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Retrograde Inhibition by a Specific Subset of Interpeduncular Α5 Nicotinic Neurons Regulates Nicotine Preference

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Retrograde Inhibition by a Specific Subset of Interpeduncular Α5 Nicotinic Neurons Regulates Nicotine Preference Retrograde inhibition by a specific subset of interpeduncular α5 nicotinic neurons regulates nicotine preference Jessica L. Ablesa,b,c, Andreas Görlicha,1, Beatriz Antolin-Fontesa,2,CuidongWanga, Sylvia M. Lipforda, Michael H. Riada, Jing Rend,e,3,FeiHud,e,4,MinminLuod,e,PaulJ.Kennyc, Nathaniel Heintza,f,5, and Ines Ibañez-Tallona,5 aLaboratory of Molecular Biology, The Rockefeller University, New York, NY 10065; bDepartment of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029; cDepartment of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029; dNational Institute of Biological Sciences, Beijing 102206, China; eSchool of Life Sciences, Tsinghua University, Beijing 100084, China; and fHoward Hughes Medical Institute, The Rockefeller University, New York, NY 10065 Contributed by Nathaniel Heintz, October 23, 2017 (sent for review October 5, 2017; reviewed by Jean-Pierre Changeux and Lorna W. Role) Repeated exposure to drugs of abuse can produce adaptive changes nicotine withdrawal, and optical activation of IPN GABAergic cells that lead to the establishment of dependence. It has been shown that is sufficient to produce a withdrawal syndrome, while blockade of allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) gene GABAergic cells in the IPN reduced symptoms of withdrawal (17). CHRNA5 is associated with higher risk of tobacco dependence. In the Taken together these studies highlight the critical role of α5in brain, α5-containing nAChRs are expressed at very high levels in the regulating behavioral responses to nicotine. Here we characterize two subpopulations of GABAergic interpeduncular nucleus (IPN). Here we identified two nonoverlapping Amigo1 Epyc α + α Amigo1 α Epyc neurons in the IPN that express α5: α5- and α5- neu- 5 cell populations ( 5- and 5- ) in mouse IPN that respond α Amigo1 α Epyc differentially to nicotine. Chronic nicotine treatment altered the trans- rons. The translational profile of 5- cells, but not 5- , lational profile of more than 1,000 genes in α5-Amigo1 neurons, includ- shows enrichment for Nos1 and Sst. While the presence of strong neuronal nitric oxide synthase (NOS1) expression in the IPN has ing neuronal nitric oxide synthase (Nos1)andsomatostatin(Sst). In α Epyc been reported in cells that project to the dorsal raphe (DR) (18), contrast, expression of few genes was altered in the 5- popula- no studies have been conducted to determine its function in IPN tion. We show that both nitric oxide and SST suppress optically evoked circuitry. Here, we show that the α5-Amigo1 population utilizes neurotransmitter release from the terminals of habenular (Hb) neu- nitric oxide (NO) and somatostatin (SST) to provide retrograde rons in IPN. Moreover, in vivo silencing of neurotransmitter release Amigo1 Epyc inhibition of excitatory inputs from the MHb to the IPN. Con- from the α5- but not from the α5- population eliminates sistent with this retrograde mechanism, MHb neurons are nicotine reward, measured using place preference. This loss of nicotine enriched with the receptors for NO (soluble guanylyl cyclases) reward was mimicked by shRNA-mediated knockdown of Nos1 in the and with SST receptors. We demonstrate that α5-Amigo1 neurons IPN. These findings reveal a proaddiction adaptive response to chronic α + nicotine in which nitric oxide and SST are released by a specific 5 Significance neuronal population to provide retrograde inhibition of the Hb-IPN circuit and thereby enhance the motivational properties of nicotine. The CHRNA5-A3-B4 gene cluster, which encodes the α5, α3, and β4 nicotinic acetylcholine receptor subunits, has been ge- nicotine | interpeduncular nucleus | retrograde | α5 nicotinic netically associated with high risk of developing nicotine de- pendence. Here we show that a specific α5 nicotinic receptor he interpeduncular nucleus (IPN) is a single midline nucleus population in the midbrain interpeduncular nucleus (IPN) re- Tbeneath the ventral tegmental area that receives the majority sponds to chronic nicotine by increasing the expression of of its input from the medial habenula (MHb) and is reciprocally genes that regulate feedback inhibition of the medial habe- connected to the raphe nuclei (1–3). Recent evidence has high- nula, the major source of input to the IPN. Inhibiting neuro- + lighted a role of the IPN in nicotine consumption and withdrawal transmitter release from this population of α5 neurons or due to its high expression of the α5 nicotinic acetylcholine re- reducing expression of one of these genes, Nos1, blocks the ceptor (nAChR) subunit gene, the allelic variation in which is rewarding effects of nicotine. Our data identify molecular linked to increased risk of nicotine dependence (4–9). mechanisms that may explain the genetic link between The α5 subunit is considered an accessory component of func- CHRNA5 and smoking predisposition in humans. tional nAChRs, active only when combined with both α-and β-nAChR subunits (8, 10). Incorporation of α5 to heteromeric Author contributions: J.L.A., A.G., M.L., P.J.K., N.H., and I.I.