Skip to main content

Advertisement

SpringerLink
Log in

Melatonin ameliorates spatial memory and motor deficits via preserving the integrity of cortical and hippocampal dendritic spine morphology in mice with neurotrauma

  • Original Article
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

We aimed to elucidate the role of cortical and hippocampal dendritic spines on neurological deficits associated with hippocampal microgliosis, hippocampal neurogenesis, and neuroinflammation in mice with cortical compact impact (CCI) injury. In the present study, we found that CCI reduced spatial memory mean latency (10 s. vs 50 s) and motor dysfunction (130 s. vs 150 s.) in mice, as determined by Morris water maze and rotarod test, respectively. Golgi staining of cortical pyramidal neurons revealed that, compared to the controls, the CCI group treated with vehicle solution had significantly lower values of dendritic order (or dendritic branch number) (4.0 vs 6.2), total spine length (400 μm vs 620 μm) and spine density (40 spines/μm vs 60 spines/μm), but had significantly higher values of dendritic beading (40 beadings/mm vs 20 beadings/mm). Additionally, Sholl analysis showed that, compared to controls, the CCI + NS group mice had significantly lower values of dendritic intersections (1.0 vs 2.0). Immunofluorescence assay also revealed that, compared to controls, the CCI + NS group mice had significantly higher values of the newly formed hippocampal cells (1250/mm2 vs 1000/mm2) but significantly lower values of dendritic order (2.0 branch # vs 4.2 branch #), total spine length (180 μm vs 320 μm) and intersection (1.0 vs 3.0). The CCI + NS group mice further showed significantly higher numbers of microglia in the dentate gyrus of the hippocampus and higher concentrations of pro-inflammatory cytokines in the cerebrospinal fluids. All the CCI-induced spatial memory (40 s) and motor (150 s) dysfunction, deranged dendritic and spine morphology of cortical pyramidal neurons or hippocampal newly formed cells, hippocampal microgliosis, and central neuroinflammation were all significantly reduced by melatonin administration during post-CCI. Simultaneously, melatonin therapy caused an enhancement in the compensatory hippocampal neurogenesis and neurotrophic growth factors (e.g., doublecortin-1) and compensatory central anti-inflammatory cytokines. Our results indicate that melatonin attenuates the spatial memory and motor deficits via the modification of cortical and hippocampal dendritic spine morphology, hippocampal microgliosis and neurogenesis, and neuroinflammation in mice with traumatic brain injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  • Alluri H et al (2016) Melatonin preserves blood-brain barrier integrity and permeability via matrix metalloproteinase-9 inhibition. PLoS ONE 11:e0154427

    Article  Google Scholar 

  • Barlow KM, Esser MJ, Veidt M, Boyd R (2019) Melatonin as a treatment after traumatic brain injury: a systematic review and meta-analysis of the pre-clinical and clinical literature. J Neurotrauma 36:523–537

    Article  Google Scholar 

  • Brown JP, Couillard-Despres S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn HG (2003) Transient expression of doublecortin during adult neurogenesis. J Comp Neurol 467:1–10

    Article  CAS  Google Scholar 

  • Campolo M, Ahmad A, Crupi R, Impellizzeri D, Morabito R, Esposito E, Cuzzocrea S (2013) Combination therapy with melatonin and dexamethasone in a mouse model of traumatic brain injury. J Endocrinol 217:291–301

    Article  CAS  Google Scholar 

  • Ceulemans AG, Zgavc T, Kooijman R, Hachimi-Idrissi S, Sarre S, Michotte Y (2010) The dual role of the neuroinflammatory response after ischemic stroke: modulatory effects of hypothermia. J Neuroinflamm 7:74

    Article  Google Scholar 

  • Chen Y, Mao H, Yang KH, Abel T, Meaney DF (2014) A modified controlled cortical impact technique to model mild traumatic brain injury mechanics in mice. Front Neurol 5:100

    PubMed  PubMed Central  Google Scholar 

  • Cheng XP, Sun H, Ye ZY, Zhou JN (2012) Melatonin modulates the GABAergic response in cultured rat hippocampal neurons. J Pharmacol Sci 119:177–185

