogenetic nicotinic responses by multiple GPI-anchored lynxes.…”

“…Such flexible tuning of nicotinic responses by lynx prototoxins in Chrna5+ neurons can provide greater dynamic range and poises them to be key players during attentional processing (Fig 9). A recent study found that developmental increase in Lynx1 expression in corticocortical neurons suppressed their nicotinic responses and preventing this by viral knockdown of Lynx1 led to altered cortical connectivity and impaired attention ( 42 ). Thus cell-type specific changes in lynx expression during development are critical for maturation of attention circuits.…”

“…The effect of Lypd6b on (α4) 2 (β2) 2 α5 nicotinic receptors is yet to be determined and may further contribute to the complex control of Chrna5+ nicotinic responses (Ochoa et al, 2016). In addition, Lynx1, a well-known negative modulator of α4β2 nicotinic receptors (Falk et al, 2021; Ibañez-Tallon et al, 2002; Miwa et al, 1999; Morishita et al, 2010) is also expressed in Chrna5+ neurons. Consistent with such complex lynx regulation, our experiments confirmed that removing GPI-anchored lynx proteins increases nicotinic response onset and amplitude potentially due to removal of Lynx1.…”

“…The effect of Lypd6b on (α4) 2 (β2) 2 α5 nicotinic receptors is yet to be determined and may further contribute to the complex control of Chrna5+ nicotinic responses (Ochoa et al, 2016). In addition, Lynx1, a well-known negative modulator of α4β2 nicotinic receptors (Falk et al, 2021;Ibañez-Tallon et al, 2002;Miwa et al, 1999;Morishita et al, 2010) is also expressed in Chrna5+ neurons.…”

“…Recent studies have examined cell-type specific modulation of nicotinic receptors by different lynx prototoxins and the consequences for cortical development and cognition (Anderson et al, 2020; Demars and Morishita, 2014; Falk et al, 2021; Miwa, 2021). Here, we discovered endogenous lynx modulation of nicotinic properties relevant for attention in subplate neurons expressing Chrna5 .…”