{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T21:11:11Z","timestamp":1773695471521,"version":"3.50.1"},"reference-count":46,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,16]],"date-time":"2021-10-16T00:00:00Z","timestamp":1634342400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK017420"],"award-info":[{"award-number":["DK017420"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM108040"],"award-info":[{"award-number":["GM108040"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Brain G-protein coupled receptors have been hypothesized to be potential targets for maintaining or restoring cognitive function in normal aged individuals or in patients with neurodegenerative disease. A number of recent reports suggest that activation of melanocortin receptors (MCRs) in the brain can significantly improve cognitive functions of normal rodents and of different rodent models of the Alzheimer\u2019s disease. However, the potential impact of normative aging on the expression of MCRs and their potential roles for modulating cognitive function remains to be elucidated. In the present study, we first investigated the expression of these receptors in six different brain regions of young (6 months) and aged (23 months) rats following assessment of their cognitive status. Correlation analysis was further performed to reveal potential contributions of MCR subtypes to spatial learning and memory. Our results revealed statistically significant correlations between the expression of several MCR subtypes in the frontal cortex\/hypothalamus and the hippocampus regions and the rats\u2019 performance in spatial learning and memory only in the aged rats. These findings support the hypothesis that aging has a direct impact on the expression and function of MCRs, establishing MCRs as potential drug targets to alleviate aging-induced decline of cognitive function.<\/jats:p>","DOI":"10.3390\/molecules26206266","type":"journal-article","created":{"date-parts":[[2021,10,17]],"date-time":"2021-10-17T23:05:47Z","timestamp":1634511947000},"page":"6266","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Aged Brains Express Less Melanocortin Receptors, Which Correlates with Age-Related Decline of Cognitive Functions"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5199-156X","authenticated-orcid":false,"given":"Yang","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica K.","family":"Chawla","sequence":"additional","affiliation":[{"name":"Evelyn F. McKnight Brain Institute, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Division of Neural Systems, Memory & Aging, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1843-9076","authenticated-orcid":false,"given":"Jose L.","family":"Rios-Monterrosa","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingzhi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc A.","family":"Zempare","sequence":"additional","affiliation":[{"name":"Evelyn F. McKnight Brain Institute, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Division of Neural Systems, Memory & Aging, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor J.","family":"Hruby","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol A.","family":"Barnes","sequence":"additional","affiliation":[{"name":"Evelyn F. McKnight Brain Institute, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Division of Neural Systems, Memory & Aging, The University of Arizona, Tucson, AZ 85721, USA"},{"name":"Department of Psychology, Neurology and Neuroscience, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9504-2091","authenticated-orcid":false,"given":"Minying","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, The University of Arizona, Tucson, AZ 85721, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"77sr71","DOI":"10.1126\/scitranslmed.3002369","article-title":"Alzheimer\u2019s disease: The challenge of the second century","volume":"3","author":"Holtzman","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1017\/S1461145712000752","article-title":"The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction","volume":"16","author":"Nathan","year":"2013","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1172\/JCI87526","article-title":"M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss","volume":"127","author":"Bradley","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.neurobiolaging.2006.02.016","article-title":"Muscarinic receptor-mediated GTP-Eu binding in the hippocampus and prefrontal cortex is correlated with spatial memory impairment in aged rats","volume":"28","author":"Zhang","year":"2007","journal-title":"Neurobiol. Aging"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1046\/j.1471-4159.1995.64041888.x","article-title":"Differential regulation of molecular subtypes of muscarinic receptors in Alzheimer\u2019s disease","volume":"64","author":"Flynn","year":"1995","journal-title":"J. Neurochem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/S0006-8993(02)03542-4","article-title":"Loss of muscarinic M4 receptors in hippocampus of Alzheimer patients","volume":"960","author":"Mulugeta","year":"2003","journal-title":"Brain Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0891-0618(02)00066-2","article-title":"Comparative distribution of binding of the muscarinic receptor ligands pirenzepine, AF-DX 384, (R,R)-I-QNB and (R,S)-I-QNB to human brain","volume":"24","author":"Piggott","year":"2002","journal-title":"J. Chem. Neuroanat."