Role of Supramammillary Nucleus Derived Substance P in Regulating Adult Hippocampal Neurogenesis and Depression and Anxiety-Like Behaviour
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Role of Supramammillary Nucleus Derived Substance P in Regulating Adult Hippocampal Neurogenesis and Depression and Anxiety-Like Behaviour

Jiayinuo Li 1*
1 RCF experimental school
*Corresponding author: angela.li2024al@gmail.com
Published on 2 October 2025
Journal Cover
TNS Vol.139
ISSN (Print): 2753-8826
ISSN (Online): 2753-8818
ISBN (Print): 978-1-80590-395-6
ISBN (Online): 978-1-80590-396-3
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Abstract

Accumulating evidence showed the adult hippocampal neurogenesis (AHN) has played an essential role in regulating cognitive functions and emotions, while the other potential regulator such as the neuropeptides has still received less attention.. In the nestin-GFP mice, our data showed that the SP-overexpressed SuM neurons inhibited the proliferation of radial neural stem cells (rNSCs) and reduced the cell densities of immature and proliferating neurons in the dentate gyrus (DG). All of these processes were accompanied by depression and anxiety-like behaviours, including the reduced exploration, the lower sucrose preference, and the prolonged immobility. However, the neurokinin-1 receptor (NK1-R) antagonist could reversed those behavioural deficits. Together, our study demonstrated that SP was an essential inhibitor of AHN and emotional behaviours, while the NK1-R antagonism may provide a potential therapeutic strategy for depression and anxiety-like behaviours.

Keywords:

adult hippocampal neurogenesis, supramammilary nucleus, substance P, neurokinin-1 receptor, depression and anxiety-like behaviours

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Li,J. (2025). Role of Supramammillary Nucleus Derived Substance P in Regulating Adult Hippocampal Neurogenesis and Depression and Anxiety-Like Behaviour. Theoretical and Natural Science,139,1-10.

References

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[2]. Fava M. Weight gain and antidepressants. J Clin Psychiatry. 2000; 61 Suppl 11: 37-41. PMID: 10926053.

[3]. Kempermann G, Song H, Gage FH. Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol. 2015 Jul 1; 7(9): a018812. doi: 10.1101/cshperspect.a018812. PMID: 26330519.

[4]. Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature. 2011 Aug 24; 476(7361): 458-61. doi: 10.1038/nature10287. PMID: 21814201.

[5]. Li YD, Luo YJ, Chen ZK, Quintanilla L, Cherasse Y, Zhang L, Lazarus M, Huang ZL, Song J. Hypothalamic modulation of adult hippocampal neurogenesis in mice confers activity-dependent regulation of memory and anxiety-like behavior. Nat Neurosci. 2022 May; 25(5): 630-645. doi: 10.1038/s41593-022-01065-x. Epub 2022 May 6. PMID: 35524139; PMCID: PMC9287980.

[6]. Ebner K, Singewald N. The role of substance P in stress and anxiety responses. Amino Acids. 2006 Sep; 31(3): 251-72. doi: 10.1007/s00726-006-0335-9. PMID: 16820980.

[7]. Iftikhar K, Siddiq A, Baig SG, Zehra S. Substance P: A neuropeptide involved in the psychopathology of anxiety disorders. Neuropeptides. 2020 Feb; 79: 101993. doi: 10.1016/j.npep.2019.101993. Epub 2019 Nov 11. PMID: 31735376.

[8]. Bassi GS, de Carvalho MC, Brandão ML. Effects of substance P and Sar-Met-SP, a NK1 agonist, in distinct amygdaloid nuclei on anxiety-like behaviour in rats. Neurosci Lett. 2014 May 21; 569: 121-5. doi: 10.1016/j.neulet.2014.03.065. Epub 2014 Apr 4. PMID: 24708929.

[9]. Kupcova, I., Danisovic, L., Grgac, I., & Harsanyi, S. (2022). Anxiety and Depression: What Do We Know of Neuropeptides? behavioral Sciences, 12(8), 262. https: //doi.org/10.3390/bs12080262

[10]. 14.McLean S. Do substance P and the NK1 receptor have a role in depression and anxiety? Curr Pharm Des. 2005; 11(12): 1529-47. doi: 10.2174/1381612053764779. PMID: 15892660.