-T. designed research; J.L.A., nAChRs channels potently increases their sensitivity to nicotine (8). A.G., B.A.-F., C.W., S.M.L., M.H.R., J.R., and F.H. performed research; M.L., P.J.K., N.H., and Mice with a null mutation of the Chrna5 gene self-administer more I.I.-T. contributed new reagents/analytic tools; J.L.A., A.G., B.A.-F., M.H.R., J.R., F.H., M.L., nicotine at higher, aversive doses, while reexpression of α5inthe N.H., and I.I.-T. analyzed data; and J.L.A., N.H., and I.I.-T. wrote the paper. MHb of α5 KO mice restored nicotine self-administration to wild- Reviewers: J.-P.C., CNRS, Institut Pasteur; and L.W.R., Stony Brook University. type (WT) levels, suggesting that α5 functions to limit nicotine intake The authors declare no conflict of interest. (6). Viral-mediated expression of the most common genetic variant Published under the PNAS license. in CHRNA5, found in heavy smokers, α5D398N, in the MHb of β4- 1Present address: Life Sciences 2: Microbiology, Immunology, Neurosciences, Deutsche overexpressing (Tabac) mice, which otherwise show enhanced Forschungsgemeinschaft, 53170 Bonn, Germany. aversion to nicotine, was sufficient to increase their nicotine intake to 2Present address: Clinical Sciences Centre, MRC London Institute of Medical Sciences, WT levels (7). α5 is also expressed in cortical interneurons, and mice Hammersmith Hospital Campus, London, W12 0NN, United Kingdom. expressing the human α5D398N variant exhibit neurocognitive be- 3Present address: Department of Neurobiology, Stanford University, Stanford, CA 94305. havioral deficits that resemble the hypofrontality observed in patients 4Present address: Department of Cellular and Molecular Biology, Division of Neurobiol- with schizophrenia and addiction (9). α5 has also been implicated in ogy, University of California, Berkeley, CA 94720. – nicotine withdrawal (11 13), characterized by somatic and affective 5To whom correspondence may be addressed. Email: [email protected] or iibanez@ symptoms, including increased anxiety (14, 15). Reexposure to nic- rockefeller.edu. otine during withdrawal increases intrinsic pacemaking activity of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. MHb cholinergic neurons (16). IPN neurons are activated during 1073/pnas.1717506114/-/DCSupplemental. 13012–13017 | PNAS | December 5, 2017 | vol. 114 | no. 49 www.pnas.org/cgi/doi/10.1073/pnas.1717506114 Downloaded by guest on September 25, 2021 increase their production of NO and SST in response to chronic profile is unique to the IPN and differs significantly from cholin- nicotine, providing greater feedback inhibition onto MHb inputs. ergic MHb neurons (Fig. 1D and Datasets S1 and S3–S5). Consis- + This action serves to limit the release of habenula-derived glu- tent with existing data (17, 18), we found that α5 cells were also tamate and enhances the motivational properties of nicotine. enriched in Sst and Nos1; however, the α5-Amigo1 population was These results reveal a critical role for the α5-Amigo1 population of more highly enriched for these two transcripts than the α5-Epyc IPN cells in regulating the rewarding properties of nicotine population (Fig. 1D). MHb ChAT neurons express the receptors for through feedback inhibition of MHb inputs. Furthermore, our both neurotransmitters at higher levels than IPN neurons (Sstr2 and findings suggest that adaptive responses in this α5-Amigo1 con- Sstr4, Gucy1b3 and Gucy1a3)(Fig.1D). High expression of these trolled molecular circuitry likely plays an important role in reg- and other enriched TRAP-translated mRNAs in the two IPN ulating the development of nicotine dependence. populations matched the in situ hybridization signal of mRNA transcripts in the Allen Brain Atlas (Fig. S2). Analysis of the three Results populations revealed a great deal of similarity among them (Fig. α5-Expressing Neurons Can Be Subdivided into Two Populations. 1E), although the profiles for α5-Amigo1 and α5-Epyc indicate that Using translating ribosomal affinity profiling (TRAP) (19) com- these are distinct subpopulations of α5-expressing IPN neurons. bined with RNA sequencing (RNA-Seq), we set out to determine which genes were being actively translated by discrete pop- α5-Amigo1 and α5-Epyc Cells Are Two Nonoverlapping Populations with + ulations of α5 cells in the IPN using Chrna5-Cre mice crossed to Complementary Distribution in the IPN. To determine the distri- ribosome-tagged EGFP-L10a mice (Fig. 1A). In Chrna5-Cre bution of the two subpopulations, we employed Cre-dependent mice, the Chrna5-Chrna3-Chrnb4 gene cluster was overexpressed adeno-associated virus (AAV)-DIO-EGFP-L10a to label nuclei, in IPN neurons (Fig. S1 and Datasets S1 and S2), which reduces AAV-DIO-ChR2-eYFP to label axons and dendrites, and AAV- the utility of these mice for investigating the behavioral actions of DIO-mCherry to label cell bodies and, to a lesser extent, dendrites nicotine, since increased nAChR levels in MHb/IPN are known to (Fig.
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