SummaryIncreased activity of the noradrenergic system in the amygdala has been suggested to contribute to the hyperarousal symptoms associated with post-traumatic stress disorder (PTSD). However, only two studies have examined the content of noradrenaline or its metabolites in the amygdala of rats previously exposed to traumatic stress showing inconsistent results. The aim of this study was to investigate the effects of an inescapable foot shock (IFS) procedure 1) on reactivity to novelty in an open-field (as an index of hyperarousal), and 2) on noradrenaline release in the amygdala during an acute stress. To test the role of noradrenaline in amygdala, we also investigated the effects of microinjections of propranolol, a β-adrenoreceptor antagonist, and clenbuterol, a β-adrenoreceptor agonist, into the amygdala of IFS and control animals. Finally, we evaluated the expression of mRNA levels of β-adrenoreceptors (β1 and β2) in the amygdala, the hippocampus and the prefrontal cortex. Male Wistar rats (3 months) were stereotaxically implanted with bilateral guide cannulae. After recovering from surgery, animals were exposed to IFS (10 shocks, 0.86 mA, and 6 seconds per shock) and seven days later either microdialysis or microinjections were performed in amygdala. Animals exposed to IFS showed a reduced locomotion compared to IFS modified the mRNA expression of β1 and β2 adrenoreceptors in the prefrontal cortex and the hippocampus. These results suggest that an increased noradrenergic activity in the amygdala contributes to the expression of hyperarousal in an animal model of PTSD.

Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline-and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock-context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkmζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory.basolateral amygdala | norepinephrine | memory accuracy | hippocampus | systems consolidation E motionally arousing experiences are well-retained in memory (1, 2). Beyond their increased strength, emotionally enhanced memories are also often characterized by increased vividness and the subjective feeling of remembering (3, 4). Both animal and human research indicate that noradrenergic activation of the basolateral amygdala (BLA) enhances memory of emotionally arousing experiences by regulating neural plasticity and information storage processes in other brain regions (5-12). A majority of studies investigating the effects of noradrenergic activation of the BLA in memory have focused on episodic (declarative) or contextual tasks that involve functioning of the hippocampus (13-17). The BLA sends extensive projections to the hippocampus (18) and has a major impact on hippocampal functioning (19-21).There is extensive evidence that the memory enhancement induced by BLA activation by norepinephrine (NE) administration or emotional arousal during or shortly after learning involves hippocampal activation (20,(22)(23)(24). This activa...

The present study was designed to investigate the modulation of the stress responses by the environmental conditions and its putative neurobiological mechanisms. For that an integrative study on the effects of environmental enrichment and isolation housing on 1/ the corticosterone, dopamine and acetylcholine responses to acute restraint stress in the prefrontal cortex (PFC) of the awake rat; 2/ the mRNA levels of glucocorticoid receptors (GRs) in the PFC; and 3/ the behavioral responses to stress, related to the PFC (habituation to a novel environment, spatial-working memory and inhibitory avoidance response) was performed. Male Wistar rats were maintained from 3 to 6 months of age in two different conditions: enriched (EC) or impoverished (IC). Animals were stereotaxically implanted with bilateral guide cannulae in the PFC to perform microdialysis experiments to evaluate the concentrations of corticosterone, dopamine and acetylcholine. EC animals showed lower increases of corticosterone and dopamine but not of acetylcholine than IC animals in the PFC in response to acute restraint stress (20min). In the PFC, GR mRNA levels showed a trend towards an enhancement in EC animals. EC reduced the days to learn the spatial working memory task (radial-water maze). Spatial working memory, however, was not different between groups in either basal or stress conditions. Inhibitory avoidance response was reduced in EC rats. The changes produced by EC in the neurochemical, neuroendocrine and behavioral parameters evaluated suggest that EC rats could show a better coping during an acute stress challenge.