[11]. Stephen Johnston, Sarah L Parylak, Stacy Kim, Nolan Mac, Christina Lim, Iryna Gallina, Cooper Bloyd, Alexander Newberry, Christian D Saavedra, Ondrej Novak, J Tiago Gonçalves, Fred H Gage, Matthew Shtrahman (2021) AAV ablates neurogenesis in the adult murine hippocampus eLife 10: e59291.

[12]. Liu MY, Yin CY, Zhu LJ, Zhu XH, Xu C, Luo CX, Chen H, Zhu DY, Zhou QG. Sucrose preference test for measurement of stress-induced anhedonia in mice. Nat Protoc. 2018 Jul; 13(7): 1686-1698. doi: 10.1038/s41596-018-0011-z. PMID: 29988104.

[13]. Chen L, Faas GC, Ferando I, Mody I. Novel insights into the behavioral analysis of mice subjected to the forced-swim test. Transl Psychiatry. 2015 Apr 14; 5(4): e551. doi: 10.1038/tp.2015.44. PMID: 25871976; PMCID: PMC4462607.

[14]. 15.Park G, Kim SS, Shim J, Lee SV. Brief guide to immunostaining. Mol Cells. 2025 Jan; 48(1): 100157. doi: 10.1016/j.mocell.2024.100157. Epub 2024 Nov 19. PMID: 39571972; PMCID: PMC11699723

[15]. Sosulina L, Strippel C, Romo-Parra H, Walter AL, Kanyshkova T, Sartori SB, Lange MD, Singewald N, Pape HC. Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation. J Neurophysiol. 2015 Oct; 114(4): 2500-8. doi: 10.1152/jn.00883.2014. Epub 2015 Sep 2. PMID: 26334021; PMCID: PMC4620133.

[16]. Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008 Sep; 31(9): 464-8. doi: 10.1016/j.tins.2008.06.006. PMID: 18675469.

[17]. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016 Jan; 16(1): 22-34. doi: 10.1038/nri.2015.5. PMID: 26689365.

[18]. Duric V, McCarson KE. Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress. Neuroscience. 2005; 133(4): 999-1006. doi: 10.1016/j.neuroscience.2005.04.002. PMID: 15964488.

[19]. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006 Jun 15; 59(12): 1116-27. doi: 10.1016/j.biopsych.2006.02.013. PMID: 16631126.

[20]. Castrén E, Rantamäki T. The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity. Dev Neurobiol. 2010 Apr; 70(5): 289-97. doi: 10.1002/dneu.20758. PMID: 20186711.

References

[1]. Kovich H, Kim W, Quaste AM. Pharmacologic Treatment of Depression. Am Fam Physician. 2023 Feb; 107(2): 173-181. PMID: 36791444.

[2]. Fava M. Weight gain and antidepressants. J Clin Psychiatry. 2000; 61 Suppl 11: 37-41. PMID: 10926053.

[3]. Kempermann G, Song H, Gage FH. Neurogenesis in the adult hippocampus. Cold Spring Harb Perspect Biol. 2015 Jul 1; 7(9): a018812. doi: 10.1101/cshperspect.a018812. PMID: 26330519.

[4]. Snyder JS, Soumier A, Brewer M, Pickel J, Cameron HA. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. Nature. 2011 Aug 24; 476(7361): 458-61. doi: 10.1038/nature10287. PMID: 21814201.

[5]. Li YD, Luo YJ, Chen ZK, Quintanilla L, Cherasse Y, Zhang L, Lazarus M, Huang ZL, Song J. Hypothalamic modulation of adult hippocampal neurogenesis in mice confers activity-dependent regulation of memory and anxiety-like behavior. Nat Neurosci. 2022 May; 25(5): 630-645. doi: 10.1038/s41593-022-01065-x. Epub 2022 May 6. PMID: 35524139; PMCID: PMC9287980.

[6]. Ebner K, Singewald N. The role of substance P in stress and anxiety responses. Amino Acids. 2006 Sep; 31(3): 251-72. doi: 10.1007/s00726-006-0335-9. PMID: 16820980.

[7]. Iftikhar K, Siddiq A, Baig SG, Zehra S. Substance P: A neuropeptide involved in the psychopathology of anxiety disorders. Neuropeptides. 2020 Feb; 79: 101993. doi: 10.1016/j.npep.2019.101993. Epub 2019 Nov 11. PMID: 31735376.

