{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:42:52Z","timestamp":1790912572138,"version":"4.1.0"},"reference-count":97,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"United States Department of Agriculture (USDA)-National Institute of Food and Agriculture","award":["2020-04545"],"award-info":[{"award-number":["2020-04545"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01NS038261"],"award-info":[{"award-number":["R01NS038261"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100019535","name":"Texas Tech University Health Sciences Center","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100019535","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Student Summer Research Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Growing evidence has revealed that gut dysbiosis is associated with the development of anxio-depressive disorders through mechanisms that involve neuroimmune signaling, neurotransmitter changes, and neuroplasticity in the brain. This study investigated the effects of gingerol-enriched ginger (GEG) on specifically anxiety-related neuroinflammation-, neuroimmunity-, neuroplasticity-, neurotransmission-, and neurotoxicity-associated genes in different brain regions, as well as on alterations linked to colonic microflora-driven dysbiosis, in the spinal nerve ligation (SNL) rat model of neuropathic pain (NP). Twenty-seven male rats were assigned to 3 groups: sham, SNL, and SNL-treated with GEG at 200 mg\/kg body weight (SNL+200GEG) via oral gavage for 5 weeks. Anxiety-like behavior was assessed on the elevated plus maze (EPM). mRNA expression was assessed by qRT-PCR using respective primers. Correlation between behavioral parameters and colonic microbiome composition was analyzed using the Spearman rank correlation. The SNL+200GEG group demonstrated decreased anxiety-like behavior in the SNL model. Compared to the SNL group, the SNL+200GEG group had increased mRNA expression of NRF2 (amygdala: left), LXR\u03b1 (amygdala: both sides), and CX3CR1 (amygdala: both sides, hippocampus: right). GEG modulated neuroplasticity as shown by increased gene expression of PGK1 (amygdala: right, hippocampus: both sides), MEK1 (frontal cortex: both sides), LDHA (frontal cortex: both sides), GPM6A (frontal cortex: both sides, amygdala: right, hippocampus: right, and hypothalamus), and GLUT1 (amygdala: right) as well by decreased gene expression of HIF1\u03b1 (in all brain regions except for the hypothalamus). GEG modulated neurotransmission via clearance of excessive glutamate release as suggested by increased gene expression of SLC1A3 (frontal cortex: both sides, hippocampus: right) and via augmenting mGluR5 signaling as shown by increased gene expression of GRM5 (hippocampus: both sides, hypothalamus) as well as downregulation of KMO, HAAO, GRIN2B, and GRIN2C influencing downstream serotonergic neurotransmission and NMDA receptor-mediated glutamatergic pathways in different brain regions. GEG further alleviated neurotoxicity through downregulated gene expression of SIRT1, KMO, IDO1, and HAAO in different brain regions. Moreover, the increased relative abundance of Bilophila spp., accompanied by decreased time spent in the EPM open arms, suggests that increased Bilophila abundance increases anxiety-like behavior. GEG supplementation mitigated anxiety-like behavior in male rats with NP, at least in part, by reducing SNL-induced inflammatory sequelae-related mRNA gene expression in different brain regions. In addition, there is a positive correlation between the abundance of Bilophila wadsworthia and the degree of anxiety-like behavior.<\/jats:p>","DOI":"10.3390\/molecules31010166","type":"journal-article","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T09:18:56Z","timestamp":1767345536000},"page":"166","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Gingerol-Enriched Ginger Extract Effects on Anxiety-like Behavior in a Neuropathic Pain Model via Colonic Microbiome-Neuroimmune Modulation"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6687-7115","authenticated-orcid":false,"given":"Roberto","family":"Mend\u00f3za","sequence":"first","affiliation":[{"name":"Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julianna M.","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Woody L. Hunt School of Dental Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2492-4537","authenticated-orcid":false,"given":"Xiaobo","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moamen M.","family":"Elmassry","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangchen","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5297-3379","authenticated-orcid":false,"given":"Takaki","family":"Kiritoshi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Neugebauer","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9595-6598","authenticated-orcid":false,"given":"Chwan-Li","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Center