    Article  CAS  Google Scholar 

  • Cheong CU, Chang CP, Chao CM, Cheng BC, Yang CZ, Chio CC (2013) Etanercept attenuates traumatic brain injury in rats by reducing brain TNF-alpha contents and by stimulating newly formed neurogenesis. Mediat Inflamm 2013:620837

    Article  Google Scholar 

  • Chio CC et al (2017) Exercise attenuates neurological deficits by stimulating a critical HSP70/NF-kappaB/IL-6/synapsin I axis in traumatic brain injury rats. J Neuroinflamm 14:90

    Article  Google Scholar 

  • Couillard-Despres S et al (2005) Doublecortin expression levels in adult brain reflect neurogenesis. Eur J Neurosci 21:1–14

    Article  Google Scholar 

  • Csuka E, Morganti-Kossmann MC, Lenzlinger PM, Joller H, Trentz O, Kossmann T (1999) IL-10 levels in cerebrospinal fluid and serum of patients with severe traumatic brain injury: relationship to IL-6, TNF-alpha, TGF-beta1 and blood-brain barrier function. J Neuroimmunol 101:211–221

    Article  CAS  Google Scholar 

  • Dehghan F, Shahrokhi N, Khaksari M, Soltani Z, Asadikorom G, Najafi A, Shahrokhi N (2018) Does the administration of melatonin during post-traumatic brain injury affect cytokine levels? Inflammopharmacology 26:1017–1023

    Article  CAS  Google Scholar 

  • Esposito E, Cuzzocrea S (2010) Anti-inflammatory activity of melatonin in central nervous system. Curr Neuropharmacol 8:228–242

    Article  CAS  Google Scholar 

  • Figueredo LZ, Moreira KM, Ferreira TL, Fornari RV, Oliveira MG (2008) Interaction between glutamatergic-NMDA and cholinergic-muscarinic systems in classical fear conditioning. Brain Res Bull 77:71–76

    Article  CAS  Google Scholar 

  • Hovda DA et al (1995) The neurochemical and metabolic cascade following brain injury: moving from animal models to man. J Neurotrauma 12:903–906

    Article  CAS  Google Scholar 

  • Ito T et al (2007) High-mobility group box 1 protein promotes development of microvascular thrombosis in rats. J Thromb Haemost 5:109–116

    Article  CAS  Google Scholar 

  • Jilg A et al (2019) Melatonin modulates daytime-dependent synaptic plasticity and learning efficiency. J Pineal Res 66:e12553

    Article  Google Scholar 

  • Kamm K, Vanderkolk W, Lawrence C, Jonker M, Davis AT (2006) The effect of traumatic brain injury upon the concentration and expression of interleukin-1beta and interleukin-10 in the rat. J Trauma 60:152–157

    Article  Google Scholar 

  • Khakpai F, Zarrindast MR, Nasehi M, Haeri-Rohani A, Eidi A (2013) The role of glutamatergic pathway between septum and hippocampus in the memory formation. EXCLI J 12:41–51

    PubMed  PubMed Central  Google Scholar 

  • Kirwan CB, Gilbert PE, Kesner RP (2005) The role of the hippocampus in the retrieval of a spatial location. Neurobiol Learn Mem 83:65–71

    Article  Google Scholar 

  • Li B, Mahmood A, Lu D, Wu H, Xiong Y, Qu C, Chopp M (2009) Simvastatin attenuates microglial cells and astrocyte activation and decreases interleukin-1beta level after traumatic brain injury. Neurosurgery 65:179–185 (discussion 185–176)

    Article  Google Scholar 

  • Lin YC, Koleske AJ (2010) Mechanisms of synapse and dendrite maintenance and their disruption in psychiatric and neurodegenerative disorders. Annu Rev Neurosci 33:349–378

    Article  CAS  Google Scholar 

  • Lin C et al (2016) Melatonin attenuates traumatic brain injury-induced inflammation: a possible role for mitophagy. J Pineal Res 61:177–186

    Article  CAS  Google Scholar 

  • Mann EO, Paulsen O (2007) Role of GABAergic inhibition in hippocampal network oscillations. Trends Neurosci 30:343–349

    Article  CAS  Google Scholar 

  • Nacher J, Crespo C, McEwen BS (2001) Doublecortin expression in the adult rat telencephalon. Eur J Neurosci 14:629–644

    Article  CAS  Google Scholar 

  • Naseem M, Parvez S (2014) Role of melatonin in traumatic brain injury and spinal cord injury. Sci World J 2014:586270

    Article  Google Scholar 

  • Paxinos G, Franklin KBJ (1982) The mouse brain in stereotaxic coordinates. Academic Press, Hong Kong

    Google Scholar 

  • Reiter RJ, Tan DX, Osuna C, Gitto E (2000) Actions of melatonin in the reduction of oxidative stress. A review. J Biomed Sci 7:444–458

    Article  CAS  Google Scholar 

  • Sholl DA (1953) Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat 87:387–406

    CAS  PubMed  PubMed Central  Google Scholar 

  • Solas M, Puerta E, Ramirez MJ (2015) Treatment options in Alzheimer’s disease: the GABA story. Curr Pharm Des 21:4960–4971

    Article  CAS  Google Scholar 

  • Thorajak P, Pannangrong W, Welbat JU, Chaijaroonkhanarak W, Sripanidkulchai K, Sripanidkulchai B (2017) Effects of aged garlic extract on cholinergic, glutamatergic and GABAergic systems with regard to cognitive impairment in Aβ-induced rats. Nutrients 9:686–698

    Article  Google Scholar 

  • Tucker LB, Fu AH, McCabe JT (2016) Performance of male and female C57BL/6J mice on motor and cognitive tasks commonly used in pre-clinical traumatic brain injury research. J Neurotrauma 33:880–894

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by the Ministry of Science and Technology of the Republic of China (MOST 108-2314-B-715-001), Mackay Memorial Hospital (MMH-MM-10807) and Mackay Medical College (1081A01) to Chen-Chia Tsai and Cheng-Hsien Lin and the Innovation Project in Military Medicine Research, PLA, P.R. China (19QNP087), Foundation of the Director of the 960th Hospital, Joint Logistics Force of PLA (2018ZX03) and Logistics Research Program of PLA (CJN13J004) to Xiaojing Lin, Ruoxu Liu, and Gang Sun.

Author information

Authors and Affiliations

  1. Department of Spinal Cord Injury and Repair, Trauma and Orthopedics Institute of Chinese PLA, The 960th Hospital of Joint Logistics Support Force of PLA, Jinan, Shandong, People’s Republic of China

    Xiao-Jing Lin & Chenyi Li

  2. Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, People’s Republic of China

    Xiao-Jing Lin, Ruoxu Liu, Chenyi Li & Bo Fu

  3. Department of Medical Imaging, The 960th Hospital of Joint Logistics Support Force of PLA, Jinan, Shandong, People’s Republic of China

    Xueqing Yi & Gang Sun

  4. Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, USA

    M. J. Walker & Xiao-Ming Xu

  5. Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, USA

    M. J. Walker & Xiao-Ming Xu

  6. Goodman and Campbell Brain and Spine, Indiana University School of Medicine, Indianapolis, USA

    M. J. Walker & Xiao-Ming Xu

  7. Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, USA

    M. J. Walker & Xiao-Ming Xu

  8. Department of Medicine, Mackay Medical College, New Taipei City, Taiwan

    Cheng-Hsien Lin

  9. Department of Medical Research, Chi Mei Medical Center, Tainan, Taiwan

    Cheng-Hsien Lin

Authors
  1. Xiao-Jing Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruoxu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chenyi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xueqing Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bo Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. J. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao-Ming Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Cheng-Hsien Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Gang Sun or Cheng-Hsien Lin.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lin, XJ., Liu, R., Li, C. et al. Melatonin ameliorates spatial memory and motor deficits via preserving the integrity of cortical and hippocampal dendritic spine morphology in mice with neurotrauma. Inflammopharmacol 28, 1553–1566 (2020). https://doi.org/10.1007/s10787-020-00750-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-020-00750-2

Keywords

Search

Navigation