Corticosterone-induced enhancement of memory and synaptic Arc protein in the medial prefrontal cortex
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.
References (57)
- et al.
Amygdala input to medial prefrontal cortex (mPFC) in the rat: A light and electron microscope study
Brain Research
(1996) - et al.
Glucocorticoids and the regulation of memory in health and disease
Frontiers in Neuroendocrinology
(2009) - et al.
Interaction between the amygdala and the medial temporal lobe memory system predicts better memory for emotional events
Neuron
(2004) - et al.
Effects of hormones on time-dependent memory storage processes
Progress in Brain Research
(1975) - et al.
The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc
Cell
(2010) - et al.
Post-training disruption of Arc protein expression in the anterior cingulate cortex impairs long-term memory for inhibitory avoidance training
Neurobiology of Learning and Memory
(2011) - et al.
Infusion into the brain of an antisense oligonucleotide to the immediate-early gene c-fos suppresses production of fos and produces a behavioral effect
Neuroscience
(1994) - et al.
Memory enhancement of classical fear conditioning by post-training injections of corticosterone in rats
Neurobiology of Learning and Memory
(2004) - et al.
Attenuated hippocampal long-term potentiation in basolateral amygdala-lesioned rats
Brain Research
(1994) - et al.
Impaired hippocampal plasticity and altered neurogenesis in adult Ube3a maternal deficient mouse model for Angelman syndrome
Experimental Neurology
(2009)
Organization of amygdaloid projections to the prefrontal cortex and associated striatum in the rat
Neuroscience
Memory-enhancing corticosterone treatment increases amygdala norepinephrine and Arc protein expression in hippocampal synaptic fractions
Neurobiology of Learning and Memory
[3H]Dexamethasone binding in rat frontal cortex
Brain Research
Effects of stress and adrenalectomy on activity-regulated cytoskeleton protein (Arc) gene expression
Neuroscience Letters
FMRI studies of successful emotional memory encoding: A quantitative meta-analysis
Neuropsychologia
Electrophysiological study of the response of medial prefrontal cortex neurons to stimulation of the basolateral nucleus of the amygdala in the rat
Brain Research
The autoradiographic localization of (3H)dexamethasone in the brain and pituitary of the rat
Brain Research
Stress and memory: Opposing effects of glucocorticoids on memory consolidation and memory retrieval
Neurobiology of Learning and Memory
Basolateral amygdala noradrenergic activity mediates corticosterone-induced enhancement of auditory fear conditioning
Neurobiology of Learning and Memory
Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites
Neuron
Interacting noradrenergic and corticosteroid systems shift human brain activation patterns during encoding
Neurobiology of Learning and Memory
Endogenous cortisol level interacts with noradrenergic activation in the human amygdala
Neurobiology of Learning and Memory
The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses
Cell
Stress signalling pathways that impair prefrontal cortex structure and function
Nature Reviews Neuroscience
Glucocorticoids in the prefrontal cortex enhance memory consolidation and impair working memory by a common neural mechanism
Proceedings of the National Academic Science United States of America
Fmr1 knockout mice are impaired in a leverpress escape/avoidance task
Genes Brain Behavior
Mild, short-term stress alters dendritic morphology in rat medial prefrontal cortex
Cerebral Cortex
Noradrenergic modulation of basolateral amygdala neuronal activity: Opposing influences of alpha-2 and beta receptor activation
Journal of Neuroscience
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