{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T22:07:09Z","timestamp":1780524429563,"version":"3.54.1"},"reference-count":49,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T00:00:00Z","timestamp":1684281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science","award":["23K14697"],"award-info":[{"award-number":["23K14697"]}]},{"name":"Japan Society for the Promotion of Science","award":["2213051"],"award-info":[{"award-number":["2213051"]}]},{"name":"Nagoya City University","award":["23K14697"],"award-info":[{"award-number":["23K14697"]}]},{"name":"Nagoya City University","award":["2213051"],"award-info":[{"award-number":["2213051"]}]},{"name":"The Hori Sciences and Arts Foundation","award":["23K14697"],"award-info":[{"award-number":["23K14697"]}]},{"name":"The Hori Sciences and Arts Foundation","award":["2213051"],"award-info":[{"award-number":["2213051"]}]},{"name":"The Nitto Foundation","award":["23K14697"],"award-info":[{"award-number":["23K14697"]}]},{"name":"The Nitto Foundation","award":["2213051"],"award-info":[{"award-number":["2213051"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The cholinergic efferent network from the medial septal nucleus to the hippocampus is crucial for learning and memory. This study aimed to clarify whether hippocampal cholinergic neurostimulating peptide (HCNP) has a rescue function in the cholinergic dysfunction of HCNP precursor protein (HCNP-pp) conditional knockout (cKO). Chemically synthesized HCNP or a vehicle were continuously administered into the cerebral ventricle of HCNP-pp cKO mice and littermate floxed (control) mice for two weeks via osmotic pumps. We immunohistochemically measured the cholinergic axon volume in the stratum oriens and functionally evaluated the local field potential in the CA1. Furthermore, choline acetyltransferase (ChAT) and nerve growth factor (NGF) receptor (TrkA and p75NTR) abundances were quantified in wild-type (WT) mice administered HCNP or the vehicle. As a result, HCNP administration morphologically increased the cholinergic axonal volume and electrophysiological theta power in HCNP-pp cKO and control mice. Following the administration of HCNP to WT mice, TrkA and p75NTR levels also decreased significantly. These data suggest that extrinsic HCNP may compensate for the reduced cholinergic axonal volume and theta power in HCNP-pp cKO mice. HCNP may function complementarily to NGF in the cholinergic network in vivo. HCNP may represent a therapeutic candidate for neurological diseases with cholinergic dysfunction, e.g., Alzheimer\u2019s disease and Lewy body dementia.<\/jats:p>","DOI":"10.3390\/ijms24108916","type":"journal-article","created":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T08:09:44Z","timestamp":1684397384000},"page":"8916","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Direct Enhancement Effect of Hippocampal Cholinergic Neurostimulating Peptide on Cholinergic Activity in the Hippocampus"],"prefix":"10.3390","volume":"24","author":[{"given":"Yuta","family":"Madokoro","sequence":"first","affiliation":[{"name":"Department of Neurology, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yo","family":"Tsuda","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Itsumi","family":"Arakawa","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toyohiro","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9530-5960","authenticated-orcid":false,"given":"Masayuki","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuto","family":"Uchida","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosei","family":"Ojika","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriyuki","family":"Matsukawa","sequence":"additional","affiliation":[{"name":"Department of Neurology, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/31709","article-title":"Modulation of AMPA receptor unitary conductance by synaptic activity","volume":"393","author":"Benke","year":"1998","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.neulet.2018.05.006","article-title":"The hippocampus and related neocortical structures in memory transformation","volume":"680","author":"Sekeres","year":"2018","journal-title":"Neurosci. Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.neuron.2011.04.026","article-title":"Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity","volume":"71","author":"Gu","year":"2011","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/nrn.2016.21","article-title":"Rhythms of the hippocampal network","volume":"17","author":"Colgin","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.neuron.2010.05.013","article-title":"Coherent theta oscillations and reorganization of spike timing in the hippocampal-prefrontal network upon learning","volume":"66","author":"Benchenane","year":"2010","journal-title":"Neuron"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/nn.2337","article-title":"Replay of rule-learning related neural patterns in the prefrontal cortex during sleep","volume":"12","author":"Peyrache","year":"2009","journal-title":"Nat. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.neuron.2008.09.014","article-title":"Entrainment of neocortical neurons and gamma oscillations by the hippocampal theta rhythm","volume":"60","author":"Sirota","year":"2008","journal-title":"Neuron"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1152\/jn.1954.17.6.533","article-title":"Hippocampal electrical activity in arousal","volume":"17","author":"Green","year":"1954","journal-title":"J. Neurophysiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1152\/jn.00135.2001","article-title":"Pacemaker neurons for the theta rhythm and their synchronization in the septohippocampal reciprocal loop","volume":"87","author":"Wang","year":"2002","journal-title":"J. Neurophysiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8394","DOI":"10.1523\/JNEUROSCI.4460-14.2015","article-title":"Synergy of direct and indirect cholinergic septo-hippocampal pathways coordinates firing in hippocampal networks","volume":"35","author":"Dannenberg","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"166","DOI":"10.3389\/fnbeh.2015.00166","article-title":"Medial septum regulates the hippocampal spatial representation","volume":"9","author":"Mamad","year":"2015","journal-title":"Front. Behav. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/0006-8993(92)90465-L","article-title":"Purification and structural analysis of hippocampal cholinergic neurostimulating peptide","volume":"572","author":"Ojika","year":"1992","journal-title":"Brain Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/S0301-0082(99)00021-0","article-title":"Hippocampal cholinergic neurostimulating peptides (Hcnp)","volume":"60","author":"Ojika","year":"2000","journal-title":"Prog. Neurobiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Madokoro, Y., Yoshino, Y., Kato, D., Sato, T., Mizuno, M., Kanamori, T., Shimazawa, M., Hida, H., Hara, H., and Yoshida, M. (2019). Reduced cholinergic activity in the hippocampus of hippocampal cholinergic neurostimulating peptide precursor protein knockout mice. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215367"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"22072","DOI":"10.1038\/s41598-021-01667-8","article-title":"Reduction of acetylcholine in the hippocampus of hippocampal cholinergic neurostimulating peptide precursor protein knockout mice","volume":"11","author":"Mizuno","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"19161","DOI":"10.1038\/s41598-022-23846-x","article-title":"Reduction of glutamatergic activity through cholinergic dysfunction in the hippocampus of hippocampal cholinergic neurostimulating peptide precursor protein knockout mice","volume":"12","author":"Suzuki","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3638","DOI":"10.1038\/s41467-018-05907-w","article-title":"Ventral hippocampal olm cells control type 2 theta oscillations and response to predator odor","volume":"9","author":"Mikulovic","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Stanciu, G.D., Luca, A., Rusu, R.N., Bild, V., Beschea Chiriac, S.I., Solcan, C., Bild, W., and Ababei, D.C. (2019). Alzheimer\u2019s disease pharmacotherapy in relation to cholinergic system involvement. Biomolecules, 10.","DOI":"10.3390\/biom10010040"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1001\/jamaneurol.2015.1807","article-title":"nerve growth factor gene therapy: Activation of neuronal responses in Alzheimer disease","volume":"72","author":"Tuszynski","year":"2015","journal-title":"JAMA Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1586\/14737175.8.11.1703","article-title":"Cholinergic system during the progression of Alzheimer\u2019s disease: Therapeutic implications","volume":"8","author":"Mufson","year":"2008","journal-title":"Expert Rev. Neurother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.bbr.2010.11.058","article-title":"The cholinergic system in aging and neuronal degeneration","volume":"221","author":"Schliebs","year":"2011","journal-title":"Behav. Brain Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1007\/s12035-012-8310-9","article-title":"Nerve growth factor and Alzheimer\u2019s disease: New facts for an old hypothesis","volume":"46","author":"Cattaneo","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.4103\/1673-5374.193224","article-title":"Impairment of the nerve growth factor pathway driving amyloid accumulation in cholinergic neurons: The incipit of the Alzheimer\u2019s disease story?","volume":"11","author":"Triaca","year":"2016","journal-title":"Neural Regen. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1038\/547153a","article-title":"Stop Alzheimer\u2019s before it starts","volume":"547","author":"McDade","year":"2017","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0165-3806(94)90043-4","article-title":"Two different molecules, Ngf and Free-Hcnp, stimulate cholinergic activity in septal nuclei in vitro in a different manner","volume":"79","author":"Ojika","year":"1994","journal-title":"Brain Res. Dev. Brain Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1126\/science.7046051","article-title":"The cholinergic hypothesis of geriatric memory dysfunction","volume":"217","author":"Bartus","year":"1982","journal-title":"Science"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1016\/j.neuron.2016.09.006","article-title":"Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline","volume":"91","author":"Ballinger","year":"2016","journal-title":"Neuron"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1002\/ana.410120517","article-title":"Alzheimer disease: Plaques, tangles, and the basal forebrain","volume":"12","author":"Whitehouse","year":"1982","journal-title":"Ann. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.biopsych.2011.06.019","article-title":"Atrophy of the cholinergic basal forebrain over the adult age range and in early stages of Alzheimer\u2019s disease","volume":"71","author":"Grothe","year":"2012","journal-title":"Biol. Psychiatry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1093\/cercor\/bhp232","article-title":"Reduction of basal forebrain cholinergic system parallels cognitive impairment in patients at high risk of developing Alzheimer\u2019s disease","volume":"20","author":"Grothe","year":"2010","journal-title":"Cereb. Cortex"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1002\/hbm.21111","article-title":"The cholinergic system in mild cognitive impairment and Alzheimer\u2019s disease: An in vivo Mri and Dti study","volume":"32","author":"Teipel","year":"2011","journal-title":"Hum. Brain Mapp."