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The Neuropeptide Y/Agouti Gene-Related Protein (AGRP) Brain Circuitry in Normal, Anorectic, and Monosodium Glutamate-Treated

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The Neuropeptide Y/Agouti Gene-Related Protein (AGRP) Brain Circuitry in Normal, Anorectic, and Monosodium Glutamate-Treated Proc. Natl. Acad. Sci. USA Vol. 95, pp. 15043–15048, December 1998 Neurobiology The neuropeptide Yyagouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice (arcuate nucleusycoexistenceyfeedingymelanocortinyparabrachial nucleus) CHRISTIAN BROBERGER*†,JEANETTE JOHANSEN‡,CAROLINA JOHANSSON‡,MARTIN SCHALLING‡, AND TOMAS HO¨KFELT* Departments of *Neuroscience and ‡Molecular Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden Contributed by Tomas Ho¨kfelt, October 19, 1998 ABSTRACT Neuropeptide Y (NPY) and the endogenous necrosis of arcuate neurons (18), including the NPY cells (11, melanocortin receptor antagonist, agouti gene-related protein 19). In addition, we studied AGRP in the mutant anorexia (AGRP), coexist in the arcuate nucleus, and both exert (anxyanx) mouse, where abnormalities in arcuate NPY histo- orexigenic effects. The present study aimed primarily at chemistry have been demonstrated (9). determining the brain distribution of AGRP. AGRP mRNA- expressing cells were limited to the arcuate nucleus, repre- MATERIALS AND METHODS senting a major subpopulation (95%) of the NPY neurons, which also was confirmed with immunohistochemistry. Animals. C57Bl6 mice (B&K Universal, Sollentuna, Swe- AGRP-immunoreactive (-ir) terminals all contained NPY and den) were injected s.c. with MSG (Sigma) at doses of 2.2, 2.5, were observed in many brain regions extending from the 2.8, 3.2, 3.4, 3.6, 3.8, 4.0, and 4.2 mgyg or 0.9% NaCl (vehicle) rostral telencephalon to the pons, including the parabrachial on postnatal days 2–10, respectively (20). Four MSG-treated nucleus. NPY-positive, AGRP-negative terminals were ob- mice and their controls were perfused at 70–80 days of age. served in many areas. AGRP-ir terminals were reduced dra- anxyanx mice and control littermates were genotyped by matically in all brain regions of mice treated neonatally with nearby simple-sequence-length polymorphisms and perfused monosodium glutamate as well as of mice homozygous for the at day 20. For immunohistochemical labeling of arcuate cell anorexia mutation. Terminals immunoreactive for the mela- bodies, three normal, two vehicle-treated, and two MSG- nocortin peptide a-melanocyte-stimulating hormone formed treated male mice were injected intracerebroventricularly with a population separate from, but parallel to, the AGRP-ir 60 mg colchicine in 10 ml 0.9% NaCl 24 h before perfusion. terminals. Our results show that arcuate NPY neurons, iden- Mice were anesthetized with sodium pentobarbital (Mebumal tified by the presence of AGRP, project more extensively in the i.p.) and perfused via the ascending aorta with formalin-picric brain than previously known and indicate that the feeding acid. The brains were dissected out, immersion-fixed, and regulatory actions of NPY may extend beyond the hypothal- rinsed (9). For in situ hybridization, brains were dissected from amus. decapitated animals and frozen. In Situ Hybridization. Brains were mounted on chucks, m Neuropeptide Y (NPY) (1)-producing neurons in the hypo- frozen, and sectioned at 14 m. Oligonucleotide probes com- thalamic arcuate nucleus (2, 3) appear to be involved in the plementary to nucleotides 1–48 of mouse AGRP mRNA regulation of feeding behavior. Intracerebral injections of (B. D. Wilson, J. Kerns, M. M. Ollmann, and G. S. Barsh, NPY induce food intake (4, 5), and starved animals increase GenBank accession no. 489486, 1997) and nucleotides 1297– NPY expression (6, 7). In genetic models of feeding disorders, 1344, 1581–1624, and 1671–1714 of the rat preproNPY mRNA arcuate NPY overexpression has been linked to hyperphagia (21) were synthesized (Scandinavian Gene Synthesis, Ko¨ping, 9 and obesity (8), and NPY deficiency has been linked to Sweden). The AGRP probe was 3 end-labeled with a 35 hypophagia and anorexia (9). However, surprisingly little [ - S]dATP (NEN) by using terminal deoxynucleotidyl trans- 3 6 z 21 information is available on the arcuate NPY projections, and ferase (Amersham) to a specific activity of 4.2 10 cpm ng targets for these neurons so far have been demonstrated only oligonucleotide and purified by using Qiaquick Nucleotide Removal Kit (Qiagen), and the NPY probes were labeled by in a limited number of hypothalamic nuclei (10–12). Recently, 9 Hahn et al. (13) and we (14) have reported that many NPY tailing the 3 end with digoxigenin-11-dUTP according to neurons in the rodent arcuate coexpress agouti gene-related published protocols (22), purified by ethanol precipitation, and protein (AGRP) (15), an endogenous antagonist of the an- dissolved in Tris-EDTA, all as described earlier (23). In situ orexigenic melanocortin peptides, e.g., a-melanocyte- hybridization was performed essentially as described previ- stimulating hormone (aMSH) (16, 17). The present study ously (23–25). The sections were incubated with radioactively aimed at investigating whether AGRP expression is limited to labeled AGRP probe and digoxigenin-labeled NPY probes. arcuate NPY neurons, using double-labeling immunohisto- After hybridization, the sections were rinsed and incubated chemistry and in situ hybridization. If so, AGRP staining could overnight with alkaline-phosphatase-conjugated antidigoxige- be used to map the terminal projections of arcuate NPY nin F(ab) fragment (1:5,000; Boehringer Mannheim). Alkaline neurons. To further ascertain the arcuate origin of AGRP- phosphatase activity was developed by incubating the sections with nitroblue tetrazoliumy5-bromo-4-chloro-3-indoyl phos- immunoreactive (ir) terminals, we also analyzed mice treated y neonatally with monosodium glutamate (MSG), which induces phate p-toluidine salt (GIBCO BRL). The sections were a a The publication costs of this article were defrayed in part by page charge Abbreviations: AGRP, agouti gene-related protein; MSH, -mela- nocyte-stimulating hormone; MSG, monosodium glutamate; NPY, payment. This article must therefore be hereby marked ‘‘advertisement’’ in neuropeptide Y; NTS, nucleus tractus solitarii; PBN, parabrachial accordance with 18 U.S.C. §1734 solely to indicate this fact. nucleus; PVH, paraventricular hypothalamic nucleus; -ir, -immunore- © 1998 by The National Academy of Sciences 0027-8424y98y9515043-6$2.00y0 active; -LI, -like immunoreactivity. PNAS is available online at www.pnas.org. †To whom reprint requests should be addressed. 15043 Downloaded by guest on September 24, 2021 15044 Neurobiology: Broberger et al. Proc. Natl. Acad. Sci. USA 95 (1998) air-dried, dipped in Ilford K5 nuclear emulsion, exposed for 1 mRNA in arcuate neurons of C57Bl6 mice could be observed; week, developed and fixed, or exposed to autoradiographic 94.9 6 1.5% of NPY mRNA-positive cells expressed AGRP film (Amersham), which was developed after 4 days. Autora- mRNA, and 98.4 6 0.3% of AGRP mRNA-positive cells diograms were quantified with NIH IMAGE software (W. Ras- expressed NPY mRNA (n 5 4; Fig. 1 a– e). AGRP mRNA was band, National Institute of Mental Health) as described (9). not detected in any other region of the brain examined, For further details see ref. 23. including the olfactory bulb, striatum, cerebral and cerebellar Immunohistochemistry. Fourteen-micrometer-thick brain cortices, preoptic area, thalamus, hypothalamus, mesenceph- sections were incubated with monoclonal mouse NPY anti- y alon, pons, brainstem, and spinal cord. Hybridization in the bodies (1:400) (26) and or polyclonal rabbit antiserum to presence of unlabeled probe abolished the signals. AGRP (1:4,000, Phoenix Pharmaceuticals, St. Joseph, MO) or Immunohistochemistry. AGRP-ir cell bodies could be de- aMSH (1:4,000; Peninsula Laboratories), rinsed, incubated tected only in the arcuate nucleus of colchicine-treated mice. with fluorescein isothiocyanate-conjugated secondary anti- bodies (1:80, Jackson ImmunoResearch) for NPY staining, The vast majority of NPY-ir cell bodies also contained AGRP- and processed by using the catalyzed reporter-deposition like immunoreactivity (-LI) and all AGRP-ir cell bodies con- method and Renaissance kit (NEN) for AGRP or aMSH tained NPY-LI (Fig. 1 f and g). AGRP-ir terminals were staining as described previously (14). Sections were incubated detected in several brain areas, and they always contained with a 1:50 dilution of biotinyl tyramide (NEN), and deposited NPY-LI (cf. Fig. 2 a, c, e, and m with b, d, f, and n, respectively). biotin was detected with Texas red-conjugated streptavidin Many NPY-ir terminals did not contain AGRP-LI. In some (1:200; Amersham). Finally, the sections were rinsed, instances, e.g., on the interface between the bed nucleus of the mounted, and examined in a Nikon Microphot FX microscope stria terminalis and the nucleus accumbens, an AGRP-iry equipped for epifluorescence with an oil dark-field condenser NPY-ir population of terminals was seen bordering to an and proper filters. Kodak T-MAX 100 film was used. The AGRP-negativeyNPY-positive population of terminals (cf. stereotaxic atlas of Franklin and Paxinos (27) was consulted. Fig. 2 c with d). For quantification of nerve terminal arborizations, a grid with In the telencephalon, low-density terminal networks were 1.0-mm side length of individual squares (Graticules, Ton- observed in the medial and posterior anterior olfactory nu- bridge, U.K.) was placed in the eye-piece. The dorsal part of cleus, medial orbital cortex, and tenia tecta. No terminals were the dorsomedial hypothalamic nucleus was selected for quan- observed in the olfactory bulb. No AGRP-LI was observed in tification, and the number
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