Neuronal injury results in increased mineralocorticoid receptor (MR) expression and is associated with increased neuronal survival, suggesting that enhancing MR signalling may have therapeutic implications. MR has a complex gene structure with at least three untranslated exons (α, β, γ) each with unique promoters and a common coding region. We examined whether distinct cellular stressors differentially regulate exon-specific MR transcripts. MRβ transcript was specifically upregulated in rat primary cortical cultures undergoing hypothermic oxygen–glucose deprivation (OGD/H) through activation of its own promoter. This effect was mediated in part by ERK signalling as blockade with PD98059 inhibited OGD/H-induced MRβ promoter activity. A specific increase in MRβ transcript expression was also found in vivo in hypothermic anoxic neonatal rat hippocampus. These results demonstrate a novel key role for the MRβ transcript in response to injury and suggest that some of the known neuroprotective effects of hypothermia may be mediated through increased MR expression.