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Current Protein & Peptide Science

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ISSN (Print): 1389-2037
ISSN (Online): 1875-5550

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Research Article

Lethal Yellow Mutation Causes Anxiety, Obsessive-compulsive Behavior and Affects the Brain Melanocortin System in Males and Females of Mice

Author(s): Arseniy E. Izyurov, Alexandra V. Plyusnina, Elizabeth A. Kulikova, Alexander V. Kulikov and Nikita V. Khotskin*

Volume 24, Issue 4, 2023

Published on: 07 April, 2023

Page: [329 - 338] Pages: 10

DOI: 10.2174/1389203724666230320145556

Price: $65

Abstract

Background: The brain melanocortin system regulates numerous physiological functions and kinds of behavior. The agouti protein inhibits melanocortin receptors in melanocytes. The lethal yellow (AY) mutation puts the Agouti gene under the control of the Raly gene promotor and causes the agouti protein expression in the brain. In the present article, we investigated the effects of the AY mutation on brain mRNA levels of Agouti, Raly, and melanocortin-related genes such as Agrp, Pomc, Mc3r, Mc4r, and their relationship to behavior.

Methods: The experiment was performed on 6-month-old males and females of AY/a and a/a (control) mice. Anxiety and obsessive-compulsive behavior were studied in elevated plus-maze and marble- burying tests. The mRNA levels were quantified by qPCR.

Results: AY mutation caused anxiety in males and obsessive-compulsive behavior in females. Positive correlation between Agouti and Raly genes mRNA levels were shown in the hypothalamus, hippocampus, and frontal cortex in AY/a mice. Reduced RNA concentrations of Mc3r and Mc4r genes were found respectively in the hypothalamus and frontal cortex in AY/a males. The Raly gene expression positively correlates with mRNA concentrations of the Mc3r gene in the hypothalamus and the Mc4r gene in the hypothalamus and frontal cortex.

Conclusion: Possible association of obsessive-compulsive behavior with reduced Raly, Mc3r, or Mc4r gene expression is suggested.

