{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:40:02Z","timestamp":1760143202640,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:00:00Z","timestamp":1705536000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Regional Development Fund (ERDF)","award":["NORTE-01-0145-FEDER-000008"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>Hydrocephalus is characterized by enlargement of the cerebral ventricles, accompanied by distortion of the periventricular tissue. Patients with hydrocephalus usually experience urinary impairments. Although the underlying etiology is not fully described, the effects of hydrocephalus in the neuronal network responsible for the control of urination, which involves periventricular areas, including the periaqueductal gray (PAG) and the noradrenergic locus coeruleus (LC). In this study, we aimed to investigate the mechanisms behind urinary dysfunction in rats with kaolin-induced hydrocephalus. For that purpose, we used a validated model of hydrocephalus\u2014the rat injected with kaolin in the cisterna magna\u2014also presents urinary impairments in order to investigate the putative involvement of noradrenergic control from the brain to the spinal cord Onuf\u2019s nucleus, a key area in the motor control of micturition. We first evaluated bladder contraction capacity using cystometry. Since our previous characterization of the LC in hydrocephalic animals showed increased levels of noradrenaline, we then evaluated the noradrenergic innervation of the spinal cord\u2019s Onuf\u2019s nucleus by measuring levels of dopamine \u03b2-hydroxylase (DBH). We also evaluated the expression of the c-Fos protooncogene, the most widely used marker of neuronal activation, in the ventrolateral PAG (vlPAG), an area that plays a major role in the control of urination by its indirect control of the LC via pontine micturition center. Hydrocephalic rats showed an increased frequency of bladder contractions and lower minimum pressure. These animals also presented increased DBH levels at the Onuf\u00b4s nucleus, along with decreased c-Fos expression in the vlPAG. The present findings suggest that impairments in urinary function during hydrocephalus may be due to alterations in descending noradrenergic modulation. We propose that the effects of hydrocephalus in the decrease of vlPAG neuronal activation lead to a decrease in the control over the LC. The increased availability of noradrenaline production at the LC probably causes an exaggerated micturition reflex due to the increased innervation of the Onuf\u00b4s nucleus, accounting for the urinary impairments detected in hydrocephalic animals. The results of the study provide new insights into the neuronal underlying mechanisms of urinary dysfunction in hydrocephalus. Further research is needed to fully evaluate the translational perspectives of the current findings.<\/jats:p>","DOI":"10.3390\/biomedicines12010215","type":"journal-article","created":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T03:50:56Z","timestamp":1705549856000},"page":"215","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Noradrenergic Pathways Involved in Micturition in an Animal Model of Hydrocephalus\u2014Implications for Urinary Dysfunction"],"prefix":"10.3390","volume":"12","author":[{"given":"Marta","family":"Lou\u00e7ano","sequence":"first","affiliation":[{"name":"Unit of Experimental Biology, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"IBMC-Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal"},{"name":"I3S-Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"Chemical and Biomolecule Sciences, School of Health, Polytechnic of Porto, 4200-072 Porto, Portugal"}]},{"given":"Ana","family":"Coelho","sequence":"additional","affiliation":[{"name":"Unit of Experimental Biology, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"IBMC-Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal"},{"name":"I3S-Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3311-7187","authenticated-orcid":false,"given":"S\u00edlvia Sousa","family":"Chambel","sequence":"additional","affiliation":[{"name":"Unit of Experimental Biology, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"IBMC-Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal"},{"name":"I3S-Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9920-936X","authenticated-orcid":false,"given":"Cristina","family":"Prud\u00eancio","sequence":"additional","affiliation":[{"name":"I3S-Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"},{"name":"Chemical and Biomolecule Sciences, School of Health, Polytechnic of Porto, 4200-072 Porto, Portugal"},{"name":"Center for Translational Health and Medical Biotechnology Research (TBIO), Polytechnic of Porto, 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8922-5713","authenticated-orcid":false,"given":"C\u00e9lia Duarte","family":"Cruz","sequence":"additional","affiliation":[{"name":"Unit of Experimental Biology, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"IBMC-Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal"},{"name":"I3S-Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5696-1239","authenticated-orcid":false,"given":"Isaura","family":"Tavares","sequence":"additional","affiliation":[{"name":"Unit of Experimental Biology, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal"},{"name":"IBMC-Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal"},{"name":"I3S-Institute of Investigation and Innovation in Health, University of Porto, 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1186\/s40001-022-00798-6","article-title":"Hydrocephalus: Historical analysis and considerations for treatment","volume":"27","author":"Hochstetler","year":"2022","journal-title":"Eur. J. Med. