Corticosterone-induced enhancement of memory and synaptic Arc protein in the medial prefrontal cortex

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Highlights

  • Posttraining corticosterone administration enhances long-term memory and Arc expression in the rat prefrontal cortex.

  • Interference with expression of the plasticity-associated protein Arc in the prefrontal cortex impairs long-term memory.

  • Antagonism of β-adrenergic receptors in the BLA blocks corticosterone-induced memory enhancement.

  • Antagonism of β-adrenergic receptors in the BLA increases corticosterone-induced Arc expression in the prefrontal cortex.

  • The BLA is involved in positive and negative regulation of Arc expression during consolidation of stressful memories.

Abstract

Acute administration of the stress hormone corticosterone enhances memory consolidation in a manner that is dependent upon the modulatory effects of the basolateral complex of the amygdala (BLA). Posttraining administration of corticosterone increases expression of the activity-regulated cytoskeletal-associated protein (Arc) in hippocampal synaptic-enriched fractions. Interference with hippocampal Arc expression impairs memory, suggesting that the corticosterone-induced increase in hippocampal Arc plays a role in the memory enhancing effect of the hormone. Blockade of β-adrenoceptors in the BLA attenuates the corticosterone-induced increase in hippocampal Arc expression and blocks corticosterone-induced memory enhancement. To determine whether posttraining corticosterone treatment affects Arc protein expression in synapses of other areas of the brain that are involved in memory processing, a memory-enhancing dose of corticosterone was administered to rats immediately after inhibitory avoidance training. As seen in the hippocampus, Arc protein expression was increased in synaptic fractions taken from the prelimbic region of the medial prefrontal cortex (mPFC). Blockade of Arc protein expression significantly impaired memory, indicating that the protein is necessary in the mPFC for long-term memory formation. To test the hypothesis that blockade of β-adrenoceptors in the BLA would block the effect of systemic corticosterone on memory and attenuate mPFC Arc expression, as it does in the hippocampus, posttraining intra-BLA microinfusions of the β-adrenoceptor antagonist propranolol were given concurrently with the systemic corticosterone injection. Although this treatment blocked corticosterone-induced memory enhancement, it increased corticosterone-induced Arc protein expression in mPFC synaptic fractions. These findings suggest that the BLA mediates stress hormone effects on memory by participating in the negative or positive regulation of corticosterone-induced synaptic plasticity in efferent brain regions.

Introduction

Adrenal stress hormones modulate memory consolidation in human and non-human animals (Cahill et al., 1994, de Quervain et al., 2009, Gold et al., 1975). Extensive evidence indicates that the basolateral complex of the amygdala (BLA) plays a critical role in this hormonal regulation of memory (McGaugh, 2004). For example, glucocorticoids interact with the noradrenergic system in the amygdala to enhance memories for emotionally arousing events in both humans and rats (Roozendaal et al., 2008, van Stegeren et al., 2007). In rodents, memory-enhancing corticosterone treatment increases norepinephrine levels in the amygdala (McReynolds et al., 2010). Studies performed in humans and rodents demonstrate that the amygdala interacts with multiple efferent brain regions, such as the hippocampus and medial prefrontal cortex (mPFC), during the memory consolidation period and this interaction is correlated with memory performance (Dolcos et al., 2004, Hayes et al., 2010, Murty et al., 2010) for review see (McGaugh, 2004). A potential mechanism of BLA modulation of memory consolidation is through an influence on synaptic plasticity (Ikegaya, Saito, & Abe, 1994) and expression of plasticity-related proteins (Holloway-Erickson et al., 2012, McIntyre et al., 2005) in efferent brain regions.

The protein product of the activity-regulated cytoskeletal-associated immediate early gene (Arc/Arg 3.1) is necessary for maintenance of hippocampal LTP and long-term memory of an aversive task (Guzowski et al., 2000, Holloway and McIntyre, 2011, McIntyre et al., 2005, Ploski et al., 2008). Our findings indicate that the BLA influences Arc protein expression in efferent brain regions. Posttraining intra-BLA infusions of the β-adrenergic agonist clenbuterol enhance memory and increase Arc protein expression in the hippocampus in a post-transcriptional manner (McIntyre et al., 2005). Arc mRNA is found in the stimulated regions of dendrites and can undergo local protein translation in vitro, suggesting regulation of Arc expression may occur at the synapse (Steward et al., 1998, Yin et al., 2002). Indeed, Arc protein expression is increased in dorsal hippocampal synapses when training on an aversive memory task is followed by memory-enhancing systemic injections of the stress hormone corticosterone. Antagonism of β-adrenoceptors in the BLA blocks corticosterone-induced enhancement of memory consolidation and attenuates the increase in hippocampal synaptic Arc protein expression (McReynolds et al., 2010). It is not yet determined that the role of the BLA as a mediator of stress hormone modulation of synaptic protein expression is conserved across brain regions.

