Medial habenula output circuit mediated by α5 nicotinic receptor-expressing GABAergic neurons in the interpeduncular nucleus.
The Chrna5 gene encodes the α5 nicotinic acetylcholine receptor subunit, an "accessory" subunit of pentameric nicotinic receptors, that has been shown to play a role in nicotine-related behaviors in rodents and is genetically linked to smoking behavior in humans. Here we have used a BAC transgenic mouse line, α5(GFP), to examine the cellular phenotype, connectivity, and function of α5-expressing neurons. Although the medial habenula (MHb) has been proposed as a site of α5 function, α5(GFP) is not detectable in the MHb, and α5 mRNA is expressed there only at very low levels. However, α5(GFP) is strongly expressed in a subset of neurons in the interpeduncular nucleus (IP), median raphe/paramedian raphe (MnR/PMnR), and dorsal tegmental area (DTg). Double-label fluorescence in situ hybridization reveals that these neurons are exclusively GABAergic. Transgenic and conventional tract tracing show that α5(GFP) neurons in the IP project principally to the MnR/PMnR and DTg/interfascicular dorsal raphe, both areas rich in serotonergic neurons. The α5(GFP) neurons in the IP are located in a region that receives cholinergic fiber inputs from the ventral MHb, and optogenetically assisted circuit mapping demonstrates a monosynaptic connection between these cholinergic neurons and α5(GFP) IP neurons. Selective inhibitors of both α4β2- and α3β4-containing nicotinic receptors were able to reduce nicotine-evoked inward currents in α5(GFP) neurons in the IP, suggesting a mixed nicotinic receptor profile in these cells. Together, these findings show that the α5-GABAergic interneurons form a link from the MHb to serotonergic brain centers, which is likely to mediate some of the behavioral effects of nicotine.
Center for Integrative Brain Research, Seattle Children's Research Institute, and Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98101, Center on Human Development and Disability and Department of Neurological Surgery, University of Washington, Seattle, Washington 98195, and Allen Institute for Brain Science, Seattle, Washington 98103.
Yun-Wei A
YW
Hsu
Lynne
L
Tempest
Lely A
LA
Quina
Aguan D
AD
Wei
Hongkui
H
Zeng
Eric E
EE
Turner
D000818:Animals; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism*; D005786:Gene Expression Regulation; D019262:Habenula / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000502:physiology*; D009924:Organ Culture Techniques; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D059326:Serotonergic Neurons / Q000378:metabolism
C496250:Gabra5 protein, mouse; D011963:Receptors, GABA-A