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/2045-8118-9-19","article-title":"The relationship between ventricular dilatation, neuropathological and neurobehavioural changes in hydrocephalic rats","volume":"9","author":"Olopade","year":"2012","journal-title":"Fluids Barriers CNS"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.neuroscience.2012.05.004","article-title":"Reactive gliosis and neuroinflammation in rats with communicating hydrocephalus","volume":"218","author":"Xu","year":"2012","journal-title":"Neuroscience"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1002\/ddrr.94","article-title":"Neuropathology and structural changes in hydrocephalus","volume":"16","year":"2010","journal-title":"Dev. Disabil. Res. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/B978-0-444-63247-0.00015-8","article-title":"Lower urinary tract dysfunction in patients with brain lesions","volume":"130","author":"Sakakibara","year":"2015","journal-title":"Handb. Clin. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1002\/nau.21222","article-title":"Correlation of right frontal hypoperfusion and urinary dysfunction in iNPH: A SPECT study","volume":"31","author":"Sakakibara","year":"2012","journal-title":"Neurourol. Urodyn."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1002\/nau.20547","article-title":"Mechanism of bladder dysfunction in idiopathic normal pressure hydrocephalus","volume":"27","author":"Sakakibara","year":"2008","journal-title":"Neurourol. Urodyn."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/B978-0-444-63247-0.00007-9","article-title":"Functional imaging of structures involved in neural control of the lower urinary tract","volume":"130","author":"Griffiths","year":"2015","journal-title":"Handb. Clin. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/apha.12019","article-title":"The micturition switch and its forebrain influences","volume":"207","author":"Griffiths","year":"2013","journal-title":"Acta Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2018","DOI":"10.3389\/fncel.2018.00133","article-title":"Neuronal activation in the periaqueductal gray matter upon electrical stimulation of the bladder","volume":"12","author":"Meriaux","year":"2018","journal-title":"Front. Cell Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"865186","DOI":"10.3389\/fncel.2022.865186","article-title":"Ventrolateral Periaqueductal Gray Neurons Are Active During Urination","volume":"16","author":"Rao","year":"2022","journal-title":"Front. Cell Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1007\/s12035-018-1131-8","article-title":"The Role of the Periaqueductal Gray Matter in Lower Urinary Tract Function","volume":"56","author":"Zare","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1113\/jphysiol.2010.202614","article-title":"GABAergic control of micturition within the periaqueductal grey matter of the male rat","volume":"589","author":"Stone","year":"2011","journal-title":"J. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0006-8993(96)00482-9","article-title":"Evidence for divergent projections to the brain noradrenergic system and the spinal parasympathetic system from Barrington\u2019s nucleus","volume":"732","author":"Valentino","year":"1996","journal-title":"Brain Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1002\/cne.23024","article-title":"Spinal projections of the A5, A6 (locus coeruleus), and A7 noradrenergic cell groups in rats","volume":"520","author":"Bruinstroop","year":"2012","journal-title":"J. Comp. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1002\/1096-9861(20001127)427:4<649::AID-CNE11>3.0.CO;2-M","article-title":"Periaqueductal gray neurons monosynaptically innervate extranuclear noradrenergic dendrites in the rat pericoerulear region","volume":"427","author":"Bajic","year":"2000","journal-title":"J. Comp. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.7554\/eLife.29917","article-title":"Brainstem network dynamics underlying the encoding of bladder information","volume":"6","author":"Manohar","year":"2017","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"572013","DOI":"10.3389\/fnana.2020.572013","article-title":"The Dual Nature of Onuf\u2019s Nucleus: Neuroanatomical Features and Peculiarities, in Health and Disease","volume":"14","author":"Schellino","year":"2020","journal-title":"Front. Neuroanat."},{"key":"ref_19","first-page":"327","article-title":"Neural control of the lower urinary tract","volume":"5","author":"Griffiths","year":"2015","journal-title":"Compr. Physiol."},{"key":"ref_20","unstructured":"Rouzade-Dominguez, M.-L., Curtis, A.L., and Valentino, R.J. (2023, August 10). \u2018Role of Barrington\u2019s Nucleus in the Activation of Rat Locus Coeruleus Neurons by Colonic Distension. Available online: www.elsevier.com\/locate\/bres."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lou\u00e7ano, M., Oliveira, J., Martins, I., Vaz, R., and Tavares, I. (2022). Pain Modulation from the Locus Coeruleus in a Model of Hydrocephalus: Searching for Oxidative Stress-Induced Noradrenergic Neuroprotection. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073970"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/BF00334666","article-title":"Neuropathological changes caused by hydrocephalus","volume":"85","year":"1993","journal-title":"Acta Neuropathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"57","DOI":"10.4236\/ojmn.2018.81004","article-title":"\u2018Animal Models of Hydrocephalus","volume":"8","year":"2018","journal-title":"Open J. Mod. Neurosurg."},{"key":"ref_24","first-page":"352","article-title":"Neuroprotective effect of memantine on hippocampal neurons in infantile rat hydrocephalus","volume":"21","author":"Cabuk","year":"2011","journal-title":"Turk. Neurosurg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s00381-011-1590-y","article-title":"Diffusion tensor imaging of white matter injury in a rat model of infantile hydrocephalus","volume":"28","author":"Yuan","year":"2012","journal-title":"Child\u2019s Nerv. Syst."