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[1]
Sohn, J.W. Network of hypothalamic neurons that control appetite. BMB Rep., 2015, 48(4), 229-233.
[http://dx.doi.org/10.5483/BMBRep.2015.48.4.272] [PMID: 25560696]
[2]
da Silva, A.A.; do Carmo, J.M.; Hall, J.E. CNS regulation of glucose homeostasis: Role of the leptin-melanocortin system. Curr. Diab. Rep., 2020, 20(7), 29.
[http://dx.doi.org/10.1007/s11892-020-01311-1] [PMID: 32451760]
[3]
Anderson, E.J.P.; Çakir, I.; Carrington, S.J.; Cone, R.D.; Ghamari-Langroudi, M.; Gillyard, T.; Gimenez, L.E.; Litt, M.J. 60 YEARS OF POMC: Regulation of feeding and energy homeostasis by α-MSH. J. Mol. Endocrinol., 2016, 56(4), T157-T174.
[http://dx.doi.org/10.1530/JME-16-0014] [PMID: 26939593]
[4]
da Silva, A.A.; do Carmo, J.M.; Wang, Z.; Hall, J.E. Melanocortin-4 receptors and sympathetic nervous system activation in hypertension. Curr. Hypertens. Rep., 2019, 21(6), 46.
[http://dx.doi.org/10.1007/s11906-019-0951-x] [PMID: 31028563]
[5]
Wang, W.; Guo, D.Y.; Lin, Y.J.; Tao, Y.X. Melanocortin regulation of inflammation. Front. Endocrinol., 2019, 10, 683.
[http://dx.doi.org/10.3389/fendo.2019.00683] [PMID: 31649620]
[6]
Martin, K.A.; Mani, M.V.; Mani, A. New targets to treat obesity and the metabolic syndrome. Eur J Pharmacol., 2015, 763(Pt A), 64-74.
[http://dx.doi.org/10.1016/j.ejphar.2015.03.093]
[7]
Milaneschi, Y.; Simmons, W.K.; van Rossum, E.F.C.; Penninx, B.W.J.H. Depression and obesity: Evidence of shared biological mechanisms. Mol. Psychiatry, 2019, 24(1), 18-33.
[http://dx.doi.org/10.1038/s41380-018-0017-5] [PMID: 29453413]
[8]
Yang, Y. Structure, function and regulation of the melanocortin receptors. Eur. J. Pharmacol., 2011, 660(1), 125-130.
[http://dx.doi.org/10.1016/j.ejphar.2010.12.020] [PMID: 21208602]
[9]
Begriche, K.; Sutton, G.M.; Butler, A.A. Homeostastic and non-homeostatic functions of melanocortin-3 receptors in the control of energy balance and metabolism. Physiol. Behav., 2011, 104(4), 546-554.
[http://dx.doi.org/10.1016/j.physbeh.2011.04.007] [PMID: 21497617]
[10]
Begriche, K.; Girardet, C.; McDonald, P.; Butler, A.A. Melanocortin-3 receptors and metabolic homeostasis. Prog. Mol. Biol. Transl. Sci., 2013, 114, 109-146.
[http://dx.doi.org/10.1016/B978-0-12-386933-3.00004-2] [PMID: 23317784]
[11]
Wolf Horrell, E.M.; Boulanger, M.C.; D’Orazio, J.A. Melanocortin 1 Receptor: Structure, function, and regulation. Front. Genet., 2016, 7, 95.
[http://dx.doi.org/10.3389/fgene.2016.00095] [PMID: 27303435]
[12]
Boston, B.A.; Blaydon, K.M.; Varnerin, J.; Cone, R.D. Independent and additive effects of central POMC and leptin pathways on murine obesity. Science, 1997, 278(5343), 1641-1644.
[http://dx.doi.org/10.1126/science.278.5343.1641] [PMID: 9374468]
[13]
Bazhan, N.M.; Yakovleva, T.V.; Kazantseva, A.Y.; Makarova, E.N. Exaggerated anorexigenic response to restraint stress in Ay mice is associated with elevated CRFR2 mRNA expression in the hypothalamus. Physiol. Behav., 2013, 120, 19-25.
[http://dx.doi.org/10.1016/j.physbeh.2013.06.023] [PMID: 23834894]
[14]
Stunkard, A.J.; Faith, M.S.; Allison, K.C. Depression and obesity. Biol. Psychiatry, 2003, 54(3), 330-337.
[http://dx.doi.org/10.1016/S0006-3223(03)00608-5] [PMID: 12893108]
[15]
Simon, G.E.; Von Korff, M.; Saunders, K.; Miglioretti, D.L.; Crane, P.K.; van Belle, G.; Kessler, R.C. Association between obesity and psychiatric disorders in the US adult population. Arch. Gen. Psychiatry, 2006, 63(7), 824-830.
[http://dx.doi.org/10.1001/archpsyc.63.7.824] [PMID: 16818872]
[16]
Luppino, F.S.; de Wit, L.M.; Bouvy, P.F.; Stijnen, T.; Cuijpers, P.; Penninx, B.W.J.H.; Zitman, F.G. Overweight, obesity, and depression: A systematic review and meta-analysis of longitudinal studies. Arch. Gen. Psychiatry, 2010, 67(3), 220-229.
[http://dx.doi.org/10.1001/archgenpsychiatry.2010.2] [PMID: 20194822]
[17]
Łojko, D.; Buzuk, G.; Owecki, M.; Ruchała, M.; Rybakowski, J.K. Atypical features in depression: Association with obesity and bipolar disorder. J. Affect. Disord., 2015, 185, 76-80.
