Abstract
Hemispheric specializations are well studied at the functional level but less is known about the underlying neural mechanisms. We identified a small cluster of cholinergic neurons in the dorsal habenula (dHb) of zebrafish, defined by their expression of the lecithin retinol acyltransferase domain containing 2 a (lratd2a) gene and their efferent connections with a subregion of the ventral interpeduncular nucleus (vIPN). The lratd2a-expressing neurons in the right dHb are innervated by a subset of mitral cells from both the left and right olfactory bulb and are activated upon exposure to the odorant cadaverine that is repellent to adult zebrafish. Using an intersectional strategy to drive expression of the botulinum neurotoxin specifically in these neurons, we find that adults no longer show aversion to cadaverine. Mutants with left-isomerized dHb that lack these neurons are also less repelled by cadaverine and their behavioral response to alarm substance, a potent aversive cue, is diminished. However, mutants in which both dHb have right identity appear more reactive to alarm substance. The results implicate an asymmetric dHb-vIPN neural circuit in the processing of repulsive olfactory cues and in modulating the resultant behavioral response.
Highlights
Fish use the sense of smell to search for food, detect danger, navigate and communicate social information by detecting chemical cues in their aquatic environment (Yoshihara, 2014)
In contrast to all other target regions, which are located on both sides of the forebrain, only the right nucleus of the dorsal habenular region (dHb) is innervated by mitral cells that emanate from medio-dorsal and ventro-medial
We describe a group of cholinergic neurons defined by their expression of the lecithin retinol acyltransferase domain containing 2a gene [formerly known as family with sequence similarity 84 member B], that are predominantly located in the right dHb where they are selectively innervated by the olfactory mitral cells that originate from both sides of the brain (Miyasaka et al, 2009), and form efferent connections with a restricted subregion of the ventral interpeduncular nucleus (IPN)
Summary
Fish use the sense of smell to search for food, detect danger, navigate and communicate social information by detecting chemical cues in their aquatic environment (Yoshihara, 2014). Disruption of synaptic transmission in lratd2a-expressing Hb neurons alone did not alter the response of zebrafish to alarm substance, which typically triggers erratic, rapid swimming and bottom dwelling, followed by freezing behavior (Diaz-Verdugo et al, 2019; Jesuthasan and Mathuru, 2008) Similar to controls, both juveniles and adults expressing BoTxBLC-GFP under 189 the control of Tg(lratd2a:QF2)c601 showed rapid swimming/darting behavior within 22-25 second after delivery of alarm substance, first doubling their speed of swimming (Figures 3H-K and Figure 3-figure supplement 4), and freezing for the duration of the 5 min recording period. To measure the reaction to cadaverine in bsxm1376/m1376 adults with bilaterally symmetric lratd2a neurons, we counted the number of cells expressing fos in the dHb and found an increase in the left nucleus compared to heterozygous siblings (Figures 5D-E). Homozygous mutants were slower swimmers than heterozygotes (Figures 5G-J); after exposure to alarm substance, their swimming speed relative to baseline was two-fold faster than that of their heterozygous siblings (Figure 5G), indicative of an enhanced response to this aversive cue
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