Two Weeks of Variable Stress Increases Gamma-H2AX Levels in the Mouse Bed Nucleus of the Stria Terminalis

Abstract

Recent reports demonstrate that DNA damage is induced, and rapidly repaired, in circuits activated by experience. Moreover, stress hormones are known to slow DNA repair, suggesting that prolonged stress may result in persistent DNA damage. Prolonged stress is known to negatively impact physical and mental health; however, DNA damage as a factor in stress pathology has only begun to be explored. Histone H2A-X phosphorylated at serine 139 (γH2AX) is a marker of DNA double-strand breaks (DSB), a type of damage that may lead to cell death if unrepaired. We hypothesized that a 14-day period of variable stress exposure sufficient to alter anxiety-like behavior in male C57BL/6J mice would produce an increase in γH2AX levels in the bed nucleus of the stria terminalis (BNST), a region implicated in anxiety and stress regulation. We observed that 14 days of variable stress, but not a single stress exposure, was associated with increased levels of γH2AX 24 h after termination of the stress paradigm. Further investigation found that phosphorylation levels of a pair of kinases associated with the DNA damage response, glycogen synthase kinase 3 β (GSK3β) and p38 mitogen-activated protein kinase (MAPK) were also elevated following variable stress. Our results suggest that unrepaired DNA DSBs and/or repetitive attempted repair may represent an important component of the allostatic load that stress places on the brain.

Role of the Bed Nucleus of the Stria Terminalis in PTSD: Insights From Preclinical Models

“…In contrast to reports of acute restraint, chronic immobilization increases BNST (but not amygdala) dendritic branching (Vyas et al, 2003), suggesting a role of stress in remodeling neurons in stress-related brain regions after the traumatic event that underlies PTSD. Chronic variable stress paradigms that include restraint stress (as well as pedestal stress, forced swim, footshock, and oscillation; but not single stress exposure) are also associated with increased levels of histone H2A-X phosphorylated at serine 139 (γH2AX), a marker of DNA damage associated with cell death in the BNST (Hare et al, 2018). Hence, chemical and morphological changes that occur in BNST as a result of restraint stress generate behavioral anxiety-like phenotypes that match human PTSD characteristics.…”

Gelatine nanostructured lipid carrier encapsulated FGF15 inhibits autophagy and improves recovery in spinal cord injury

“…The consequences of pathological changes in the neurons cause damage to the neurons and glial cells and ultimately impair mobility estimated by the BBB scale. Certain studies suggested that autophagy [38][39][40][41] . During autophagy, p62, one of the ubiquitinbinding proteins, ubiquitinates proteins 42 and forms a complex located on the inner membrane of the autophagosome, which is degrades in autophagic lysosomes.…”

“…Long-term stress and progressive autophagy can eventually result in cell death. Stimulation of excessive autophagy and cellular self-consumption may exceed the damage threshold of the cell and result in cell death 38 – 41 . During autophagy, p62, one of the ubiquitin-binding proteins, ubiquitinates proteins 42 and forms a complex located on the inner membrane of the autophagosome, which is degrades in autophagic lysosomes.…”

Pathologic Replication-Independent Endogenous DNA Double-Strand Breaks Repair Defect in Chronological Aging Yeast

“…They are associated with a decrease in the cell’s viability ( Thongsroy et al, 2013 ). In addition, the findings that γ-H2AX foci were observed in mice brains supported the existence of Path-RIND-EDSBs in non-dividing cells ( Barral et al, 2014 ; Hare et al, 2018 ). When non-dividing cells age, they are produced in large numbers, possibly due to a reduction of Physiologic RIND-EDSBs (Phy-RIND-EDSBs) another type of RIND-EDSBs.…”