Dorsal raphe nucleus-hippocampus serotonergic circuit underlies the depressive and cognitive impairments in 5×FAD male mice.

Publisher: BioMed Central Country of Publication: England NLM ID: 101591861 Publication Model: Electronic Cited Medium: Print ISSN: 2047-9158 (Print) Linking ISSN: 20479158 NLM ISO Abbreviation: Transl Neurodegener Subsets: MEDLINE

Original Publication: [London] : BioMed Central, 2012-

Dorsal Raphe Nucleus*/metabolism ; Cognitive Dysfunction*/genetics ; Cognitive Dysfunction*/metabolism ; Cognitive Dysfunction*/psychology ; Cognitive Dysfunction*/physiopathology ; Serotonergic Neurons*/metabolism ; Serotonergic Neurons*/physiology ; Depression*/metabolism ; Depression*/genetics ; Depression*/psychology ; Mice, Transgenic* ; Disease Models, Animal* ; Alzheimer Disease*/genetics ; Alzheimer Disease*/metabolism ; Alzheimer Disease*/psychology; Animals ; Male ; Mice ; Hippocampus/metabolism ; Serotonin/metabolism ; Optogenetics ; Neural Pathways/metabolism ; Neural Pathways/physiopathology

Background: Depressive symptoms often occur in patients with Alzheimer's disease (AD) and exacerbate the pathogenesis of AD. However, the neural circuit mechanisms underlying the AD-associated depression remain unclear. The serotonergic system plays crucial roles in both AD and depression.
Methods: We used a combination of in vivo trans-synaptic circuit-dissecting anatomical approaches, chemogenetic manipulations, optogenetic manipulations, pharmacological methods, behavioral testing, and electrophysiological recording to investigate dorsal raphe nucleus serotonergic circuit in AD-associated depression in AD mouse model.
Results: We found that the activity of dorsal raphe nucleus serotonin neurons (DRN ^5-HT ) and their projections to the dorsal hippocampal CA1 (dCA1) terminals (DRN ^5-HT -dCA1 ^CaMKII ) both decreased in brains of early 5×FAD mice. Chemogenetic or optogenetic activation of the DRN ^5-HT -dCA1 ^CaMKII neural circuit attenuated the depressive symptoms and cognitive impairments in 5×FAD mice through serotonin receptor 1B (5-HT 1B R) and 4 (5-HT 4 R). Pharmacological activation of 5-HT 1B R or 5-HT 4 R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DRN ^5-HT -dCA1 ^CaMKII neural circuit to improve synaptic plasticity.
Conclusions: These findings provide a new mechanistic connection between depression and AD and provide potential pharmaceutical prevention targets for AD.
(© 2024. The Author(s).)

