{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:16:42Z","timestamp":1760235402244,"version":"build-2065373602"},"reference-count":63,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["CRC1080 C02"],"award-info":[{"award-number":["CRC1080 C02"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"LOEWE Research Center for Translational Medicine and Pharmacology, TMP","award":["TP23"],"award-info":[{"award-number":["TP23"]}]},{"DOI":"10.13039\/501100003185","name":"Fraunhofer-Gesellschaft","doi-asserted-by":"publisher","award":["Cluster of Excellence for Immune Mediated Diseases, CIMD"],"award-info":[{"award-number":["Cluster of Excellence for Immune Mediated Diseases, CIMD"]}],"id":[{"id":"10.13039\/501100003185","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Trehalose, a sugar from fungi, mimics starvation due to a block of glucose transport and induces Transcription Factor EB- mediated autophagy, likely supported by the upregulation of progranulin. The pro-autophagy effects help to remove pathological proteins and thereby prevent neurodegenerative diseases such as Alzheimer\u2019s disease. Enhancing autophagy also contributes to the resolution of neuropathic pain in mice. Therefore, we here assessed the effects of continuous trehalose administration via drinking water using the mouse Spared Nerve Injury model of neuropathic pain. Trehalose had no effect on drinking, feeding, voluntary wheel running, motor coordination, locomotion, and open field, elevated plus maze, and Barnes Maze behavior, showing that it was well tolerated. However, trehalose reduced nerve injury-evoked nociceptive mechanical and thermal hypersensitivity as compared to vehicle. Trehalose had no effect on calcium currents in primary somatosensory neurons, pointing to central mechanisms of the antinociceptive effects. In IntelliCages, trehalose-treated mice showed reduced activity, in particular, a low frequency of nosepokes, which was associated with a reduced proportion of correct trials and flat learning curves in place preference learning tasks. Mice failed to switch corner preferences and stuck to spontaneously preferred corners. The behavior in IntelliCages is suggestive of sedative effects as a \u201cside effect\u201d of a continuous protracted trehalose treatment, leading to impairment of learning flexibility. Hence, trehalose diet supplements might reduce chronic pain but likely at the expense of alertness.<\/jats:p>","DOI":"10.3390\/nu13092953","type":"journal-article","created":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T23:25:50Z","timestamp":1629933950000},"page":"2953","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Trehalose Reduces Nerve Injury Induced Nociception in Mice but Negatively Affects Alertness"],"prefix":"10.3390","volume":"13","author":[{"given":"Vanessa","family":"Kraft","sequence":"first","affiliation":[{"name":"Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katja","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annett","family":"Wilken-Schmitz","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerd","family":"Geisslinger","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt, Germany"},{"name":"Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), 60596 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7581-0951","authenticated-orcid":false,"given":"Marco","family":"Sisignano","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 60596 Frankfurt, Germany"},{"name":"Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD), 60596 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irmgard","family":"Tegeder","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/pro.3","article-title":"Effect of trehalose on protein structure","volume":"18","author":"Jain","year":"2008","journal-title":"Protein Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jare.2019.01.009","article-title":"Trehalase localization in the cerebral cortex, hippocampus and cerebellum of mouse brains","volume":"18","author":"Halbe","year":"2019","journal-title":"J. Adv. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"17R","DOI":"10.1093\/glycob\/cwg047","article-title":"New insights on trehalose: A multifunctional molecule","volume":"13","author":"Elbein","year":"2003","journal-title":"Glycobiology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s12986-020-00443-1","article-title":"Trehalose itself plays a critical role on lipid metabolism: Trehalose increases jejunum cytoplasmic lipid droplets which negatively correlated with mesenteric adipocyte size in both HFD-fed trehalase KO and WT mice","volume":"17","author":"Arai","year":"2020","journal-title":"Nutr. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1080\/21505594.2020.1868825","article-title":"The involvement of the Candida glabrata trehalase enzymes in stress resistance and gut colonization","volume":"12","author":"Timmermans","year":"2021","journal-title":"Virulence"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1080\/00365520802308862","article-title":"Characterization of alpha, alpha-trehalase released in the intestinal lumen by the probiotic saccharomyces boulardii","volume":"43","author":"Buts","year":"2008","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1093\/molbev\/msz127","article-title":"Trehalase Gene as a Molecular Signature of Dietary Diversification in Mammals","volume":"36","author":"Jiao","year":"2019","journal-title":"Mol. Biol. Evol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1080\/14756366.2020.1837125","article-title":"Synthesis, trehalase hydrolytic resistance and inhibition properties of 4- and 6-substituted trehalose derivatives","volume":"35","author":"Dhaene","year":"2020","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1080\/19490976.2020.1750273","article-title":"Microbial and metabolic impacts of trehalose and trehalose analogues","volume":"11","author":"Zhang","year":"2020","journal-title":"Gut Microbes"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"127929","DOI":"10.1016\/j.bmcl.2021.127929","article-title":"Trehalose-based neuroprotective autophagy inducers","volume":"40","author":"Assoni","year":"2021","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1402","DOI":"10.1053\/j.gastro.2019.11.295","article-title":"Lactotrehalose, an Analog of Trehalose, Increases Energy Metabolism Without Promoting Clostridioides difficile Infection in Mice","volume":"158","author":"Zhang","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1080\/15548627.2018.1434373","article-title":"TFEB and trehalose drive the macrophage autophagy-lysosome system to protect against atherosclerosis","volume":"14","author":"Evans","year":"2018","journal-title":"Autophagy"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.neuro.2014.07.006","article-title":"Neuroprotective effect of the chemical chaperone, trehalose in a chronic mptp-induced parkinson\u2019s disease mouse model","volume":"44","author":"Sarkar","year":"2014","journal-title":"Neurotoxicology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1167\/iovs.61.10.26","article-title":"Trehalose Induces Autophagy Against Inflammation by Activating TFEB Signaling Pathway in Human Corneal Epithelial Cells Exposed to Hyperosmotic Stress","volume":"61","author":"Liu","year":"2020","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"ra21","DOI":"10.1126\/scisignal.aac5472","article-title":"Trehalose inhibits solute carrier 2A (SLC2A) proteins to induce autophagy and prevent hepatic steatosis","volume":"9","author":"DeBosch","year":"2016","journal-title":"Sci. Signal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5641","DOI":"10.1074\/jbc.M609532200","article-title":"Trehalose, a novel mtor-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein","volume":"282","author":"Sarkar","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"588","DOI":"10.4161\/auto.27710","article-title":"MTOR-independent, autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis","volume":"10","author":"Zhang","year":"2014","journal-title":"Autophagy"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1080\/15548627.2018.1535292","article-title":"Trehalose induces autophagy via lysosomal-mediated TFEB activation in models of motoneuron degeneration","volume":"15","author":"Rusmini","year":"2019","journal-title":"Autophagy"},{"key":"ref_19","first-page":"1","article-title":"Autophagy Upregulation by the TFEB Inducer Trehalose Protects against Oxidative Damage and Cell Death Associated with NRF2 Inhibition in Human RPE Cells","volume":"2020","author":"Abokyi","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5829","DOI":"10.7150\/thno.44051","article-title":"Activation of TFEB-mediated autophagy by trehalose attenuates mitochondrial dysfunction in cisplatin-induced acute kidney injury","volume":"10","author":"Zhu","year":"2020","journal-title":"Theranostics"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Jeong, S.J., Stitham, J., Evans, T.D., Zhang, X., Rodriguez-Velez, A., Yeh, Y.S., Tao, J., Takabatake, K., Epelman, S., and Lodhi, I.J. (2021). Trehalose causes low-grade lysosomal stress to activate tfeb and the autophagy-lysosome biogenesis response. Autophagy, 1\u201313.","DOI":"10.1080\/15548627.2021.1896906"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.cell.2017.09.003","article-title":"Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation","volume":"171","author":"Yoon","year":"2017","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.nbd.2005.02.003","article-title":"Trehalose differentially inhibits aggregation and neurotoxicity of beta-amyloid 40 and 42","volume":"20","author":"Liu","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.bbamem.2010.09.024","article-title":"Effect of trehalose on the interaction of alzheimer\u2019s a\u03b2-peptide and anionic lipid monolayers","volume":"1808","author":"Izmitli","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1111\/jphp.12108","article-title":"Trehalose rescues alzheimer\u2019s disease phenotypes in app\/ps1 transgenic mice","volume":"65","author":"Du","year":"2013","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"549","DOI":"10.3233\/JAD-170322","article-title":"Trehalose Improves Cognition in the Transgenic Tg2576 Mouse Model of Alzheimer\u2019s Disease","volume":"60","author":"Portbury","year":"2017","journal-title":"J. Alzheimer Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3150","DOI":"10.1007\/s12035-020-01942-1","article-title":"Trehalose Inhibits A\u03b2 Generation and Plaque Formation in Alzheimer\u2019s Disease","volume":"57","author":"Liu","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/nm985","article-title":"Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease","volume":"10","author":"Tanaka","year":"2004","journal-title":"Nat. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.4161\/auto.25188","article-title":"Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons","volume":"9","author":"Castillo","year":"2013","journal-title":"Autophagy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s12640-018-9865-7","article-title":"Autophagic Modulation by Trehalose Reduces Accumulation of TDP-43 in a Cell Model of Amyotrophic Lateral Sclerosis via TFEB Activation","volume":"34","author":"Wang","year":"2018","journal-title":"Neurotox. Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Portbury, S.D., Hare, D., Finkelstein, D., and Adlard, P.A. (2017). Trehalose improves traumatic brain injury-induced cognitive impairment. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183683"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1039\/C8MT00068A","article-title":"Trehalose elevates brain zinc levels following controlled cortical impact in a mouse model of traumatic brain injury","volume":"10","author":"Portbury","year":"2018","journal-title":"Metallomics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1038\/emboj.2012.32","article-title":"A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB","volume":"31","author":"Settembre","year":"2012","journal-title":"EMBO J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/bs.mcb.2014.11.011","article-title":"TFEB and the CLEAR network","volume":"126","author":"Settembre","year":"2015","journal-title":"Methods Cell Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-016-0114-3","article-title":"Trehalose upregulates progranulin expression in human and mouse models of GRN haploinsufficiency: A novel therapeutic lead to treat frontotemporal dementia","volume":"11","author":"Holler","year":"2016","journal-title":"Mol. Neurodegener."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1186\/s40478-014-0078-x","article-title":"Possible involvement of lysosomal dysfunction in pathological changes of the brain in aged progranulin-deficient mice","volume":"2","author":"Tanaka","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1084\/jem.20160999","article-title":"Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation","volume":"214","author":"Chang","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3332","DOI":"10.1523\/JNEUROSCI.3498-17.2019","article-title":"Genetic Regulation of Neuronal Progranulin Reveals a Critical Role for the Autophagy-Lysosome Pathway","volume":"39","author":"Elia","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.nbd.2016.09.010","article-title":"Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy","volume":"96","author":"Altmann","year":"2016","journal-title":"Neurobiol. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-016-0132-1","article-title":"Progranulin promotes peripheral nerve regeneration and reinnervation: Role of notch signaling","volume":"11","author":"Altmann","year":"2016","journal-title":"Mol. Neurodegener."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2555","DOI":"10.1089\/ars.2013.5494","article-title":"Hypoxia-Inducible Factor 1 Regulates Heat and Cold Pain Sensitivity and Persistence","volume":"20","author":"Kanngiesser","year":"2014","journal-title":"Antioxid. Redox Signal."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1007\/s00018-020-03553-4","article-title":"Prevention of age-associated neuronal hyperexcitability with improved learning and attention upon knockout or antagonism of LPAR2","volume":"78","author":"Fischer","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-71879-x","article-title":"Low brain endocannabinoids associated with persistent non-goal directed nighttime hyperactivity after traumatic brain injury in mice","volume":"10","author":"Vogel","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.bbr.2015.12.006","article-title":"Multiple rodent models and behavioral measures reveal unexpected responses to FTY720 and DMF in experimental autoimmune encephalomyelitis","volume":"300","author":"Schmitz","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Hempenstall, K., Nurmikko, T.J., Johnson, R.W., A\u2019Hern, R.P., and Rice, A.S. (2005). Analgesic Therapy in Postherpetic Neuralgia: A Quantitative Systematic Review. PLoS Med., 2.","DOI":"10.1371\/journal.pmed.0020164"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1016\/j.bbadis.2017.07.014","article-title":"Loss of synaptic zinc transport in progranulin deficient mice may contribute to progranulin-associated psychopathology and chronic pain","volume":"1863","author":"Hardt","year":"2017","journal-title":"Biochim. Biophys. Acta BBA Mol. Basis Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"174","DOI":"10.3389\/fnbeh.2013.00174","article-title":"Learning and memory with neuropathic pain: Impact of old age and progranulin deficiency","volume":"7","author":"Albuquerque","year":"2013","journal-title":"Front. Behav. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"102054","DOI":"10.1016\/j.redox.2021.102054","article-title":"Reduced exploratory behavior in neuronal nucleoredoxin knockout mice","volume":"45","author":"Tran","year":"2021","journal-title":"Redox Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1007\/s12035-015-9173-7","article-title":"Treatment with Trehalose Prevents Behavioral and Neurochemical Deficits Produced in an AAV \u03b1-Synuclein Rat Model of Parkinson\u2019s Disease","volume":"53","author":"He","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1093\/brain\/aws143","article-title":"Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy","volume":"135","author":"Schaeffer","year":"2012","journal-title":"Brain"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10528","DOI":"10.1074\/jbc.M116.719286","article-title":"Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein","volume":"291","author":"Tien","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.bbrc.2015.08.076","article-title":"Trehalose intake induces chaperone molecules along with autophagy in a mouse model of Lewy body disease","volume":"465","author":"Tanji","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"858","DOI":"10.4161\/auto.20055","article-title":"Autophagosome assembly and cargo capture in the distal axon","volume":"8","author":"Maday","year":"2012","journal-title":"Autophagy"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.devcel.2014.06.001","article-title":"Autophagosome Biogenesis in Primary Neurons Follows an Ordered and Spatially Regulated Pathway","volume":"30","author":"Maday","year":"2014","journal-title":"Dev. Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.matbio.2020.11.005","article-title":"When lipid homeostasis runs havoc: Lipotoxicity links lysosomal dysfunction to autophagy","volume":"100-101","author":"Tegeder","year":"2021","journal-title":"Matrix Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"38586","DOI":"10.1038\/srep38586","article-title":"SLC2A8 (GLUT8) is a mammalian trehalose transporter required for trehalose-induced autophagy","volume":"6","author":"Mayer","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1080\/07853890.2020.1770849","article-title":"Unravelling the health effects of fasting: A long road from obesity treatment to healthy life span increase and improved cognition","volume":"52","author":"Grundler","year":"2020","journal-title":"Ann. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.1080\/15548627.2017.1368596","article-title":"Intermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway","volume":"13","author":"Liu","year":"2017","journal-title":"Autophagy"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.arr.2006.04.002","article-title":"Caloric restriction and intermittent fasting: Two potential diets for successful brain aging","volume":"5","author":"Martin","year":"2006","journal-title":"Ageing Res. Rev."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Pratscher, S., Mickle, A., Marks, J., Rocha, H., Bartsch, F., Schmidt, J., Tejera, L., Garcia, S., Custodero, C., and Jean, F. (2021). Optimizing Chronic Pain Treatment with Enhanced Neuroplastic Responsiveness: A Pilot Randomized Controlled Trial. Nutrients, 13.","DOI":"10.3390\/nu13051556"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.biopsych.2007.09.020","article-title":"Deficiency in Inhibitory Cortical Interneurons Associates with Hyperactivity in Fibroblast Growth Factor Receptor 1 Mutant Mice","volume":"63","author":"Smith","year":"2008","journal-title":"Biol. Psychiatry"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.neuron.2017.11.031","article-title":"Reward-Based Learning Drives Rapid Sensory Signals in Medial Prefrontal Cortex and Dorsal Hippocampus Necessary for Goal-Directed Behavior","volume":"97","author":"Esmaeili","year":"2018","journal-title":"Neuron"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1152\/jn.00069.2020","article-title":"Cortical processing of chemosensory and hedonic features of taste in active licking mice","volume":"123","author":"Bouaichi","year":"2020","journal-title":"J. Neurophysiol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/9\/2953\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:51:46Z","timestamp":1760165506000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/9\/2953"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,25]]},"references-count":63,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["nu13092953"],"URL":"https:\/\/doi.org\/10.3390\/nu13092953","relation":{},"ISSN":["2072-6643"],"issn-type":[{"type":"electronic","value":"2072-6643"}],"subject":[],"published":{"date-parts":[[2021,8,25]]}}}