Noradrenergic activation of the basolateral amygdala maintains hippocampus-dependent accuracy of remote memory.

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.

Glucocorticoids interact with the noradrenergic arousal system in the nucleus accumbens shell to enhance memory consolidation of both appetitive and aversive taste learning.

It is well established that glucocorticoid hormones strengthen the consolidation of long-term memory of emotionally arousing experiences but have little effect on memory of low-arousing experiences. Although both positive and negative emotionally arousing events tend to be well remembered, studies investigating the neural mechanism underlying glucocorticoid-induced memory enhancement focused primarily on negatively motivated training experiences. In the present study we show an involvement of glucocorticoids within the nucleus accumbens (NAc) in enhancing memory consolidation of both an appetitive and aversive form of taste learning. The specific glucocorticoid receptor (GR) agonist RU 28362 (1 or 3ng) administered bilaterally into the NAc shell, but not core, of male Sprague-Dawley rats immediately after an appetitive saccharin drinking experience dose-dependently enhanced 24-h retention of the safe taste, resulting in a facilitated attenuation of neophobia. Similarly, GR agonist infusions given into the NAc shell immediately after pairing of the saccharin taste with a malaise-inducing agent enhanced memory of this negative experience, resulting in an intensified conditioned aversion. Importantly, a suppression of noradrenergic activity within the NAc shell with the ß-adrenoceptor antagonist propranolol blocked the facilitating effect of a concurrently administered GR agonist on memory consolidation in both the appetitive and aversive learning task. Thus, these findings indicate that GR activation interacts with the noradrenergic arousal system within the NAc to enhance memory consolidation of emotionally arousing training experiences regardless of valence.

Effects of nociceptin/orphanin FQ in the acquisition of contextual and tone fear conditioning in rats.

Nociceptin, or orphanin FQ (N/OFQ), the endogenous ligand of NOP receptors, is known to regulate learning and memory processes. To verify the role of N/OFQ in the acquisition of contextual (CFC) and tone fear conditioning (TFC), Wistar male rats received intracerebroventricular injections of N/OFQ (0.1-5.0 nmol) before training, and were tested 24 and 48 hr later to access the freezing response to context and tone, respectively. The intermediate doses (1.0 and 2.5 nmol) impaired the CFC test, sparing TFC. The highest dose (5.0 nmol) reduced freezing during both tests, a result that may be due to nonspecific effects. The posttraining injection of N/OFQ (1 or 5 nmol) did not interfere with CFC and TFC, suggesting a specific effect of the peptide in acquisition processes. Moreover, the impairment observed with N/OFQ (1 nmol) in CFC cannot be attributed to a state-dependent learning because it was not reversed by its pretest administration. The data support the negative role of N/OFQ in the acquisition of aversively motivated tasks, which encompass a spatial component and depend on the hippocampus.

Endocannabinoid signaling within the basolateral amygdala integrates multiple stress hormone effects on memory consolidation.

Glucocorticoid hormones are known to act synergistically with other stress-activated neuromodulatory systems, such as norepinephrine and corticotropin-releasing factor (CRF), within the basolateral complex of the amygdala (BLA) to induce optimal strengthening of the consolidation of long-term memory of emotionally arousing experiences. However, as the onset of these glucocorticoid actions appear often too rapid to be explained by genomic regulation, the neurobiological mechanism of how glucocorticoids could modify the memory-enhancing properties of norepinephrine and CRF remained elusive. Here, we show that the endocannabinoid system, a rapidly activated retrograde messenger system, is a primary route mediating the actions of glucocorticoids, via a glucocorticoid receptor on the cell surface, on BLA neural plasticity and memory consolidation. Furthermore, glucocorticoids recruit downstream endocannabinoid activity within the BLA to interact with both the norepinephrine and CRF systems in enhancing memory consolidation. These findings have important implications for understanding the fine-tuned crosstalk between multiple stress hormone systems in the coordination of (mal)adaptive stress and emotional arousal effects on neural plasticity and memory consolidation.

Involvement of the insular cortex in regulating glucocorticoid effects on memory consolidation of inhibitory avoidance training.

Glucocorticoids are known to enhance the consolidation of memory of emotionally arousing experiences by acting upon a network of interconnected brain regions. Although animal studies typically do not consider the insular cortex (IC) to be part of this network, the present findings indicate that the IC is importantly involved in regulating glucocorticoid effects on memory consolidation of emotionally arousing inhibitory avoidance training. The specific glucocorticoid receptor (GR) agonist RU 28362 (3 or 10 ng in 0.5 µl) infused bilaterally into the IC of male Sprague-Dawley rats immediately after one-trial inhibitory avoidance training dose-dependently enhanced 48 h retention performance. Moreover, training on the inhibitory avoidance task increased neuronal activity of the IC, as assessed by an increased number of cells expressing immunoreactivity for phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2). However, systemic administration of a memory-enhancing dose of corticosterone (1 mg/kg) after inhibitory avoidance training rapidly reduced the number of pERK1/2-positive cells in the IC, suggesting that glucocorticoid administration reduces overall neuronal activity of the IC. To investigate which components of the inhibitory avoidance training experience were influenced by the intra-IC glucocorticoid administration, in the last experiment rats were trained on a modified inhibitory avoidance task in which context exposure and footshock training occur on two sequential days. RU 28362 administration into the IC enhanced later retention when infused immediately after either the context or footshock training. Thus, these findings indicate that the IC mediates glucocorticoid effects on the consolidation of memory of different components of inhibitory avoidance training and suggest that the IC might be an important element of the rodent brain network involved in emotional regulation of learning and memory.

Rodent stereotaxic surgery and animal welfare outcome improvements for behavioral neuroscience.

Stereotaxic surgery for the implantation of cannulae into specific brain regions has for many decades been a very successful experimental technique to investigate the effects of locally manipulated neurotransmitter and signaling pathways in awake, behaving animals. Moreover, the stereotaxic implantation of electrodes for electrophysiological stimulation and recording studies has been instrumental to our current understanding of neuroplasticity and brain networks in behaving animals. Ever-increasing knowledge about optimizing surgical techniques in rodents(1-4), public awareness concerning animal welfare issues and stringent legislation (e.g., the 2010 European Union Directive on the use of laboratory animals(5)) prompted us to refine these surgical procedures, particularly with respect to implementing new procedures for oxygen supplementation and the continuous monitoring of blood oxygenation and heart rate levels during the surgery as well as introducing a standardized protocol for post-surgical care. Our observations indicate that these modifications resulted in an increased survival rate and an improvement in the general condition of the animals after surgery (e.g. less weight loss and a more active animal). This video presentation will show the general procedures involved in this type of stereotaxic surgery with special attention to our several modifications. We will illustrate these surgical procedures in rats, but it is also possible to perform this type of surgery in mice or other small laboratory animals by using special adaptors for the stereotaxic apparatus(6).