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1267\/ahc.07011","article-title":"Fragmentation of protein kinase N (PKN) in the hydrocephalic rat brain","volume":"40","author":"Okii","year":"2007","journal-title":"Acta Histochem. Cytochem."},{"key":"ref_27","first-page":"105","article-title":"Neurobehavioral Deficits in Progressive Experimental Hydrocephalus in Neonatal Rats","volume":"31","author":"Olopade","year":"2017","journal-title":"Niger. J. Physiol. Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.brainres.2006.07.089","article-title":"Inhibition of pain behavior by GABAB receptors in the thalamic ventrobasal complex: Effect on normal rats subjected to the formalin test of nociception","volume":"1115","author":"Potes","year":"2006","journal-title":"Brain Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1006\/exnr.1996.0023","article-title":"Motor performance score: A new algorithm for accurate behavioral testing of spinal cord injury in rats","volume":"137","author":"Akesson","year":"1996","journal-title":"Exp. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.expneurol.2016.05.029","article-title":"Impairment of sensory afferents by intrathecal administration of botulinum toxin A improves neurogenic detrusor overactivity in chronic spinal cord injured rats","volume":"285","author":"Coelho","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1016\/j.neurobiolaging.2009.12.023","article-title":"Changes with aging in the dopaminergic and noradrenergic innervation of rat neocortex","volume":"32","author":"Allard","year":"2011","journal-title":"Neurobiol. Aging"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.jchemneu.2019.01.002","article-title":"Distinct regional patterns in noradrenergic innervation of the rat prefrontal cortex","volume":"96","author":"Cerpa","year":"2019","journal-title":"J. Chem. Neuroanat."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1016\/j.pain.2013.05.010","article-title":"Endogenous analgesic action of the pontospinal noradrenergic system spatially restricts and temporally delays the progression of neuropathic pain following tibial nerve injury","volume":"154","author":"Hughes","year":"2013","journal-title":"Pain."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1111\/j.1365-2826.2008.01734.x","article-title":"Measurement of Immediate-Early Gene Activation-c-fos and Beyond","volume":"20","year":"2008","journal-title":"J. Neuroendocrinol."},{"key":"ref_35","first-page":"e53613","article-title":"The c-FOS Protein Immunohistological Detection: A Useful Tool as a Marker of Central Pathways Involved in Specific Physiological Responses In Vivo and Ex Vivo","volume":"110","author":"Jeton","year":"2016","journal-title":"J. Vis. Exp."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4560","DOI":"10.1007\/s12035-017-0658-4","article-title":"Fos Protein as a Marker of Neuronal Activity: A Useful Tool in the Study of the Mechanism of Action of Natural Products with Analgesic Activity","volume":"55","author":"Santos","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_37","unstructured":"Paxinos, G., and Watson, C. (2004). The Rat Brain in Stereotaxic Coordinates, Elsevier Science & Technology Books. [5th ed.]."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"147754","DOI":"10.1016\/j.brainres.2021.147754","article-title":"The role of lumbosacral innervating noradrenergic neurons in micturition control","volume":"1777","author":"Ma","year":"2022","journal-title":"Brain Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1016\/j.neuroscience.2007.05.019","article-title":"Neuronal activation at the spinal cord and medullary pain control centers after joint stimulation: A c-fos study in acute and chronic articular inflammation","volume":"147","author":"Pinto","year":"2007","journal-title":"Neuroscience"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.1111\/j.1460-9568.2008.06276.x","article-title":"GABAergic mechanism mediated via D receptors in the rat periaqueductal gray participates in the micturition reflex: An in vivo microdialysis study","volume":"27","author":"Kitta","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e21200001","DOI":"10.14440\/bladder.2023.854","article-title":"How brain diseases affect the lower urinary tract function?","volume":"10","author":"Sakakibara","year":"2023","journal-title":"Bladder"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1055\/s-0032-1328066","article-title":"Normal pressure hydrocephalus as cause of urinary incontinence\u2014A shunt for incontinence","volume":"72","author":"Rendtorff","year":"2012","journal-title":"Geburtshilfe Frauenheilkd."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"102059","DOI":"10.1016\/j.jchemneu.2021.102059","article-title":"The association of Edaravone with shunt surgery improves behavioral performance, reduces astrocyte reaction and apoptosis, and promotes neuroprotection in young hydrocephalic rats","volume":"119","author":"Romeiro","year":"2022","journal-title":"J. Chem. Neuroanat."}],"container-title":["Biomedicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9059\/12\/1\/215\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:49:17Z","timestamp":1760104157000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9059\/12\/1\/215"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,18]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["biomedicines12010215"],"URL":"https:\/\/doi.org\/10.3390\/biomedicines12010215","relation":{},"ISSN":["2227-9059"],"issn-type":[{"type":"electronic","value":"2227-9059"}],"subject":[],"published":{"date-parts":[[2024,1,18]]}}}