of Excellence for Translational Neuroscience and Therapeutics, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"},{"name":"Center of Excellence for Integrative Health, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e38282","DOI":"10.1016\/j.heliyon.2024.e38282","article-title":"A narrative review of the complex panorama regarding chronic neuropathic pain mainly for the psychological issues","volume":"10","author":"Martins","year":"2024","journal-title":"Heliyon"},{"key":"ref_2","unstructured":"School, H.M. (2017, August 21). National Comorbidity Survey (NCS). Available online: https:\/\/www.hcp.med.harvard.edu\/ncs\/index.php."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"(2020). The Lancet Global Health. Mental health matters. Lancet Glob. Health, 8, e1352.","DOI":"10.1016\/S2214-109X(20)30432-0"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1007\/s40273-021-01019-4","article-title":"The Economic Burden of Adults with Major Depressive Disorder in the United States (2010 and 2018)","volume":"39","author":"Greenberg","year":"2021","journal-title":"Pharmacoeconomics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.bbr.2017.12.025","article-title":"Understanding the pathophysiology of depression: From monoamines to the neurogenesis hypothesis model\u2014Are we there yet?","volume":"341","author":"Jesulola","year":"2018","journal-title":"Behav. Brain Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/s41398-021-01469-6","article-title":"Gene expression studies in Depression development and treatment: An overview of the underlying molecular mechanisms and biological processes to identify biomarkers","volume":"11","author":"Mariani","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1016\/j.drudis.2020.05.001","article-title":"Role of oxidative stress in depression","volume":"25","author":"Bhatt","year":"2020","journal-title":"Drug Discov. Today"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Suneson, K., Lindahl, J., Chamli Harsmar, S., Soderberg, G., and Lindqvist, D. (2021). Inflammatory Depression-Mechanisms and Non-Pharmacological Interventions. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041640"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Menke, A. (2019). Is the HPA Axis as Target for Depression Outdated, or Is There a New Hope? . Front. Psychiatry, 10.","DOI":"10.3389\/fpsyt.2019.00101"},{"key":"ref_10","first-page":"151","article-title":"The Hypothalamic-Pituitary-Adrenal Axis in Major Depressive Disorder: A Brief Primer for Primary Care Physicians","volume":"3","author":"Varghese","year":"2001","journal-title":"Prim. Care Companion J. Clin. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/npp.2014.181","article-title":"Mineralocorticoid Receptor Stimulation Improves Cognitive Function and Decreases Cortisol Secretion in Depressed Patients and Healthy Individuals","volume":"40","author":"Otte","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/s41582-020-00435-y","article-title":"Neuroinflammation and microglial activation in Alzheimer disease: Where do we go from here?","volume":"17","author":"Leng","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nri.2017.125","article-title":"Microglia and macrophages in brain homeostasis and disease","volume":"18","author":"Li","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wang, R., Santos, J.M., Dufour, J.M., Stephens, E.R., Miranda, J.M., Washburn, R.L., Hibler, T., Kaur, G., Lin, D., and Shen, C.L. (2022). Ginger Root Extract Improves GI Health in Diabetic Rats by Improving Intestinal Integrity and Mitochondrial Function. Nutrients, 14.","DOI":"10.3390\/nu14204384"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2","DOI":"10.30773\/pi.2019.08.09","article-title":"Neuroinflammation, Gut-Brain Axis and Depression","volume":"17","author":"Evrensel","year":"2020","journal-title":"Psychiatry Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"718288","DOI":"10.1038\/s41467-020-19931-2","article-title":"Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system","volume":"11","author":"Chevalier","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Irum, N., Afzal, T., Faraz, M.H., Aslam, Z., and Rasheed, F. (2023). The role of gut microbiota in depression: An analysis of the gut-brain axis. Front. Behav. Neurosci., 17.","DOI":"10.3389\/fnbeh.2023.1185522"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lin, P., Li, D., Shi, Y., Li, Q.T., Guo, X.K., Dong, K., Chen, Q., Lou, X., Li, Z., and Li, P. (2023). Dysbiosis of the Gut Microbiota and Kynurenine (Kyn) Pathway Activity as Potential Biomarkers in Patients with Major Depressive Disorder. Nutrients, 15.","DOI":"10.3390\/nu15071752"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zhu, Z., Cheng, Y., Liu, X., Xu, X., Ding, W., Ling, Z., Liu, J., and Cai, G. (2025). The microbiota-gut-brain axis in depression: Unraveling the relationships and therapeutic opportunities. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1644160"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s40168-024-01756-6","article-title":"Gut dysbiosis induces the development of depression-like behavior through abnormal synapse pruning in microglia-mediated by complement C3","volume":"12","author":"Hao","year":"2024","journal-title":"Microbiome"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Liaqat, H., Parveen, A., and Kim, S.Y. (2022). Neuroprotective Natural Products\u2019 Regulatory Effects on Depression via Gut-Brain Axis Targeting Tryptophan. Nutrients, 14.","DOI":"10.3390\/nu14163270"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"101982","DOI":"10.1016\/j.xcrm.2025.101982","article-title":"The gut microbiota-immune-brain axis: Therapeutic implications","volume":"6","author":"Moloney","year":"2025","journal-title":"Cell. Rep. Med."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Shen, C.L., Wang, R., Yakhnitsa, V., Santos, J.M., Watson, C., Kiritoshi, T., Ji, G., Hamood, A.N., and Neugebauer, V. (2022). Gingerol-Enriched Ginger Supplementation Mitigates Neuropathic Pain via Mitigating Intestinal Permeability and Neuroinflammation: Gut-Brain Connection. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.912609"},{"key":"ref_24","first-page":"301","article-title":"The Effect of 6-gingerol on Growth Factors and Apoptosis Indices in Rats Exposed to Gold Nanoparticles","volume":"12","author":"Yazdi","year":"2021","journal-title":"Basic. Clin. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3126\/ajms.v12i6.34480","article-title":"Effects of oral administration of an aqueous ginger extract on anxiety behavior and tryptophan and serotonin metabolism in the rat","volume":"12","author":"Bano","year":"2021","journal-title":"Asian J. Med. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1021\/acsomega.1c04155","article-title":"6-Shogaol Attenuates Traumatic Brain Injury-Induced Anxiety\/Depression-like Behavior via Inhibition of Oxidative Stress-Influenced Expressions of Inflammatory Mediators TNF-\u03b1, IL-1\u03b2, and BDNF: Insight into the Mechanism","volume":"7","author":"Afzal","year":"2022","journal-title":"Acs Omega"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.nutres.2024.01.014","article-title":"Ginger alleviates mechanical hypersensitivity and anxio-depressive behavior in rats with diabetic neuropathy through beneficial actions on gut microbiome composition, mitochondria, and neuroimmune cells of colon and spinal cord","volume":"124","author":"Shen","year":"2024","journal-title":"Nutr. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Shen, C.L., Santos, J.M., Elmassry, M.M., Bhakta, V., Driver, Z., Ji, G.C., Yakhnitsa, V., Kiritoshi, T., Lovett, J., and Hamood, A.N. (2024). Ginger Polyphenols Reverse Molecular Signature of Amygdala Neuroimmune Signaling and Modulate Microbiome in Male Rats with Neuropathic Pain: Evidence for Microbiota-Gut-Brain Axis. Antioxidants, 13.","DOI":"10.3390\/antiox13050502"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1089\/jmf.2021.K.0141","article-title":"Protective Effects of Zingerone Against Depression-Like Behavior and Biochemical Changes in Chronic Stressed Rats: Antioxidant Effects","volume":"25","author":"Upadhyaya","year":"2022","journal-title":"J. Med. Food"},{"key":"ref_30","first-page":"208","article-title":"Antidepressant effect of methanolic ginger extract in diabetic mice using forced-swim test","volume":"22","author":"Farzin","year":"2013","journal-title":"J. Maz. Univ. Med. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"56","DOI":"10.15296\/ijwhr.2013.10","article-title":"Androgenic activity evaluation of ginger rhizome in reducing depression in the forced swimming test of rats Exposed to Electromagnetic Field (EMF)","volume":"1","author":"Khaki","year":"2013","journal-title":"Int. J. Women\u2019s Heal. Reprod. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1007\/s00394-025-03639-4","article-title":"6-Shogaol, a neuro-nutraceutical derived from ginger, alleviates motor symptoms and depression-like behaviors and modulates the release of monoamine neurotransmitters in Parkinson\u2019s disease mice","volume":"64","author":"Kim","year":"2025","journal-title":"Eur. J. Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.21123\/bsj.2023.9035","article-title":"Red Ginger\u2019s Anti-Anxiety Effect on BALB\/c Strain Mice (Mus musculus) Pro-Inflammatory and Anti-Inflammatory Measurements as Anxiety Model","volume":"20","author":"Dania","year":"2023","journal-title":"Baghdad Sci. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e103211","DOI":"10.1016\/j.cdnut.2024.103211","article-title":"Effects of ginger supplementation on neuroinflammation and mitochondrial function in spinal cords of rats with neuropathic pain: Evidence for sex differences","volume":"8","author":"Shen","year":"2024","journal-title":"Curr. Dev. Nutr."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1017\/S1461145709009924","article-title":"A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder","volume":"12","author":"Khairova","year":"2009","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.1016\/j.psyneuen.2013.03.020","article-title":"Nrf2 participates in depressive disorders through an anti-inflammatory mechanism","volume":"38","author":"Budni","year":"2013","journal-title":"Psychoneuroendocrinology"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Salcudean, A., Popovici, R.A., Pitic, D.E., S\u00e2rbu, D., Boroghina, A., Jomaa, M., Salehi, M.A., Kher, A.A.M., Lica, M.M., and Bodo, C.R. (2025). Unraveling the Complex Interplay Between Neuroinflammation and Depression: A Comprehensive Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26041645"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Sandoval-Hern\u00e1ndez, A.G., Buitrago, L., Moreno, H., Cardona-G\u00f3mez, G.P., and Arboleda, G. (2015). Role of Liver X Receptor in AD Pathophysiology. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0145467"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/j.tjnut.2025.04.006","article-title":"Novel Insights into Dietary Bioactive Compounds and Major Depressive Disorders: Evidence from Animal Studies and Future Perspectives","volume":"155","author":"Shen","year":"2025","journal-title":"J. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1021\/tx500211x","article-title":"Ginger Compound [6]-Shogaol and Its Cysteine-Conjugated Metabolite (M2) Activate Nrf2 in Colon Epithelial Cells in Vitro and in Vivo","volume":"27","author":"Chen","year":"2014","journal-title":"Chem. Res. Toxicol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2813","DOI":"10.1039\/C5FO00214A","article-title":"Activation of Nrf2 target enzymes conferring protection against oxidative stress in PC12 cells by ginger principal constituent 6-shogaol","volume":"6","author":"Peng","year":"2015","journal-title":"Food Funct."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Dixon, E.D., Nardo, A.D., Claudel, T., and Trauner, M. (2021). The role of lipid sensing nuclear receptors (PPARs and LXR) and metabolic lipases in obesity, diabetes and NAFLD. Genes, 12.","DOI":"10.3390\/genes12050645"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.bbi.2021.02.026","article-title":"Activation of liver X receptors prevents emotional and cognitive dysfunction by suppressing microglial M1-polarization and restoring synaptic plasticity in the hippocampus of mice","volume":"94","author":"Xu","year":"2021","journal-title":"Brain Behav. Immun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/1742-2094-7-93","article-title":"Fractalkine receptor (CXCR1) deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide","volume":"7","author":"Corona","year":"2010","journal-title":"J. Neuroinflamm."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"15106","DOI":"10.1523\/JNEUROSCI.1167-12.2012","article-title":"Deficiency of the Microglial Receptor CX3CR1 Impairs Postnatal Functional Development of Thalamocortical Synapses in the Barrel Cortex","volume":"32","author":"Hoshiko","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Calderone, A., Latella, D., Cardile, D., Gangemi, A., Corallo, F., Rifici, C., Quartarone, A., and Calabr\u00f2, R.S. (2024). The Role of Neuroinflammation in Shaping Neuroplasticity and Recovery Outcomes Following Traumatic Brain Injury: A Systematic Review. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252111708"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/s41380-019-0615-x","article-title":"Neuroplasticity in cognitive and psychological mechanisms of depression: An integrative model","volume":"25","author":"Price","year":"2020","journal-title":"Mol. Psychiatry"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.3892\/etm.2021.10565","article-title":"Neuroplasticity and depression: Rewiring the brain\u2019s networks through pharmacological therapy (Review)","volume":"22","author":"Radulescu","year":"2021","journal-title":"Exp. Ther. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/B978-0-12-823493-8.00015-8","article-title":"Amygdala function in emotion, cognition, and behavior","volume":"187","author":"Vuilleumier","year":"2022","journal-title":"Handb. Clin. Neurol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1038\/nrn1825","article-title":"Cognitive neuroscience of emotional memory","volume":"7","author":"LaBar","year":"2006","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"657928","DOI":"10.1155\/2015\/657928","article-title":"Modulation of hippocampal neural plasticity by glucose-related signaling","volume":"2015","author":"Mainardi","year":"2015","journal-title":"Neural Plast."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.brs.2022.04.008","article-title":"Complex negative emotions induced by electrical stimulation of the human hypothalamus","volume":"15","author":"Parvizi","year":"2022","journal-title":"Brain Stimul."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1016\/j.neuron.2021.06.008","article-title":"Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo","volume":"109","author":"Shao","year":"2021","journal-title":"Neuron"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1007\/s11427-014-4638-x","article-title":"Emotional regulation of pain: The role of noradrenaline in the amygdala","volume":"57","author":"Strobel","year":"2014","journal-title":"Sci. China Life Sci."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Chai, W.W., Eaton, S., Rasmussen, H.E., and Tao, M.H. (2021). Associations of Dietary Lipid-Soluble Micronutrients with Hepatic Steatosis among Adults in the United States. Biomedicines, 9.","DOI":"10.3390\/biomedicines9091093"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e209378","DOI":"10.1212\/WNL.0000000000209378","article-title":"What Is the Role of Lactate in Brain Metabolism, Plasticity, and Neurodegeneration?","volume":"102","author":"Benarroch","year":"2024","journal-title":"Neurology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"eadn6016","DOI":"10.1126\/sciadv.adn6016","article-title":"Phosphoglycerate kinase is a central leverage point in Parkinson\u2019s disease-driven neuronal metabolic deficits","volume":"10","author":"Kokotos","year":"2024","journal-title":"Sci. Adv."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Liu, Y.W., Zhong, C.H., Yang, Y.X., Hu, J.B., Yi, X.Y., Huang, J.T., Li, H., Liu, X., Xue, K., and Chen, X. (2025). The Role of Mitochondrial Energy Metabolism in the Mechanism of Exercise Improving Depression. Curr. Issues Mol. Biol., 47.","DOI":"10.3390\/cimb47050382"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Wefers, B., Hitz, C., H\u00f6lter, S.M., Tr\u00fcmbach, D., Hansen, J., Weber, P., P\u00fctz, B., Deussing, J.M., De Angelis, M.H., and Roenneberg, T. (2012). MAPK Signaling Determines Anxiety in the Juvenile Mouse Brain but Depression-Like Behavior in Adults. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035035"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Aparicio, G.I., Le\u00f3n, A., Fuster, R.G., Ravenscraft, B., Monje, P.V., and Scorticati, C. (2023). Endogenous Glycoprotein GPM6a Is Involved in Neurite Outgrowth in Rat Dorsal Root Ganglion Neurons. Biomolecules, 13.","DOI":"10.3390\/biom13040594"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neuroscience.2015.04.057","article-title":"Altered Expression of Neuroplasticity-Related Genes in the Brain of Depressed Suicides","volume":"299","author":"Fuchsova","year":"2015","journal-title":"Neuroscience"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1146\/annurev.nu.16.070196.001315","article-title":"Structure, function, and regulation of the mammalian facilitative glucose transporter gene family","volume":"16","author":"Olson","year":"1996","journal-title":"Annu. Rev. Nutr."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.pnpbp.2013.01.003","article-title":"The alteration of hypoxia inducible factor-1 (HIF-1) and its target genes in mood disorder patients","volume":"43","author":"Shibata","year":"2013","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Harvey, B.K., Airavaara, M., Hinzman, J., Wires, E.M., Chiocco, M.J., Howard, D.B., Shen, H., Gerhardt, G., Hoffer, B.J., and Wang, Y. (2011). Targeted Over-Expression of Glutamate Transporter 1 (GLT-1) Reduces Ischemic Brain Injury in a Rat Model of Stroke. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022135"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Rodek, P., Kowalczyk, M., Kowalski, J., Owczarek, A., Choreza, P., and Kucia, K. (2022). Association Study of the SLC1A2 (rs4354668), SLC6A9 (rs2486001), and SLC6A5 (rs2000959) Polymorphisms in Major Depressive Disorder. J. Clin. Med., 11.","DOI":"10.21203\/rs.3.rs-900559\/v1"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1176\/appi.ajp.2011.09111607","article-title":"Reduced metabotropic glutamate receptor 5 density in major depression determined by [(11)C]ABP688 PET and postmortem study","volume":"168","author":"Deschwanden","year":"2011","journal-title":"Am. J. Psychiatry"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e94931","DOI":"10.7554\/eLife.94931","article-title":"A \u2018double-edged\u2019 role for type-5 metabotropic glutamate receptors in pain disclosed by light-sensitive drugs","volume":"13","author":"Notartomaso","year":"2024","journal-title":"eLife"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1038\/nn.4028","article-title":"mGluR5 in the nucleus accumbens is critical for promoting resilience to chronic stress","volume":"18","author":"Shin","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.bcp.2019.05.012","article-title":"Ameliorative effect of imperatorin in chemically induced fibromyalgia: Role of NMDA\/NFkB mediated downstream signaling","volume":"166","author":"Kaur","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1586\/ecp.11.17","article-title":"Targeting N-methyl-D-aspartate receptors for treatment of neuropathic pain","volume":"4","author":"Zhou","year":"2011","journal-title":"Expert. Rev. Clin. Pharmacol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1016\/j.ajhg.2022.05.009","article-title":"Identification and functional evaluation of GRIA1 missense and truncation variants in individuals with ID: An emerging neurodevelopmental syndrome","volume":"109","author":"Ismail","year":"2022","journal-title":"Am. J. Hum. Genet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1016\/j.biopha.2016.08.052","article-title":"Zerumbone alleviates chronic constriction injury-induced allodynia and hyperalgesia through serotonin 5-HT receptors","volume":"83","author":"Chia","year":"2016","journal-title":"Biomed. Pharmacother."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.jneuroim.2019.04.012","article-title":"Effect of donepezil on the expression and responsiveness to LPS of CHRNA7 and CHRFAM7A in macrophages: A possible link to the cholinergic anti-inflammatory pathway","volume":"332","author":"Maroli","year":"2019","journal-title":"J. Neuroimmunol."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Forteza, M.J., Polyzos, K.A., Baumgartner, R., Suur, B.E., Mussbacher, M., Johansson, D.K., Hermansson, A., Hansson, G.K., and Ketelhuth, D.F.J. (2018). Activation of the Regulatory T-Cell\/Indoleamine 2,3-Dioxygenase Axis Reduces Vascular Inflammation and Atherosclerosis in Hyperlipidemic Mice. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00950"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Huang, X.T., Zhang, F., Wang, X.B., and Liu, K. (2022). The Role of Indoleamine 2, 3-Dioxygenase 1 in Regulating Tumor Microenvironment. Cancers, 14.","DOI":"10.3390\/cancers14112756"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1210\/me.2007-0079","article-title":"Sirtuin functions in health and disease","volume":"21","author":"Yamamoto","year":"2007","journal-title":"Mol. Endocrinol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/j.cell.2011.10.054","article-title":"SIRT1 Activates MAO-A in the Brain to Mediate Anxiety and Exploratory Drive","volume":"147","author":"Libert","year":"2011","journal-title":"Cell"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/s00702-014-1362-4","article-title":"Modulation of monoamine oxidase (MAO) expression in neuropsychiatric disorders: Genetic and environmental factors involved in type A MAO expression","volume":"123","author":"Naoi","year":"2016","journal-title":"J. Neural Transm."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s13550-021-00841-3","article-title":"Evaluation of intracellular processes in quinolinic acid-induced brain damage by imaging reactive oxygen species generation and mitochondrial complex I activity","volume":"11","author":"Hosoi","year":"2021","journal-title":"EJNMMI Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/BF03033790","article-title":"Excitotoxicity of quinolinic acid: Modulation by endogenous antagonists","volume":"2","author":"Jhamandas","year":"2000","journal-title":"Neurotox. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.jpsychires.2023.02.017","article-title":"gene expression is increased in the anterior cingulate cortex in major depression","volume":"160","author":"Brown","year":"2023","journal-title":"J. Psychiatr. Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"884","DOI":"10.5498\/wjp.v12.i7.884","article-title":"Genetic variables of the glutamatergic system associated with treatment-resistant depression: A review of the literature","volume":"12","author":"Saez","year":"2022","journal-title":"World J. Psychiatry"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1053\/j.gastro.2011.04.052","article-title":"The Intestinal Microbiota Affect Central Levels of Brain-Derived Neurotropic Factor and Behavior in Mice","volume":"141","author":"Bercik","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Zhang, H.X., Liu, M., Zhong, W.L., Zheng, Y.P., Li, Y.N., Guo, L.P., Zhang, Y., Ran, Y., Zhao, J., and Zhou, L. (2021). Leaky Gut Driven by Dysbiosis Augments Activation and Accumulation of Liver Macrophages RIP3 Signaling Pathway in Autoimmune Hepatitis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.624360"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1186\/s13099-017-0208-7","article-title":"A human stool-derived strain caused systemic inflammation in specific-pathogen-free mice","volume":"9","author":"Feng","year":"2017","journal-title":"Gut Pathogens"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2802","DOI":"10.1038\/s41467-018-05249-7","article-title":"Bilophila wadsworthia aggravates high fat diet induced metabolic dysfunctions in mice","volume":"9","author":"Natividad","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/s41398-021-01755-3","article-title":"Gut microbiota, innate immune pathways, and inflammatory control mechanisms in patients with major depressive disorder","volume":"11","author":"Caso","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1016\/j.chom.2021.07.004","article-title":"Alterations in the gut microbiota contribute to cognitive impairment induced by the ketogenic diet and hypoxia","volume":"29","author":"Olson","year":"2021","journal-title":"Cell Host Microbe"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1001\/archpsyc.58.5.445","article-title":"Cytokine-associated emotional and cognitive disturbances in humans","volume":"58","author":"Reichenberg","year":"2001","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Sominsky, L., Fuller, E.A., Bondarenko, E., Ong, L.K., Averell, L., Nalivaiko, E., Dunkley, P.R., Dickson, P.W., and Hodgson, D.M. (2013). Functional programming of the autonomic nervous system by early life immune exposure: Implications for anxiety. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057700"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1016\/j.psyneuen.2013.01.002","article-title":"Differential association of somatic and cognitive symptoms of depression and anxiety with inflammation: Findings from the Netherlands Study of Depression and Anxiety (NESDA)","volume":"38","author":"Duivis","year":"2013","journal-title":"Psychoneuroendocrinology"},{"key":"ref_92","first-page":"35","article-title":"Segmental spinal nerve ligation model of neuropathic pain","volume":"99","author":"Chung","year":"2004","journal-title":"Methods Mol. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1744806918804441","DOI":"10.1177\/1744806918804441","article-title":"Fear extinction learning ability predicts neuropathic pain behaviors and amygdala activity in male rats","volume":"14","author":"Ji","year":"2018","journal-title":"Mol. Pain."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"108904","DOI":"10.1016\/j.jnutbio.2021.108904","article-title":"Dietary supplementation of gingerols- and shogaols-enriched ginger root extract attenuate pain-associated behaviors while modulating gut microbiota and metabolites in rats with spinal nerve ligation","volume":"100","author":"Shen","year":"2022","journal-title":"J. Nutr. Biochem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1186\/1744-8069-3-13","article-title":"Pain-related anxiety-like behavior requires CRF1 receptors in the amygdala","volume":"3","author":"Ji","year":"2007","journal-title":"Mol. Pain"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Shen, C.L., Santos, J.M., Elmassry, M.M., Chen, F., Ji, G.C., Presto, P., Kiritoshi, T., Liu, X., and Neugebauer, V. (2025). Crosstalk Among Gut Microbiota, Fecal Metabolites, and Amygdala Neuropathology Genes After Ginger Polyphenol Administration in Female Rats with Neuropathic Pain: Evidence for Microbiota-Gut-Brain Connection. Nutrients, 17.","DOI":"10.3390\/nu17091444"},{"key":"ref_97","first-page":"71","article-title":"An improvement of the 2^(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis","volume":"3","author":"Rao","year":"2013","journal-title":"Biostat. Bioinforma Biomath."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/1\/166\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T05:19:23Z","timestamp":1767417563000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/1\/166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,1]]},"references-count":97,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["molecules31010166"],"URL":"https:\/\/doi.org\/10.3390\/molecules31010166","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,1]]}}}