Dataset Information

Medial habenula output circuit mediated by ?5 nicotinic receptor-expressing GABAergic neurons in the interpeduncular nucleus.

ABSTRACT: The Chrna5 gene encodes the ?5 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, ?5(GFP), to examine the cellular phenotype, connectivity, and function of ?5-expressing neurons. Although the medial habenula (MHb) has been proposed as a site of ?5 function, ?5(GFP) is not detectable in the MHb, and ?5 mRNA is expressed there only at very low levels. However, ?5(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 ?5(GFP) neurons in the IP project principally to the MnR/PMnR and DTg/interfascicular dorsal raphe, both areas rich in serotonergic neurons. The ?5(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 ?5(GFP) IP neurons. Selective inhibitors of both ?4?2- and ?3?4-containing nicotinic receptors were able to reduce nicotine-evoked inward currents in ?5(GFP) neurons in the IP, suggesting a mixed nicotinic receptor profile in these cells. Together, these findings show that the ?5-GABAergic interneurons form a link from the MHb to serotonergic brain centers, which is likely to mediate some of the behavioral effects of nicotine.

SUBMITTER: Hsu YW

PROVIDER: S-EPMC3828458 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Medial habenula output circuit mediated by α5 nicotinic receptor-expressing GABAergic neurons in the interpeduncular nucleus.

Hsu Yun-Wei A YW Tempest Lynne L Quina Lely A LA Wei Aguan D AD Zeng Hongkui H Turner Eric E EE

The Journal of neuroscience : the official journal of the Society for Neuroscience 20131101 46

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 no ...[more]

PMID: 24227714

Similar Datasets

Project description:Allelic variation in CHRNA3, the gene encoding the α3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for α3-containing (α3*) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. α3* nAChRs are densely expressed by medial habenula (mHb) neurons, which project almost exclusively to the interpeduncular nucleus (IPn) and are known to regulate nicotine avoidance behaviors. We found that Chrna3tm1.1Hwrt hypomorphic mice, which express constitutively low levels of α3* nAChRs, self-administer greater quantities of nicotine (0.4 mg kg-1 per infusion) than their wild-type littermates. Microinfusion of a lentivirus vector to express a short-hairpin RNA into the mHb or IPn to knock-down Chrna3 transcripts markedly increased nicotine self-administration behavior in rats (0.01-0.18 mg kg-1 per infusion). Using whole-cell recordings, we found that the α3β4* nAChR-selective antagonist α-conotoxin AuIB almost completely abolished nicotine-evoked currents in mHb neurons. By contrast, the α3β2* nAChR-selective antagonist α-conotoxin MII only partially attenuated these currents. Finally, micro-infusion of α-conotoxin AuIB (10 μm) but not α-conotoxin MII (10 μm) into the IPn in rats increased nicotine self-administration behavior. Together, these data suggest that α3β4* nAChRs regulate the stimulatory effects of nicotine on the mHb-IPn circuit and thereby regulate nicotine avoidance behaviors. These findings provide mechanistic insights into how CHRNA3 risk alleles can increase the risk of tobacco dependence and smoking-related diseases in human smokers.SIGNIFICANCE STATEMENT Allelic variation in CHRNA3, which encodes the α3 nicotinic acetylcholine receptor (nAChR) subunit gene, increases risk of tobacco dependence but underlying mechanisms are unclear. We report that Chrna3 hypomorphic mice consume greater quantities of nicotine than wild-type mice and that knock-down of Chrna3 gene transcripts in the habenula or interpeduncular nucleus (IPn) increases nicotine intake in rats. α-Conotoxin AuIB, a potent antagonist of the α3β4 nAChR subtype, reduced the stimulatory effects of nicotine on habenular neurons, and its infusion into the IPn increased nicotine intake in rats. These data suggest that α3β4 nAChRs in the habenula-IPn circuit regulate the motivational properties of nicotine.

Dataset Information

Medial habenula output circuit mediated by ?5 nicotinic receptor-expressing GABAergic neurons in the interpeduncular nucleus.

Publications

Medial habenula output circuit mediated by α5 nicotinic receptor-expressing GABAergic neurons in the interpeduncular nucleus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets