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Age-Induced Spatial Memory Deficits in Rats Are Correlated with Specific Brain Region Alterations in Microglial Morphology and Gene Expression

Abstract

Effect of age and ladostigil treatment (1 mg/kg/day), given for 6 months to 16 month old rats, was investigated on microglial morphology in brain regions associated with control of spatial learning. This was assessed in the Morris water maze (MWM). Microglial morphology was assessed with diaminobenzidine and fluorescent staining with Iba1 and CD11b in these brain regions. Aging did not change the number of microglia in the parietal cortex (PC) or hippocampal CA1 region (CA1-HC), but decreased microglial process tips in the CA1-HC, increased the area fraction stained by CD11b and number of bulbs on processes in PC and CA1-HC and thickness of microglial processes in corpus callosum (CC) and fornix (Fx). Performance in MWM (distance swam to escape platform) was negatively correlated with number of bulbs in PC and thickness of process in CC, and positively correlated with number of process tips in CA1-HC. Aging increased expression of MHC class II genes and others associated with motility and membrane adhesion in the PC and hippocampus, but Adora2a (Adenosine A2a receptor), only in hippocampus. Age-related increase in the number of bulbs and expression of inflammatory genes was prevented by ladostigil in PC. In the CA1-HC, ladostigil increased the number of process tips and prevented the increase in expression of Adora2a and genes regulating ion channels. Ladostigil also decreased thickening of the processes in CC and Fx. The data show brain region-specific relations induced by age in spatial learning, microglial morphology and associated genes and their response to ladostigil treatment.

Graphical Abstract

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Abbreviations

CA1-HC:

hippocampal CA1 region

CC:

corpus callosum

DAB:

diaminobenzidine

FPKM:

Fragments per kilobase million

Fx:

fornix

HC:

hippocampus

Iba1:

Ionized calcium binding adaptor molecule 1 protein

MWM:

Morris water maze

PC:

parietal cortex

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Acknowledgements

We gratefully acknowledge the help given by Netanel Dwolatzky, Ayelet Gottstein and Coral Haddad in performing the microglial measurements, Tsiona Eliyahu for RNA preparation for sequencing and Amos Stern for data analysis.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors, but was supported by research funds of MW at the Hebrew University.

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Correspondence to Marta Weinstock.

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Shoham, S., Linial, M. & Weinstock, M. Age-Induced Spatial Memory Deficits in Rats Are Correlated with Specific Brain Region Alterations in Microglial Morphology and Gene Expression. J Neuroimmune Pharmacol 14, 251–262 (2019). https://doi.org/10.1007/s11481-018-9817-2

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Keywords

  • Hippocampus
  • KEGG pathway
  • Microglial morphology
  • Parietal cortex
  • RNA-Seq