Acute stress enhances glutamatergic transmission in prefrontal cortex and facilitates working memory

Abstract

The prefrontal cortex (PFC), a key brain region controlling cognition and emotion, is strongly influenced by stress. While chronic stress often produces detrimental effects on these measures, acute stress has been shown to enhance learning and memory, predominantly through the action of corticosteroid stress hormones. We used a combination of electrophysiological, biochemical, and behavioral approaches in an effort to identify the cellular targets of acute stress. We found that behavioral stressors in vivo cause a long-lasting potentiation of NMDAR- and AMPAR-mediated synaptic currents via glucocorticoid receptors (GRs) selectively in PFC pyramidal neurons. This effect is accompanied by increased surface expression of NMDAR and AMPAR subunits in acutely stressed animals. Furthermore, behavioral tests indicate that working memory, a key function relying on recurrent excitation within networks of PFC neurons, is enhanced by acute stress via a GR-dependent mechanism. These results have identified a form of long-term potentiation of synaptic transmission induced by natural stimuli in vivo, providing a potential molecular and cellular mechanism for the beneficial effects of acute stress on cognitive processes subserved by PFC.

Fig. 1.

Acute stressors of diverse types enhance NMDAR- and AMPAR-mediated synaptic currents in PFC pyramidal neurons via activation of glucocorticoid receptors. (A–D) Dot plots showing the amplitude of NMDAR-EPSC and AMPAR-EPSC in PFC pyramidal neurons taken from control or animals exposed to forced swim stress (A), acute restraint stress (B), elevated platform stress (C), or i.p. injected with saline vs. corticosterone (20 mg/kg, D). (E) Bar graphs showing the blood concentrations of corticosterone in control vs. rats exposed to different behavioral stressors (examined right after stressor cessation) or injected with corticosterone. *, P < 0.001, ANOVA. (F) Dot plots showing the amplitude of NMDAR-EPSC and AMPAR-EPSC in PFC pyramidal neurons taken from control or animals exposed to forced-swim stress with i.p. injection of GR antagonist RU486 or MR antagonist RU28318 (both 10 mg/kg, 30 min before stress). Inset (A and F) Representative synaptic current traces. [Scale bars, 100 pA, 100 ms (NMDAR-EPSC); 25 pA, 10 ms (AMPAR-EPSC).]

Fig. 2.

Acute stress does not alter glutamate release, but increases the postsynaptic AMPAR response in PFC. (A and B) Dot plots showing the paired-pulse ratio (PPR) of NMDAR-EPSC (A, interstimuli interval: 100 ms) or AMPAR-EPSC (B, interstimuli interval: 50 ms) in PFC slices taken from control vs. stressed animals. (C) Cumulative plot of the distribution of mEPSC amplitudes in PFC slices taken from control vs. stressed animals. Inset: Representative mEPSC traces. (Scale bars, 25 pA, 1 s.) (D) Bar graphs (mean ± SEM) showing the mEPSC amplitude and frequency in PFC pyramidal neurons from control vs. stressed animals.

Fig. 3.

Acute stress increases the level of surface NMDARs and AMPARs in PFC slices. (A) Immunoblots of the surface and total NR1, NR2A, NR2B, GluR1, GluR2 and GABA_AR β2/3 subunits in lysates of PFC slices taken from control (con) vs. stressed (S) animals (examined at 1–4 h, 24 h and 5 days poststress). (B and C) Quantification analysis (mean ± SEM) showing the normalized level of NMDAR subunits (B) or AMPAR subunits and GABA_AR subunits (C) in PFC slices from control vs. stressed animals. *, P < 0.001, ANOVA.

Fig. 4.

In vivo acute stress enhances working memory via glucocorticoid receptors. (A) Cumulative data (mean ± SEM) showing percentage correct of responses in T-maze tests in control vs. stressed (forced-swim) rats examined at various pre- and poststress time points. *, P < 0.01, ANOVA. (B) Cumulative data (mean ± SEM) showing percentage correct in T-maze tests before and after forced-swim stress in rats injected with saline vs. RU486. *, P < 0.01, ANOVA. (C and D) Cumulative data (mean ± SEM) showing the duration of immobility in tail-suspension tests (C) or the time at the center in open-field tests (D) in control vs. stressed (forced-swim) rats examined at pre- and poststress time points.