[http://dx.doi.org/10.1016/j.jad.2015.06.020] [PMID: 26148463]
[18]
Khotskin, N.V.; Plyusnina, A.V.; Kulikova, E.A.; Bazhenova, E.Y.; Fursenko, D.V.; Sorokin, I.E.; Kolotygin, I.; Mormede, P.; Terenina, E.E.; Shevelev, O.B.; Kulikov, A.V. On association of the lethal yellow (A) mutation in the agouti gene with the alterations in mouse brain and behavior. Behav. Brain Res., 2019, 359, 446-456.
[http://dx.doi.org/10.1016/j.bbr.2018.11.013] [PMID: 30447239]
[19]
Fursenko, D.V.; Bazhenova, E.Y.; Khotskin, N.V.; Sorokin, I.E.; Kulikova, E.A.; Kulikov, A.V. Effect of photoperiod and lethal yellow mutation on depression-like behavior and expression of proinflammatory cytokines in the hypothalamus in mice. Bull. Exp. Biol. Med., 2019, 167(1), 100-103.
[http://dx.doi.org/10.1007/s10517-019-04470-8] [PMID: 31177455]
[20]
Bazhenova, E.Y.; Fursenko, D.V.; Khotskin, N.V.; Sorokin, I.E.; Kulikov, A.V. Effect of lethal yellow (AY) mutation and photoperiod alterations on mouse behavior. Vavilovskii Zhurnal Genet. Selektsii, 2019, 23(1), 55-61.
[http://dx.doi.org/10.18699/VJ19.461]
[21]
Miller, M.W.; Duhl, D.M.; Vrieling, H.; Cordes, S.P.; Ollmann, M.M.; Winkes, B.M.; Barsh, G.S. Cloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the lethal yellow mutation. Genes Dev., 1993, 7(3), 454-467.
[http://dx.doi.org/10.1101/gad.7.3.454] [PMID: 8449404]
[22]
Klebig, M.L.; Wilkinson, J.E.; Geisler, J.G.; Woychik, R.P. Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur. Proc. Natl. Acad. Sci. USA, 1995, 92(11), 4728-4732.
[http://dx.doi.org/10.1073/pnas.92.11.4728] [PMID: 7761391]
[23]
Yen, T.T.; Gill, A.M.; Frigeri, L.G.; Barsh, G.S.; Wolff, G.L. Obesity, diabetes, and neoplasia in yellow Avy/‐ mice: Ectopic expression of the agouti gene. FASEB J., 1994, 8(8), 479-488.
[http://dx.doi.org/10.1096/fasebj.8.8.8181666] [PMID: 8181666]
[24]
Derkach, K.; Zakharova, I.; Zorina, I.; Bakhtyukov, A.; Romanova, I.; Bayunova, L.; Shpakov, A. The evidence of metabolic-improving effect of metformin in Ay/a mice with genetically-induced melanocortin obesity and the contribution of hypothalamic mechanisms to this effect. PLoS One, 2019, 14(3), e0213779.
[http://dx.doi.org/10.1371/journal.pone.0213779] [PMID: 30870482]
[25]
Paylor, R.; Spencer, C.; Yuvapaylor, L.; Piekedahl, S. The use of behavioral test batteries, II: Effect of test interval. Physiol. Behav., 2006, 87(1), 95-102.
[http://dx.doi.org/10.1016/j.physbeh.2005.09.002] [PMID: 16197969]
[26]
Võikar, V.; Vasar, E.; Rauvala, H. Behavioral alterations induced by repeated testing in C57BL/6J and 129S2/Sv mice: implications for phenotyping screens. Genes Brain Behav., 2004, 3(1), 27-38.
[http://dx.doi.org/10.1046/j.1601-183X.2003.0044.x] [PMID: 14960013]
[27]
Kulikov, A.V.; Tikhonova, M.A.; Kulikov, V.A. Automated measurement of spatial preference in the open field test with transmitted lighting. J. Neurosci. Methods, 2008, 170(2), 345-351.
[http://dx.doi.org/10.1016/j.jneumeth.2008.01.024] [PMID: 18342949]
[28]
Kulikov, V.A.; Khotskin, N.V.; Nikitin, S.V.; Lankin, V.S.; Kulikov, A.V.; Trapezov, O.V. Application of 3-D imaging sensor for tracking minipigs in the open field test. J. Neurosci. Methods, 2014, 235, 219-225.
[http://dx.doi.org/10.1016/j.jneumeth.2014.07.012] [PMID: 25066208]
[29]
Kulikova, E.A.; Khotskin, N.V.; Illarionova, N.B.; Sorokin, I.E.; Bazhenova, E.Y.; Kondaurova, E.M.; Volcho, K.P.; Khomenko, T.M.; Salakhutdinov, N.F.; Ponimaskin, E.; Naumenko, V.S.; Kulikov, A.V. Inhibitor of Striatal-Enriched Protein Tyrosine Phos-] phatase, 8-(Trifluoromethyl)-1,2,3,4,5-Benzopentathiepin-6-Amine hydrochloride (TC-2153), Produces Antidepressant-Like Effect and Decreases Functional Activity and Protein Level of 5-HT2A Receptor in the Brain. Neuroscience, 2018, 394, 220-231.
[http://dx.doi.org/10.1016/j.neuroscience.2018.10.031] [PMID: 30367948]
[30]
