Glucocorticoids in the prefrontal cortex enhance memory consolidation and impair working memory by a common neural mechanism

Abstract

It is well established that acute administration of adrenocortical hormones enhances the consolidation of memories of emotional experiences and, concurrently, impairs working memory. These different glucocorticoid effects on these two memory functions have generally been considered to be independently regulated processes. Here we report that a glucocorticoid receptor agonist administered into the medial prefrontal cortex (mPFC) of male Sprague-Dawley rats both enhances memory consolidation and impairs working memory. Both memory effects are mediated by activation of a membrane-bound steroid receptor and depend on noradrenergic activity within the mPFC to increase levels of cAMP-dependent protein kinase. These findings provide direct evidence that glucocorticoid effects on both memory consolidation and working memory share a common neural influence within the mPFC.

Fig. 1.

Glucocorticoid administration into the mPFC impairs working memory and enhances memory consolidation. (A) The GR agonist RU 28362 (3 or 10 ng) infused bilaterally into the mPFC 60 min before working memory testing impaired delayed alternation performance (n = 12) but not performance on a control task without delays between trials (n = 9). Results represent mean ± SEM percentage correct choices. **P < 0.01 vs. vehicle. (B) RU 28362 did not affect response times on either task. (C) RU 28362 (3 or 10 ng) infused into the mPFC immediately after inhibitory avoidance training enhanced 48-h retention latencies (n = 10–11). Data represent 48-h retention latencies (mean ± SEM) in seconds. **P < 0.01 vs. vehicle. (D) Infusions were distributed along the rostro-caudal axis of the prelimbic region of the mPFC (delayed alternation: open diamonds, n = 12; inhibitory avoidance: black circles, n = 32). PRL, prelimbic; IL, infralimbic. (E) Correlation between cannula location within the mPFC and response accuracy on the delayed alternation task after infusions of RU 28362 (3 or 10 ng). Circles represent individual cases. Lines show the mean accuracy per location. (F) Correlation between cannula placement within the mPFC and 48-h inhibitory avoidance retention latencies of animals given posttraining infusions of RU 28362 (3 or 10 ng).

Fig. 2.

Unilateral glucocorticoid administration into the mPFC does not impair working memory but enhances memory consolidation. (A) The GR agonist RU 28362 (3 or 10 ng) infused unilaterally into the left mPFC 60 min before working memory testing did not impair delayed alternation performance (n = 8). Results represent mean ± SEM percentage correct choices. (B) RU 28362 (3 or 10 ng) infused unilaterally into the left mPFC immediately after inhibitory avoidance training enhanced 48-h retention latencies (n = 10–14). Data represent 48-h retention latencies (mean ± SEM) in seconds. *P < 0.05 vs. vehicle.

Fig. 3.

Glucocorticoid effects in the mPFC on both working memory and memory consolidation require β-adrenoceptor–cAMP/PKA activity. (A) The β-adrenoceptor antagonist atenolol (1.25 μg), cAMP inhibitor Rp-cAMPS (10 μg), or PKA inhibitor PKI 14-22 amide (0.3 μg), but not α₁-adrenoceptor antagonist urapidil (0.3 μg), infused bilaterally into the mPFC 60 min before working memory testing blocked the impairing effects induced by concurrent infusions of the GR agonist RU 28362 (3 or 10 ng) on delayed alternation performance. Results represent mean ± SEM percentage correct choices. *P < 0.05; **P < 0.01 vs. vehicle (n = 9–13). (B) The β-adrenoceptor antagonist atenolol (1.25 μg), cAMP inhibitor Rp-cAMPS (10 μg), or PKA inhibitor PKI 14-22 amide (0.3 μg), but not α₁-adrenoceptor antagonist urapidil (0.3 μg), infused into the mPFC immediately after inhibitory avoidance training blocked the enhancing effects induced by concurrent infusions of RU 28362 (3 or 10 ng) on 48-h retention performance. Data represent 48-h retention latencies (mean ± SEM) in seconds. *P < 0.05; **P < 0.01 vs. vehicle (n = 9–11).

Fig. 4.

Glucocorticoids increase PKA activity in the mPFC in relation to working memory and memory consolidation. (A) Illustration of pPKA-s immunoreactivity (magenta) in a subpopulation of mPFC neurons as visualized by a DAPI nuclear counterstain. (B) Systemic corticosterone (1 mg/kg) increased pPKA-s immunoreactivity levels in the mPFC of animals subjected to either working memory testing (n = 7) or inhibitory avoidance training (n = 6), but not in home cage controls (n = 5), as compared with simultaneously processed vehicle-injected rats. Average pPKA-s immunoreactivity levels in the mPFC were determined in the dark area shown in the diagram. *P < 0.05 vs. vehicle.

Fig. 5.

Activation of PKA in the mPFC is sufficient to impair working memory and enhance memory consolidation. (A) The selective PKA activator Sp-cAMPS (5 μg in 0.5 μL) infused bilaterally into the mPFC 60 min before working memory testing impaired delayed alternation performance (n = 11; repeated-measures ANOVA). Results represent mean ± SEM percentage correct choices. **P < 0.01 vs. saline. (B) Sp-cAMPS (5 μg in 0.5 μL) infused into the mPFC immediately after inhibitory avoidance training enhanced 48-h retention latencies (n = 11–12). Data represent 48-h retention latencies (mean ± SEM) in seconds. **P < 0.01 vs. saline.

Fig. 6.

Activation of a membrane steroid receptor in the mPFC impairs working memory and enhances memory consolidation. (A) The membrane-impermeable ligand cort:BSA (3 or 10 ng) infused into the mPFC 60 min before working memory testing impaired delayed alternation performance. Coinfusion of the GR antagonist RU 38486 (5 ng), but not mineralocorticoid receptor antagonist RU 28318 (5 ng), blocked the cort:BSA effect. Results represent mean ± SEM percentage correct choices. *P < 0.05; **P < 0.01 vs. vehicle (n = 9–10). (B) Cort:BSA (3 or 10 ng) infused into the mPFC immediately after inhibitory avoidance training enhanced 48-h retention latencies. Coadministration of the GR antagonist RU 38486 (5 ng), but not mineralocorticoid receptor antagonist RU 28318 (5 ng) blocked the cort:BSA effect. Data represent 48-h retention latencies (mean ± SEM) in seconds. *P < 0.05; **P < 0.01 vs. vehicle (n = 8–12). (C) Diagram of the proposed action of glucocorticoids, via membrane GRs, on the noradrenergic system as well as its classic genomic pathway. Gs, stimulatory G protein; NE, norepinephrine.