[8]. Bassi GS, de Carvalho MC, Brandão ML. Effects of substance P and Sar-Met-SP, a NK1 agonist, in distinct amygdaloid nuclei on anxiety-like behaviour in rats. Neurosci Lett. 2014 May 21; 569: 121-5. doi: 10.1016/j.neulet.2014.03.065. Epub 2014 Apr 4. PMID: 24708929.

[9]. Kupcova, I., Danisovic, L., Grgac, I., & Harsanyi, S. (2022). Anxiety and Depression: What Do We Know of Neuropeptides? behavioral Sciences, 12(8), 262. https: //doi.org/10.3390/bs12080262

[10]. 14.McLean S. Do substance P and the NK1 receptor have a role in depression and anxiety? Curr Pharm Des. 2005; 11(12): 1529-47. doi: 10.2174/1381612053764779. PMID: 15892660.

[11]. Stephen Johnston, Sarah L Parylak, Stacy Kim, Nolan Mac, Christina Lim, Iryna Gallina, Cooper Bloyd, Alexander Newberry, Christian D Saavedra, Ondrej Novak, J Tiago Gonçalves, Fred H Gage, Matthew Shtrahman (2021) AAV ablates neurogenesis in the adult murine hippocampus eLife 10: e59291.

[12]. Liu MY, Yin CY, Zhu LJ, Zhu XH, Xu C, Luo CX, Chen H, Zhu DY, Zhou QG. Sucrose preference test for measurement of stress-induced anhedonia in mice. Nat Protoc. 2018 Jul; 13(7): 1686-1698. doi: 10.1038/s41596-018-0011-z. PMID: 29988104.

[13]. Chen L, Faas GC, Ferando I, Mody I. Novel insights into the behavioral analysis of mice subjected to the forced-swim test. Transl Psychiatry. 2015 Apr 14; 5(4): e551. doi: 10.1038/tp.2015.44. PMID: 25871976; PMCID: PMC4462607.

[14]. 15.Park G, Kim SS, Shim J, Lee SV. Brief guide to immunostaining. Mol Cells. 2025 Jan; 48(1): 100157. doi: 10.1016/j.mocell.2024.100157. Epub 2024 Nov 19. PMID: 39571972; PMCID: PMC11699723

[15]. Sosulina L, Strippel C, Romo-Parra H, Walter AL, Kanyshkova T, Sartori SB, Lange MD, Singewald N, Pape HC. Substance P excites GABAergic neurons in the mouse central amygdala through neurokinin 1 receptor activation. J Neurophysiol. 2015 Oct; 114(4): 2500-8. doi: 10.1152/jn.00883.2014. Epub 2015 Sep 2. PMID: 26334021; PMCID: PMC4620133.

[16]. Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008 Sep; 31(9): 464-8. doi: 10.1016/j.tins.2008.06.006. PMID: 18675469.

[17]. Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016 Jan; 16(1): 22-34. doi: 10.1038/nri.2015.5. PMID: 26689365.

[18]. Duric V, McCarson KE. Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress. Neuroscience. 2005; 133(4): 999-1006. doi: 10.1016/j.neuroscience.2005.04.002. PMID: 15964488.

[19]. Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006 Jun 15; 59(12): 1116-27. doi: 10.1016/j.biopsych.2006.02.013. PMID: 16631126.

[20]. Castrén E, Rantamäki T. The role of BDNF and its receptors in depression and antidepressant drug action: Reactivation of developmental plasticity. Dev Neurobiol. 2010 Apr; 70(5): 289-97. doi: 10.1002/dneu.20758. PMID: 20186711.

Cite this article

Li,J. (2025). Role of Supramammillary Nucleus Derived Substance P in Regulating Adult Hippocampal Neurogenesis and Depression and Anxiety-Like Behaviour. Theoretical and Natural Science,139,1-10.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

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Volume title: Proceedings of ICBioMed 2025 Symposium: AI for Healthcare: Advanced Medical Data Analytics and Smart Rehabilitation

ISBN: 978-1-80590-395-6(Print) / 978-1-80590-396-3(Online)
Editor: Alan Wang
Conference website: https://2025.icbiomed.org/auckland.html
Conference date: 17 October 2025
Series: Theoretical and Natural Science
Volume number: Vol.139
ISSN: 2753-8818(Print) / 2753-8826(Online)

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