Overview
Chronic stress begins as an endocrine event but ends as a self-sustaining electrical process. Cortisol released from the adrenal cortex enters neurons, binds cytoplasmic glucocorticoid receptors, and the complex translocates into the nucleus to regulate genes through glucocorticoid response elements. This normally forms a feedback loop that dampens excitatory signaling and restores homeostasis once stress resolves.
When stress is prolonged, the NR3C1 promoter becomes hypermethylated, lowering GR expression and weakening this hormonal feedback. As GRs decline, transcriptional control shifts from glucocorticoid response elements to cAMP response elements driven by CREB and Nur77 (NR4A1). Neural activity itself begins to dictate gene expression. Calcium influx from glutamatergic signaling keeps CREB phosphorylated, maintaining transcription of NMDA and AMPA receptor subunits.
This creates a positive feedback loop. More receptor expression increases calcium entry, which further activates CREB and perpetuates receptor synthesis. Mitochondrial calcium overload generates reactive oxygen species that damage membranes and DNA. The cell becomes locked in a state of CRE activity dependent excitotoxicity, where receptor upregulation is sustained by firing frequency rather than endocrine regulation (Heling et al., 2025), (Watkeys et al., 2018), (Yehuda et al., 2016), (Weaver et al., 2004).
Mechanistic Sequence
- Cortisol entry and GR cycling. Free cortisol diffuses into the cytoplasm, binds GR, and the complex moves to the nucleus to regulate GRE-containing genes that normally reduce excitatory tone.
- Prolonged activation. Sustained cortisol exposure traps GR in the nucleus, leads to receptor degradation, and suppresses new synthesis.
- Promoter hypermethylation. Chronic stress activates DNA methylation machinery that hypermethylates NR3C1 and reduces GR transcription, a pattern consistently reported across trauma-related cohorts (Watkeys et al., 2018), with supportive human and animal evidence (Yehuda et al., 2016), (Weaver et al., 2004).
- Loss of the cytoplasmic GR pool. With fewer receptors, cortisol can no longer regulate transcription through GREs.
- Unopposed CREB–Nur77 activation. In the absence of GR repression, CREB and Nur77 occupy CRE sites on excitatory receptor genes, sustaining NMDA and AMPA subunit transcription (Heling et al., 2025).
- Activity-dependent upregulation. Receptor expression becomes driven by neuronal firing and intracellular calcium flux rather than hormonal feedback. Each activation event phosphorylates CREB, perpetuating transcription.
- Runaway excitotoxicity. Excess NMDA and AMPA receptors amplify calcium entry, induce mitochondrial ROS, and drive progressive oxidative damage.
Functional Interpretation
The shift from hormonal to activity-driven transcription is the last stage of the stress–excitotoxicity cascade. Once NR3C1 is hypermethylated and cytoplasmic GRs decline, the cortisol–GR feedback brake is lost. CREB and Nur77 become dominant regulators at open excitatory promoters, so NMDA and AMPA expression scales with neuronal activity rather than endocrine control. Repeated stress therefore drives receptor proliferation, calcium overload, and mitochondrial oxidation that culminates in degeneration.
Conversely, hypomethylation at NR3C1 yields higher GR expression and stronger feedback. This permits rapid shutdown of CREB–Nur77 programs and lowers oxidative stress. Animal and human data indicate that demethylated NR3C1 states are protective and link early-life environment to long-term resilience (Weaver et al., 2004), (Yehuda et al., 2016). The broader literature review supports that hypermethylation at NR3C1 is the consistent trauma-associated signal when methodological noise is accounted for (Watkeys et al., 2018).
Key Points
- GR restrains Nur77 and shortens stress-induced transcription; loss of GR changes Nur77 DNA-binding dynamics and removes repression (Heling et al., 2025).
- NR3C1 hypermethylation reduces GR expression and abolishes endocrine feedback across trauma-related conditions (Watkeys et al., 2018), with converging evidence from human and animal studies (Yehuda et al., 2016), (Weaver et al., 2004).
- CREB and Nur77 take over transcriptional control of GRIN and GRIA loci, maintaining NMDA and AMPA expression under activity drive.
- Receptor density becomes usage-dependent, which couples stress and neural activity to excitotoxic risk.