Table 2.

Summary of studies that tested associations between stressors and 5-hmC levels in the brain

Study author (citation)	Stressor	Model organism/cell line	Tissue	Sex	Method to measure 5-hnrC	Direction of differential 5-hnrC	Genomic scale of differential 5-hnrC	Differentially hydroxynrethylated gene IDs
Cheng et al. 2018 [49]	Chronic restraint stress	C57BL/6 WT mice	Prefrontal cortex	Male	Dot plot (global), T4 bacteriophage β-glucosyltransferase chemical tagging (genonre-wide)	Decreased (global), Bidirectional (genonre-wide)	Global, genonre-wide	1251 and 3239 genes with hyper- and hypo-DhMRs
Li et al. 2015 [50]	Acute restraint	C57BL/6J mice stress	Hippocampus	Male	Immunohistochenristry and LC-MS (global), tet-assisted bisulfite sequencing (CpG-level)	No effect (global), Increased (CpG-level)	Global, CpG-level	Nr3cl
Li et al. 2016 [51]	Acute restraint stress	C57BL/6J mice	Hippocampus	Male and female	T4 bacteriophage β-glucosyltransferase chemical tagging (genonre-wide)	Bidirectional (increased and decreased)	Genonre-wide	Notch 1, Notch2, Notch3, Irs2, Crebbp, etc. (470 and 166 genes with hyper- and hypo-DhMRs)
Papale et al. 2016 [52]	Acute restraint stress	C57BL/6J mice	Hippocampus	Male and female	T4 bacteriophage β-glucosyltransferase chemical tagging (genonre-wide)	Bidirectional (increased and decreased)	Genonre-wide	Nr3cl, Ntrk2, etc. (241 and 128 genes with hyper- and hypo-DhMRs)
Dong et al. 2015 [53]	Prenatal restraint stress	Swiss albino ND4 mice	Frontal cortex and hippocampus	Male	hMeDIP-qPCR	Increased	Gene-level	Bdnf
Dong et al. 2016 [54]	Prenatal restraint stress	Swiss albino ND4 mice	Frontal cortex	Male	hMeDIP-qPCR	Increased	Gene-level	Gadl, Rein, and Bdnf
Papale et al. 2017 [55]	Variable, mild early-life stressors (e.g., novel noise, saturated bedding, 5-nrin restraint, etc.)	C57BL/6J mice	Hypothalamus	Female	T4 bacteriophage β-glucosyltransferase chemical tagging (genonre-wide)	Bidirectional (increased and decreased)	Genonre-wide	474 genes and 482 genes with hyper- and hypo-DhMRs

In the last 5 years, a small number of studies have investigated the effects of chronic and acute stressors on 5-hmC in the brain using animal models. Here, we summarize the results of these studies, and also provide information regarding the specific exposure, model organism, tissue, sex, and methods used to measure 5-hmC. As shown in the eighth column (from the left), much of the available data from stress studies measured genome-wide 5-hmC using enrichment-based methods, which allow investigators to determine whether stress leads to gene-level changes in 5-hmC. However, these enrichment-based methods do not provide base-pair resolution 5-hmC data. Only one study by Li et al. 2015 [50] measured 5-hmC at the CpG-level