The mPFC has a high density of glucocorticoid receptors (GRs) and has substantial anatomical connections with the BLA (McDonald, 1991, Meaney and Aitken, 1985, Reul and de Kloet, 1985). The prelimbic region of the mPFC is critically involved in the expression of conditioned fear and consolidation of aversive memories (Barsegyan et al., 2010, Corcoran and Quirk, 2007). Infusions of a GR agonist into either the BLA or the mPFC enhance the consolidation of long-term memory whereas inhibiting the MAPK cascade in either region prevents the memory-enhancing effect of a GR agonist infused into the other. This suggests that the mPFC and BLA must function as a circuit to modulate memory consolidation (Roozendaal et al., 2009).

If the role of the BLA as a mediator of stress hormone modulation of synaptic protein expression is conserved across brain regions, memory-enhancing glucocorticoids should exert their effects through noradrenergic actions in the BLA which, in turn, increase synaptic plasticity-associated proteins such as Arc in regions of the brain that support long-term memory. According to evidence that the prelimbic (PL) region of the mPFC is critically involved in the consolidation of conditioned fear and aversive memory, memory-enhancing corticosteroid administration should increase expression of Arc protein in synapses of the PL and inactivation of the noradrenergic system within the BLA should attenuate that Arc effect. The present study examined the effect of posttraining administration of corticosterone on memory and synaptic Arc protein expression in synaptoneurosomes taken from the rat mPFC. In order to determine whether Arc protein expression in the mPFC was a critical component of memory consolidation, Arc translation to protein was blocked with intra-mPFC microinfusions of Arc antisense oligodeoxynucleotides. Finally, to test the hypothesis that BLA norepinephrine interacts with corticosterone-induced Arc protein expression in the mPFC, intra-BLA infusions of the β-adrenoceptor antagonist propranolol were administered immediately following training and administration of corticosterone. In order to target the consolidation phase of memory processing while avoiding performance effects, all interventions were given immediately after training.

Section snippets

Subjects

Two hundred and two male Sprague–Dawley rats (250–275 g upon arrival), purchased from Charles River Breeding Laboratories, were housed individually in a temperature-controlled (22 °C) colony room, with food and water available ad libitum. Animals were maintained on a 12 h light–12 h dark cycle (7:00–19:00 h, lights on) and kept in the animal colony for one week before commencement of surgical or behavioral procedures. All experimental procedures were in compliance with the National Institutes of

Immediate posttraining systemic injections of corticosterone enhance memory consolidation for the inhibitory avoidance task

Rats were trained on the inhibitory avoidance task and given immediate posttraining systemic injections of corticosterone (3 mg/kg) or vehicle. Training latencies did not significantly differ between corticosterone treated rats (mean training latency ± SEM: 23.71 s ± 7.04) and vehicle treated rats (mean training latency ± SEM: 17.13 s ± 3.49; t(13) = −.873; p = .40). However, a two-sample t-test revealed that the rats given posttraining corticosterone injections had a significantly higher latency to enter

Discussion

The main finding of this study is that posttraining systemic administration of corticosterone increases Arc protein expression in synaptic-enriched fractions of the mPFC and Arc protein expression in the mPFC is necessary for consolidation of long-term memory for the aversive inhibitory avoidance task. Results are consistent with the previously observed effect in the hippocampus and support the hypothesis that corticosterone influences memory consolidation through an influence on expression of

Conclusion

Results support a role for stress and stress hormone effects on neuroplasticity, particularly synaptic expression of the plasticity-associated protein Arc, in the consolidation of emotionally arousing memories. Arc protein expression plays a critical role in the consolidation of long-term memories. Here, it is evident that stress-induced modulation of Arc expression occurs in the mPFC as well as in the hippocampus. A negative relationship between Arc expression in the mPFC and memory

Acknowledgments

The authors thank Dr. Jon Ploski for helpful feedback on a draft of this manuscript. This research was funded by the Department of Behavioral and Brain Sciences at The University of Texas at Dallas. The authors declare no competing financial interest.

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