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.neuropharm.2017.11.018","article-title":"Muscarinic receptor subtype distribution in the central nervous system and relevance to aging and Alzheimer\u2019s disease","volume":"136","author":"Lebois","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3457","DOI":"10.1523\/JNEUROSCI.5192-13.2014","article-title":"Prefrontal cortical GABAergic dysfunction contributes to age-related working memory impairment","volume":"34","author":"Banuelos","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.molmed.2015.05.002","article-title":"Molecular aspects of age-related cognitive decline: The role of GABA signaling","volume":"21","author":"McQuail","year":"2015","journal-title":"Trends Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.brainres.2005.02.046","article-title":"Expression of groups I and II metabotropic glutamate receptors in the rat brain during aging","volume":"1043","author":"Simonyi","year":"2005","journal-title":"Brain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.2967\/jnumed.117.206516","article-title":"Age-related change in 5-HT6 receptor availability in healthy male volunteers measured with (11)C-GSK215083 PET","volume":"59","author":"Radhakrishnan","year":"2018","journal-title":"J. Nucl. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S1054-3589(10)58002-5","article-title":"Chemistry and pharmacology of GABAB receptor ligands","volume":"58","author":"Froestl","year":"2010","journal-title":"Adv. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1515\/revneuro-2014-0013","article-title":"5-HT6 receptor antagonists as treatment for age-related cognitive decline","volume":"25","author":"Quiedeville","year":"2014","journal-title":"Rev. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s12264-013-1406-z","article-title":"M1 muscarinic acetylcholine receptor in Alzheimer\u2019s disease","volume":"30","author":"Jiang","year":"2014","journal-title":"Neurosci. Bull."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.neuropharm.2016.04.044","article-title":"The impact of metabotropic glutamate receptors into active neurodegenerative processes: A \u201cdark side\u201d in the development of new symptomatic treatments for neurologic and psychiatric disorders","volume":"115","author":"Bruno","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1080\/17460441.2017.1351940","article-title":"Novel approaches to the design of bioavailable melanotropins","volume":"12","author":"Zhou","year":"2017","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8856","DOI":"10.1073\/pnas.90.19.8856","article-title":"Identification of a receptor for gamma melanotropin and other proopiomelanocortin peptides in the hypothalamus and limbic system","volume":"90","author":"Mountjoy","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8246","DOI":"10.1016\/S0021-9258(18)53088-X","article-title":"Molecular cloning of a novel melanocortin receptor","volume":"268","author":"Gantz","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"15174","DOI":"10.1016\/S0021-9258(18)82452-8","article-title":"Molecular cloning, expression, and gene localization of a fourth melanocortin receptor","volume":"268","author":"Gantz","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_21","first-page":"1298","article-title":"Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain","volume":"8","author":"Mountjoy","year":"1994","journal-title":"Mol. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"Uhlen","year":"2015","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nature05453","article-title":"Genome-wide atlas of gene expression in the adult mouse brain","volume":"445","author":"Lein","year":"2007","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/nature11405","article-title":"An anatomically comprehensive atlas of the adult human brain transcriptome","volume":"489","author":"Hawrylycz","year":"2012","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/0149-7634(82)90042-2","article-title":"Alpha-melanocyte-stimulating hormone and behavior","volume":"6","author":"Datta","year":"1982","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1016\/S0196-9781(01)00550-2","article-title":"Effects of peptides on animal and human behavior: A review of studies published in the first twenty years of the journal Peptides","volume":"22","author":"McLay","year":"2001","journal-title":"Peptides"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/0031-9384(77)90095-6","article-title":"Influence of neonatal injections of alpha-MSH on learning, memory and attention in rats","volume":"18","author":"Beckwith","year":"1977","journal-title":"Physiol. Behav."