Neuron. 2017 Jan 4;93(1):33-47. (PMID: 27989459)
Brain Res. 1995 Dec 1;701(1-2):249-54. (PMID: 8925288)
Biomolecules. 2023 Jun 08;13(6):. (PMID: 37371543)
Trends Cogn Sci. 2008 Jan;12(1):31-40. (PMID: 18069045)
Br J Pharmacol. 2003 Jan;138(1):71-80. (PMID: 12522075)
Psychopharmacology (Berl). 2018 May;235(5):1317-1334. (PMID: 29546551)
J Neurophysiol. 1996 Aug;76(2):799-807. (PMID: 8871200)
J Neurosci. 1999 May 15;19(10):4034-45. (PMID: 10234032)
Neurosci Bull. 2018 Oct;34(5):736-746. (PMID: 30099679)
MMWR Morb Mortal Wkly Rep. 2023 Mar 10;72(10):249-255. (PMID: 36893045)
Brain. 2021 Mar 3;144(2):553-573. (PMID: 33324984)
CNS Neurosci Ther. 2014 Jul;20(7):582-90. (PMID: 24935787)
Brain Behav Immun. 2021 Jul;95:216-225. (PMID: 33775832)
Curr Opin Neurobiol. 2023 Apr;79:102701. (PMID: 36878147)
Biochem Pharmacol. 2020 May;175:113870. (PMID: 32088264)
Brain Res. 2011 Apr 12;1384:69-79. (PMID: 21291871)
Nat Neurosci. 2023 Jan;26(1):53-63. (PMID: 36522497)
J Neurosci Res. 2004 Oct 15;78(2):268-78. (PMID: 15378508)
Life Sci. 2002 Dec 20;72(4-5):375-87. (PMID: 12467878)
Mol Psychiatry. 2004 Nov;9(11):980-1. (PMID: 15263906)
Handb Clin Neurol. 2019;167:231-255. (PMID: 31753135)
Neuropharmacology. 2008 Nov;55(6):922-31. (PMID: 18603269)
J Physiol. 2023 Aug;601(15):3403-3437. (PMID: 36734280)
Neuroreport. 2002 Jul 2;13(9):1175-8. (PMID: 12151764)
Psychopharmacology (Berl). 2022 Dec;239(12):3875-3892. (PMID: 36282287)
Nature. 2021 Nov;599(7883):96-101. (PMID: 34616037)
Neuropharmacology. 2020 May 15;168:107985. (PMID: 32035145)
Psychopharmacology (Berl). 2005 May;179(3):673-7. (PMID: 15551121)
Drugs. 2014 May;74(7):729-36. (PMID: 24802806)
J Clin Psychopharmacol. 2007 Oct;27(5):484-7. (PMID: 17873681)
Molecules. 2019 Jul 31;24(15):. (PMID: 31370232)
Neuropsychopharmacology. 2008 Sep;33(10):2427-34. (PMID: 18075492)
Neuropharmacology. 2003 Jun;44(8):1022-30. (PMID: 12763095)
Neurosci Res. 2004 Mar;48(3):229-38. (PMID: 15154669)
Expert Opin Ther Pat. 2020 Jul;30(7):495-508. (PMID: 32400221)
Int J Mol Sci. 2021 Mar 30;22(7):. (PMID: 33808456)
Int Psychogeriatr. 2023 Nov;35(11):623-632. (PMID: 36714990)
Neurosci Biobehav Rev. 2019 Oct;105:39-51. (PMID: 31377218)
Ann Neurol. 1985 Jun;17(6):573-7. (PMID: 4026228)
Neuropsychopharmacology. 1998 Jun;18(6):407-30. (PMID: 9571651)
Cell Rep. 2023 Mar 28;42(3):112152. (PMID: 36821438)
Ann N Y Acad Sci. 2007 Dec;1122:35-49. (PMID: 18077563)
Physiol Rev. 1992 Jan;72(1):165-229. (PMID: 1731370)
J Med Chem. 2021 Aug 12;64(15):10641-10665. (PMID: 34251799)
Neuropsychopharmacology. 2004 Feb;29(2):410-6. (PMID: 14571255)
Brain Res. 1996 May 20;721(1-2):59-65. (PMID: 8793084)
Cell Commun Signal. 2022 May 28;20(1):74. (PMID: 35643536)
Cell Rep. 2016 Dec 13;17(11):2882-2890. (PMID: 27974203)
Trends Pharmacol Sci. 2008 Sep;29(9):482-92. (PMID: 19086256)
Gut Microbes. 2021 Jan-Dec;13(1):1-16. (PMID: 33535879)
J Physiol. 1998 Apr 1;508 ( Pt 1):119-29. (PMID: 9490827)
Neuropsychopharmacology. 2001 Nov;25(5):662-8. (PMID: 11682249)
Neuropharmacology. 2020 May 1;167:107703. (PMID: 31299228)
Alzheimers Dement. 2022 Apr;18(4):700-789. (PMID: 35289055)
J Clin Psychiatry. 2011 Nov;72(11):e1563-9. (PMID: 22127200)
Prog Neurobiol. 2012 Oct;99(1):15-41. (PMID: 22766041)
Neuropharmacology. 2001 Oct;41(5):529-38. (PMID: 11587707)
Front Psychiatry. 2019 Jan 07;9:734. (PMID: 30666218)
Mol Pharmacol. 1992 Jan;41(1):1-7. (PMID: 1732716)
Proc Natl Acad Sci U S A. 2012 May 29;109(22):8740-5. (PMID: 22592800)
EMBO J. 1991 Dec;10(13):4017-23. (PMID: 1836757)
Exp Neurol. 2007 Jan;203(1):274-8. (PMID: 16978609)
Mol Psychiatry. 2023 Mar;28(3):1303-1311. (PMID: 36474000)
Front Pharmacol. 2021 Sep 06;12:735876. (PMID: 34552493)
Int J Mol Sci. 2023 Mar 03;24(5):. (PMID: 36902322)
Behav Brain Res. 2008 Dec 16;195(1):198-213. (PMID: 18571247)
J Alzheimers Dis. 2010;20 Suppl 2:S527-33. (PMID: 20442496)
Cell. 2018 Oct 4;175(2):472-487.e20. (PMID: 30146164)
Neuron. 2018 Nov 7;100(3):551-563.e7. (PMID: 30220511)
Neuropharmacology. 2000 Aug 23;39(11):2017-27. (PMID: 10963745)
Front Aging Neurosci. 2013 Dec 24;5:96. (PMID: 24399967)
Behav Brain Res. 2015 Feb 1;278:496-505. (PMID: 25446812)
Mol Neurodegener. 2016 Jun 18;11(1):45. (PMID: 27315796)
Neuron. 2011 Sep 8;71(5):898-910. (PMID: 21903082)
Neuron. 2018 Jun 6;98(5):992-1004.e4. (PMID: 29754752)
Annu Rev Med. 2009;60:355-66. (PMID: 19630576)
Prog Brain Res. 2021;261:41-81. (PMID: 33785137)
Nat Rev Neurol. 2023 Jan;19(1):19-38. (PMID: 36513730)
CNS Neurosci Ther. 2023 Feb;29(2):646-658. (PMID: 36510669)
J Alzheimers Dis. 2015;46(1):63-73. (PMID: 25697700)
Transl Neurosci. 2016 May 9;7(1):35-49. (PMID: 28123820)
Br J Pharmacol. 1995 Mar;114(5):993-8. (PMID: 7780656)
Cell Death Dis. 2011 Sep 15;2:e210. (PMID: 21918544)
Brain Struct Funct. 2016 Jan;221(1):535-61. (PMID: 25403254)
Lancet Neurol. 2021 Mar;20(3):222-234. (PMID: 33609479)

92149303 National Natural Science Foundation of China; 81925010 National Natural Science Foundation of China; 91849205 National Natural Science Foundation of China; U1905207 National Natural Science Foundation of China; NV20230010 Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education; NV20230014 Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education; 2021YFS0385 Project of Sichuan Department of Science and Technology

Keywords: 5-HT neurons; Alzheimer’s disease; Cognitive impairment; Depressive symptoms; Dorsal hippocampal CA1; Dorsal raphe nucleus; Serotonin receptor

333DO1RDJY (Serotonin)

Date Created: 20240723 Date Completed: 20240724 Latest Revision: 20240726

20240726

PMC11267773

10.1186/s40035-024-00425-w

39044270