Doctor of Medicine, University Of Oulu (2014)
Doctor of Philosophy, University Of Oulu (2017)
Transient forebrain ischemia, as occurs with cardiac arrest and resuscitation, results in impaired cognitive function secondary to delayed neuronal cell death in hippocampal cornu ammonis-1 (CA1). Comparatively, hippocampal neurons in the adjacent dentate gyrus (DG) survive, suggesting that elucidating the molecular mechanisms underpinning hippocampal sub-regional differences in ischemic tolerance could be central in the development of novel interventions to improve outcome in survivors of forebrain ischemia. MicroRNAs (miRNAs) are non-coding RNAs that modulate the translation of target genes and have been established as an effective therapeutic target for other models of injury. The objective of the present study was to assess and compare post-injury miRNA profiles between CA1 and DG using a rat model of forebrain ischemia. CA1 and DG sub-regions were dissected from rat hippocampi following 10 min of forebrain ischemia at three time points (3 h, 24 h, and 72 h) and at baseline. Pronounced differences between CA1 and DG were observed for several select miRNAs, including miR-181a-5p, a known regulator of cerebral ischemic injury. We complexed fluorescent in situ hybridization with immunohistochemistry to observe cell-type specific and temporal differences in mir-181a-5p expression between CA1 and DG in response to injury. Using established miRNA-mRNA prediction algorithms, we extended our observations in CA1 miRNA dysregulation to identify key functional pathways as potential modulators of CA1 ischemic vulnerability. In summary, our observations support a central role for miRNAs in selective CA1 ischemic vulnerability and suggest that cell-specific miRNA targeting could be a viable clinical approach to preserve CA1 neurons and improve cognitive outcomes for survivors of transient forebrain ischemia.
View details for DOI 10.1016/j.mcn.2019.05.003
View details for PubMedID 31128240
Mild traumatic brain injury (mTBI) can result in permanent impairment in memory and learning and may be a precursor to other neurological sequelae. Clinical treatments to ameliorate the effects of mTBI are lacking. Inhibition of microRNA-181a (miR-181a) is protective in several models of cerebral injury, but its role in mTBI has not been investigated. In the present study, miR-181a-5p antagomir was injected intracerebroventricularly 24h prior to closed-skull cortical impact in young adult male mice. Paw withdrawal, open field, zero maze, Y maze, object location and novel object recognition tests were performed to assess neurocognitive dysfunction. Brains were assessed immunohistologically for the neuronal marker NeuN, the perineuronal net marker wisteria floribunda lectin (WFA), cFos, and the interneuron marker parvalbumin. Protein quantification was performed with immunoblots for synaptophysin and postsynaptic density 95 (PSD95). Fluorescent in situ hybridization was utilized to localize hippocampal miR-181a expression. MiR-181a antagomir treatment reduced neuronal miR-181a expression after mTBI, restored deficits in novel object recognition and increased hippocampal parvalbumin expression in the dentate gyrus. These changes were associated with decreased dentate gyrus hyperactivity indicated by a relative reduction in PSD95 and cFos expression. These results suggest that miR-181a inhibition may be a therapeutic approach to reduce hippocampal excitotoxicity and prevent cognitive dysfunction following mTBI.
View details for PubMedID 30900118