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1016\/j.celrep.2016.10.043","article-title":"Stimulation of the hippocampal POMC\/MC4R circuit alleviates synaptic plasticity impairment in an Alzheimer\u2019s disease model","volume":"17","author":"Shen","year":"2016","journal-title":"Cell Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.neurobiolaging.2013.08.030","article-title":"Melanocortins protect against progression of Alzheimer\u2019s disease in triple-transgenic mice by targeting multiple pathophysiological pathways","volume":"35","author":"Giuliani","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.ejphar.2014.06.063","article-title":"Melanocortins protect against brain damage and counteract cognitive decline in a transgenic mouse model of moderate Alzheimer\u2019s disease","volume":"740","author":"Giuliani","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.mcn.2015.05.004","article-title":"NDP-\u03b1-MSH induces intense neurogenesis and cognitive recovery in Alzheimer transgenic mice through activation of melanocortin MC4 receptors","volume":"67","author":"Giuliani","year":"2015","journal-title":"Mol. Cell Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.1021\/jm00132a010","article-title":"Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: Design based on molecular dynamics","volume":"32","author":"Castrucci","year":"1989","journal-title":"J. Med. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8115","DOI":"10.1021\/ja101428m","article-title":"Multiple N-methylation of MT-II backbone amide bonds leads to melanocortin receptor subtype hMC1R selectivity: Pharmacological and conformational studies","volume":"132","author":"Doedens","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"9773","DOI":"10.1021\/acs.jmedchem.5b01285","article-title":"Discovery of Novel Potent and Selective Agonists at the Melanocortin-3 Receptor","volume":"58","author":"Carotenuto","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3665","DOI":"10.1021\/jm010165y","article-title":"Selective, high affinity peptide antagonists of alpha-melanotropin action at human melanocortin receptor 4: Their synthesis and biological evaluation in vitro","volume":"44","author":"Bednarek","year":"2001","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.1021\/jm701181n","article-title":"Design and microwave-assisted synthesis of novel macrocyclic peptides active at melanocortin receptors: Discovery of potent and selective hMC5R receptor antagonists","volume":"51","author":"Grieco","year":"2008","journal-title":"J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/S0165-0173(01)00067-4","article-title":"Applications of the Morris water maze in the study of learning and memory","volume":"36","year":"2001","journal-title":"Brain Res. Brain Res. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1002\/bip.22976","article-title":"Design of cyclized selective melanotropins","volume":"106","author":"Cai","year":"2016","journal-title":"Biopolymers"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.cell.2016.03.014","article-title":"On the dependency of cellular protein levels on mRNA abundance","volume":"165","author":"Liu","year":"2016","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1523\/JNEUROSCI.3282-12.2013","article-title":"Melanocortin-4 receptor regulates hippocampal synaptic plasticity through a protein kinase A-dependent mechanism","volume":"33","author":"Shen","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.yfrne.2012.04.001","article-title":"Melanocortins as potential therapeutic agents in severe hypoxic conditions","volume":"33","author":"Giuliani","year":"2012","journal-title":"Front. Neuroendocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"362ra146","DOI":"10.1126\/scitranslmed.aaf8732","article-title":"Melanocortin-1 receptor activation is neuroprotective in mouse models of neuroinflammatory disease","volume":"8","author":"Mykicki","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s12974-021-02078-2","article-title":"Activation of MC1R with BMS-470539 attenuates neuroinflammation via cAMP\/PKA\/Nurr1 pathway after neonatal hypoxic-ischemic brain injury in rats","volume":"18","author":"Yu","year":"2021","journal-title":"J. Neuroinflam."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/j.1749-6632.2010.05726.x","article-title":"Role of inflammation in cognitive impairment: Results of observational epidemiological studies and clinical trials","volume":"1207","author":"Gorelick","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/0197-4580(96)00020-6","article-title":"Age-related decrease in cholinergic synaptic transmission in three hippocampal subfields","volume":"17","author":"Shen","year":"1996","journal-title":"Neurobiol. Aging"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/0166-4328(93)90131-9","article-title":"Animal models of normal aging: Relationship between cognitive decline and markers in hippocampal circuitry","volume":"57","author":"Gallagher","year":"1993","journal-title":"Behav. Brain Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/20\/6266\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:16:08Z","timestamp":1760166968000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/20\/6266"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,16]]},"references-count":46,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["molecules26206266"],"URL":"https:\/\/doi.org\/10.3390\/molecules26206266","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,16]]}}}