Cholinergic left-right asymmetry in the habenulo-interpeduncular pathway

Abstract

Significance The forebrain habenular nuclei (Hb) and their connections to the midbrain interpeduncular nucleus (IPN) have emerged as a valuable model to study left-right differences in the zebrafish brain. However, whether this pathway is enriched in the neurotransmitter acetylcholine and involved in nicotine addiction as in mammals is unresolved. We discovered a duplicated cholinergic gene locus that is predominantly expressed in the right Hb at larval stages. Through electrophysiology and pharmacology, we show that this asymmetrical cholinergic pathway is functional. Moreover, specific nicotinic acetylcholine receptor subunits localize to the same subregions of the IPN that are activated by exposure of adults to nicotine. Our study firmly establishes the zebrafish as a valid model to study how Hb-IPN circuitry influences nicotine addiction.