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1002\/ana.410130304","article-title":"Basal forebrain neurons in the dementia of Parkinson disease","volume":"13","author":"Whitehouse","year":"1983","journal-title":"An. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1136\/jnnp.48.5.413","article-title":"Cholinergic correlates of cognitive impairment in Parkinson\u2019s disease: Comparisons with Alzheimer\u2019s disease","volume":"48","author":"Perry","year":"1985","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1177\/0891988704267463","article-title":"Role of cholinesterase inhibitors in Parkinson\u2019s disease and dementia with Lewy bodies","volume":"17","author":"Aarsland","year":"2004","journal-title":"J. Geriatr. Psychiatry Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s007020050176","article-title":"Dementia with Lewy bodies: Choline acetyltransferase parallels nucleus basalis pathology","volume":"106","author":"Lippa","year":"1999","journal-title":"J. Neural. Transm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7355","DOI":"10.1007\/s12035-019-1605-3","article-title":"Cholinergic differentiation of human neuroblastoma Sh-Sy5y cell line and its potential use as an in vitro model for Alzheimer\u2019s disease studies","volume":"56","author":"Rico","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"19567","DOI":"10.1073\/pnas.1319297110","article-title":"Bmp9 ameliorates amyloidosis and the cholinergic defect in a mouse model of Alzheimer\u2019s disease","volume":"110","author":"Burke","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1093\/brain\/awy132","article-title":"The cholinergic system in the pathophysiology and treatment of Alzheimer\u2019s disease","volume":"141","author":"Hampel","year":"2018","journal-title":"Brain"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1007\/s007020050100","article-title":"The time course of nerve growth factor content in different neuropsychiatric diseases\u2013a unifying hypothesis","volume":"105","author":"Hellweg","year":"1998","journal-title":"J. Neural. Transm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4279","DOI":"10.2174\/1381612827666210820100723","article-title":"A recent update on intranasal delivery of high molecular weight proteins, peptides, and hormones","volume":"27","author":"Sharma","year":"2021","journal-title":"Cur. Pharm. Des."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/S0006-8993(02)04194-X","article-title":"Specific binding of 125i-hippocampal cholinergic neurostimulating peptide (Hcnp) to rat brain membranes: Characterization and regional distribution","volume":"965","author":"Morishita","year":"2003","journal-title":"Brain Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1213\/00000539-200202000-00015","article-title":"The Anesthetic Mechanism of Urethane: The Effects on Neurotransmitter-Gated Ion Channels","volume":"94","author":"Hara","year":"2002","journal-title":"Anesth. Analg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3645","DOI":"10.1152\/jn.00040.2006","article-title":"Septo-Hippocampal Networks in Chronically Epileptic Rats: Potential Antiepileptic Effects of Theta Rhythm Generation","volume":"95","author":"Colom","year":"2006","journal-title":"J. Neurophysiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/0301-0082(93)90007-F","article-title":"Extrinsic and Intrinsic Properties Underlying Oscillation and Synchrony in Limbic Cortex","volume":"41","author":"Bland","year":"1993","journal-title":"Prog. Neurobiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s00221-011-2666-3","article-title":"Theta Synchronization between the Hippocampus and the Nucleus Incertus in Urethane-Anesthetized Rats","volume":"211","year":"2011","journal-title":"Exp. Brain Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13535","DOI":"10.1073\/pnas.1411233111","article-title":"Optogenetic Activation of Septal Cholinergic Neurons Suppresses Sharp Wave Ripples and Enhances Theta Oscillations in the Hippocampus","volume":"111","author":"Vandecasteele","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","unstructured":"Paxinos, G., and Franklin, K.B.J. (2008). The Mouse Brain in Stereotaxic Coordinates, Academic Press. [3rd ed.]."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Takata, N., Yoshida, K., Komaki, Y., Xu, M., Sakai, Y., Hikishima, K., Mimura, M., Okano, H., and Tanaka, K.F. (2015). Optogenetic activation of Ca1 pyramidal neurons at the dorsal and ventral hippocampus evokes distinct brain-wide responses revealed by mouse Fmri. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121417"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1152\/jn.00548.2017","article-title":"The modulation of hippocampal theta rhythm by the vestibular system","volume":"119","author":"Aitken","year":"2018","journal-title":"J. Neurophysiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8916\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:37:08Z","timestamp":1760125028000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8916"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,17]]},"references-count":49,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24108916"],"URL":"https:\/\/doi.org\/10.3390\/ijms24108916","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,17]]}}}