Extensive evidence indicates that the basolateral amygdala (BLA) interacts with other brain regions in mediating stress hormone and emotional arousal effects on memory consolidation. Brain activation studies have shown that arousing conditions lead to the activation of large-scale neural networks and several functional connections between brain regions beyond the BLA. Whether such distal interactions on memory consolidation also depend on BLA activity is not as yet known. We investigated, in male Sprague-Dawley rats, whether BLA activity enables prelimbic cortex (PrL) interactions with the anterior insular cortex (aIC) and dorsal hippocampus (dHPC) in regulating glucocorticoid effects on different components of object recognition memory. The glucocorticoid receptor (GR) agonist RU 28362 administered into the PrL, but not infralimbic cortex, immediately after object recognition training enhanced 24-hour memory of both the identity and location of the object via functional interactions with the aIC and dHPC, respectively. Importantly, posttraining inactivation of the BLA by the noradrenergic antagonist propranolol abolished the effect of GR agonist administration into the PrL on memory enhancement of both the identity and location of the object. BLA inactivation by propranolol also blocked the effect of GR agonist administration into the PrL on inducing changes in neuronal activity within the aIC and dHPC during the postlearning consolidation period as well as on structural changes in spine morphology assessed 24 hours later. These findings provide evidence that BLA noradrenergic activity enables functional interactions between the PrL and the aIC and dHPC in regulating stress hormone and emotional arousal effects on memory.basolateral amygdala | medial prefrontal cortex | anterior insular cortex | dorsal hippocampus | norepinephrine S tressful and emotional experiences activate hormonal and brain systems that create strong memories (1, 2). Extensive evidence indicates that noradrenergic activation of the basolateral amygdala (BLA), induced by emotional arousal, is crucially involved in strengthening the consolidation of long-term memory (2). We have reported extensive evidence indicating that noradrenergic activation of the BLA also plays a critical role in enabling the enhancing effects of adrenal stress hormones, that is, epinephrine and glucocorticoids, on memory consolidation (3-5). Many previous studies have investigated how such BLA activation enhances the consolidation of memory by influencing neural plasticity and information storage processes within specific target regions, such as the hippocampus (2, 6-10). Accumulating evidence from brain activation studies indicates that arousing conditions increase activation of large-scale neural networks (11-13) and also affect numerous functional interactions between brain regions beyond the amygdala (14, 15). However, it is not known whether BLA activity is required for regulating emotional arousal effects on functional interactions between such distal brain regio...

2 HIGHLIGHTS-Infralimbic stimulation increases basal plasma levels of corticosterone.-Environmental enrichment enhances the effects of infralimbic stimulation.-Infralimbic inhibition reduces stress-induced corticosterone in control animals.-Infralimbic cortex contributes to HPA activation during stress and aversive memory. 3 ABSTRACTThe aim of the present study was to investigate the effects of the stimulation and inhibition of the ventral part of the medial prefrontal cortex (infralimbic cortex) on basal and stress-induced plasma levels of corticosterone and on the acquisition of aversive memory in animals maintained in control and environmental enrichment (EE) conditions. Intracortical microinjections of the GABA A antagonist picrotoxin and agonist muscimol were performed in male Wistar rats to stimulate and inhibit, respectively, the activity of the infralimbic cortex. Injections were performed 60 min before foot shock stress and training in the inhibitory avoidance task. Picrotoxin injections into the infralimbic cortex increased basal plasma levels of corticosterone.These increases were higher in EE rats which suggest that EE enhances the control exerted by infralimbic cortex over the hypothalamus-pituitary-adrenal (HPA) axis and corticosterone release. Muscimol injections into the infralimbic cortex reduced the stress-induced plasma levels of corticosterone and the retention latency 24 h after training in the inhibitory avoidance performance in control and EE animals, respectively. These results further suggest that the infralimbic cortex is required for the activation of the HPA axis during stress and for the acquisition of contextual aversive memories.

These results suggest that the hypofunction of NMDA receptors in the PFC produces corticolimbic hyperactivity through the activation of prefrontal efferent projections to subcortical/limbic areas.

These results suggest that the hypofunction of prefrontal NMDA receptors does not change the sensitivity to acute stress of dopamine and noradrenaline projections to amygdala but impairs the acquisition of aversive memory.

Extensive evidence indicates that noradrenergic activation is essentially involved in mediating the enhancing effects of emotional arousal on memory consolidation. Our current understanding of the neurobiological mechanisms underlying the memory-modulatory effects of the noradrenergic system is primarily based on pharmacological studies in rats, employing targeted administration of noradrenergic drugs into specific brain regions. However, the further delineation of the specific neural circuitry involved would benefit from experimental tools that are currently more readily available in mice. Previous studies have not, as yet, investigated the effect of noradrenergic enhancement of memory in mice, which show different cognitive abilities and higher endogenous arousal levels induced by a training experience compared to rats. In the present study, we investigated the effect of posttraining noradrenergic activation in male C57BL/6J mice on the consolidation of object recognition and object location memory. We found that the noradrenergic stimulant yohimbine (0.3 or 1.0 mg/kg) administered systemically immediately after an object training experience dose-dependently enhanced 24-h memory of both the identity and location of the object. Thus, these findings indicate that noradrenergic activation also enhances memory consolidation processes in mice, paving the way for a systematic investigation of the neural circuitry underlying these emotional arousal effects on memory. LAY SUMMARY: The current study successfully validated the effect of noradrenergic activation on both object recognition and object location memory in mice. This study thereby provides a fundamental proof-of-principle for the investigation of the neural circuitry underlying noradrenergic and arousal effects on long-term memory in mice.