Kulikov, A.V.; Naumenko, V.S.; Voronova, I.P.; Tikhonova, M.A.; Popova, N.K. Quantitative RT-PCR assay of 5-HT1A and 5-HT2A serotonin receptor mRNAs using genomic DNA as an external standard. J. Neurosci. Methods, 2005, 141(1), 97-101.
[http://dx.doi.org/10.1016/j.jneumeth.2004.06.005] [PMID: 15585293]
[31]
Naumenko, V.S.; Osipova, D.V.; Kostina, E.V.; Kulikov, A.V. Utilization of a two-standard system in real-time PCR for quantification of gene expression in the brain. J. Neurosci. Methods, 2008, 170(2), 197-203.
[http://dx.doi.org/10.1016/j.jneumeth.2008.01.008] [PMID: 18308402]
[32]
Cornella, N.; Tebaldi, T.; Gasperini, L.; Singh, J.; Padgett, R.A.; Rossi, A.; Macchi, P. The hnRNP RALY regulates transcription and cell proliferation by modulating the expression of specific factors including the proliferation marker E2F1. J. Biol. Chem., 2017, 292(48), 19674-19692.
[http://dx.doi.org/10.1074/jbc.M117.795591] [PMID: 28972179]
[33]
Gasperini, L.; Rossi, A.; Cornella, N.; Peroni, D.; Zuccotti, P.; Potrich, V.; Quattrone, A.; Macchi, P. The hnRNP RALY regulates PRMT1 expression and interacts with the ALS-linked protein FUS: implication for reciprocal cellular localization. Mol. Biol. Cell, 2018, 29(26), 3067-3081.
[http://dx.doi.org/10.1091/mbc.E18-02-0108] [PMID: 30354839]
[34]
Tenzer, S.; Moro, A.; Kuharev, J.; Francis, A.C.; Vidalino, L.; Provenzani, A.; Macchi, P. Proteome-wide characterization of the RNA-binding protein RALY-interactome using the in vivo-biotinylation-pulldown-quant (iBioPQ) approach. J. Proteome Res., 2013, 12(6), 2869-2884.
[http://dx.doi.org/10.1021/pr400193j] [PMID: 23614458]
[35]
Girardet, C.; Butler, A.A. Neural melanocortin receptors in obesity and related metabolic disorders. Biochim. Biophys. Acta Mol. Basis Dis., 2014, 1842(3), 482-494.
[http://dx.doi.org/10.1016/j.bbadis.2013.05.004] [PMID: 23680515]
[36]
Slominski, A.; Plonka, P.M.; Pisarchik, A.; Smart, J.L.; Tolle, V.; Wortsman, J.; Low, M.J. Preservation of eumelanin hair pigmentation in proopiomelanocortin-deficient mice on a nonagouti (a/a) genetic background. Endocrinology, 2005, 146(3), 1245-1253.
[http://dx.doi.org/10.1210/en.2004-0733] [PMID: 15564334]
[37]
Belzung, C.; Griebel, G. Measuring normal and pathological anxiety-like behaviour in mice: a review. Behav. Brain Res., 2001, 125(1-2), 141-149.
[http://dx.doi.org/10.1016/S0166-4328(01)00291-1] [PMID: 11682105]
[38]
Prut, L.; Belzung, C. The open field as a paradigm to measure the effects of drugs on anxiety-like behaviors: A review. Eur. J. Pharmacol., 2003, 463(1-3), 3-33.
[http://dx.doi.org/10.1016/S0014-2999(03)01272-X] [PMID: 12600700]
[39]
Milner, L.C.; Crabbe, J.C. Three murine anxiety models: Results from multiple inbred strain comparisons. Genes Brain Behav., 2008, 7(4), 496-505.
[http://dx.doi.org/10.1111/j.1601-183X.2007.00385.x] [PMID: 18182070]
[40]
Albelda, N.; Joel, D. Animal models of obsessive-compulsive disorder: Exploring pharmacology and neural substrates. Neurosci. Biobehav. Rev., 2012, 36(1), 47-63.
[http://dx.doi.org/10.1016/j.neubiorev.2011.04.006] [PMID: 21527287]
[41]
Lu, D.; Willard, D.; Patel, I.R.; Kadwell, S.; Overton, L.; Kost, T.; Luther, M.; Chen, W.; Woychik, R.P.; Wilkison, W.O. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature, 1994, 371(6500), 799-802.
[http://dx.doi.org/10.1038/371799a0]
[42]
Amiri, S.; Behnezhad, S. Obesity and anxiety symptoms: A systematic review and meta-analysis. Neuropsychiatrie, 2019, 33(2), 72-89.
[http://dx.doi.org/10.1007/s40211-019-0302-9] [PMID: 30778841]
[43]
Sharma, A.N.; Elased, K.M.; Garrett, T.L.; Lucot, J.B. Neurobehavioral deficits in db/db diabetic mice. Physiol. Behav., 2010, 101(3), 381-388.
[http://dx.doi.org/10.1016/j.physbeh.2010.07.002]
[44]
Abramovitch, A.; Anholt, G.E.; Cooperman, A.; van Balkom, A.J.L.M.; Giltay, E.J.; Penninx, B.W.; van Oppen, P. Body mass index in obsessive-compulsive disorder. J. Affect. Disord., 2019, 245, 145-151.
[http://dx.doi.org/10.1016/j.jad.2018.10.116] [PMID: 30388557]

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