Inhibitory Avoidance Memory In Rats Research Articles

Recovery of memory from infantile amnesia is developmentally constrained.

Episodic memories formed during infancy are rapidly forgotten, a phenomenon associated with infantile amnesia, the inability of adults to recall early-life memories. In both rats and mice, infantile memories, although not expressed, are actually stored long term in a latent form. These latent memories can be reinstated later in life by certain behavioral reminders or by artificial reactivations of neuronal ensembles activated at training. Whether the recovery of infantile memories is limited by developmental age, maternal presence, or contingency of stimuli presentation remains to be determined. Here, we show that the return of inhibitory avoidance memory in rats following a behavioral reactivation consisting of an exposure to the context (conditioned stimuli [CS]) and footshock (unconditioned stimuli [US]) given in a temporally unpaired fashion, is evident immediately after US and is limited by the developmental age at which the reactivations are presented; however, it is not influenced by maternal presence or the time interval between training and reactivation. We conclude that one limiting factor for infantile memory reinstatement is developmental age, suggesting that a brain maturation process is necessary to allow the recovery of a “lost” infantile memory.

Post-training reversible disconnection of the ventral hippocampal-basolateral amygdaloid circuits impairs consolidation of inhibitory avoidance memory in rats.

The ventral hippocampus (VH) and the basolateral amygdala (BLA) are both crucial in inhibitory avoidance (IA) memory. However, the exact role of the VH–BLA circuit in IA memory consolidation is unclear. This study investigated the effect of post-training reversible disconnection of the VH–BLA circuit in IA memory consolidation. Male Wistar rats with implanted guide cannulae were trained with a one-trial IA task, then received immediate intracerebral injections of muscimol or saline, and were tested 24 h later. Muscimol injection into the bilateral BLA, or the unilateral VH and contralateral BLA, but not the unilateral VH and ipsilateral BLA, significantly decreased the retention latencies (versus saline treatment). The results suggest that the VH–BLA circuit could be an important circuit to modulate consolidation of IA memory in rats.

Administration of a Histone Deacetylase Inhibitor into the Basolateral Amygdala Enhances Memory Consolidation, Delays Extinction, and Increases Hippocampal BDNF Levels.

Gene expression related to the formation and modification of memories is regulated epigenetically by chromatin remodeling through histone acetylation. Memory formation and extinction can be enhanced by treatment with inhibitors of histone deacetylases (HDACs). The basolateral amygdala (BLA) is a brain area critically involved in regulating memory for inhibitory avoidance (IA). However, previous studies have not examined the effects of HDAC inhibition in the amygdala on memory for IA. Here we show that infusion of an HDAC inhibitor (HDACi), trichostatin A (TSA), into the BLA, enhanced consolidation of IA memory in rats when given at 1.5, 3, or 6 h posttraining, but not when the drug was infused immediately after training. In addition, intra-BLA administration of TSA immediately after retrieval delayed extinction learning. Moreover, we show that intra-BLA TSA in rats given IA training increased the levels of brain-derived neurotrophic factor in the dorsal hippocampus, but not in the BLA itself. These findings reveal novel aspects of the regulation of fear memory by epigenetic mechanisms in the amygdala.

Synaptic Consolidation: From Synapses to Behavioral Modeling

Synaptic plasticity, a key process for memory formation, manifests itself across different time scales ranging from a few seconds for plasticity induction up to hours or even years for consolidation and memory retention. We developed a three-layered model of synaptic consolidation that accounts for data across a large range of experimental conditions. Consolidation occurs in the model through the interaction of the synaptic efficacy with a scaffolding variable by a read-write process mediated by a tagging-related variable. Plasticity-inducing stimuli modify the efficacy, but the state of tag and scaffold can only change if a write protection mechanism is overcome. Our model makes a link from depotentiation protocols in vitro to behavioral results regarding the influence of novelty on inhibitory avoidance memory in rats.

Functional Connectivity Changes during Consolidation of Inhibitory Avoidance Memory in Rats: A Manganese-Enhanced MRI Study

Consolidation of memory involves transfer of encoded information into a durable neural representation, but how this is transacted in the nervous system remains elusive. It has been proposed that memory consolidation is subserved by formation of a cell assembly due to coincidence of pre- and post-synaptic activity therein after learning. To capture such off-line changes, manganese-enhanced magnetic resonance imaging (MEMRI) was used to trace brain activity during the memory consolidation period. Male Wistar rats were trained on the one-trial inhibitory avoidance task and received intraventricular infusion of manganese ion shortly after training. The MEMRI taken 1 day later showed that brain areas including the prelimbic, insular and anterior pirifrom cortices of the learning group had significantly lower memory-related MEMRI signal than those of the control group. The functional network was revealed by correlating the MEMRI signals among regions followed by graph theoretical analysis. Learning sculpted the non-discriminative connectivity among many brain regions in the controls into a network in the trained rats with selected connectivity among regions implicated in inhibitory avoidance learning. The network could be organized into three clusters presumably subserving different functions. The results suggest that the brain prunes excessive functional connectivity in a cell assembly to consolidate new memory.

Posttraining optogenetic manipulations of basolateral amygdala activity modulate consolidation of inhibitory avoidance memory in rats

Memory consolidation studies, including those examining the role of the basolateral amygdala (BLA), have traditionally used techniques limited in their temporal and spatial precision. The development of optogenetics provides increased precision in the control of neuronal activity that can be used to address the temporal nature of the modulation of memory consolidation. The present experiments, therefore, investigated whether optogenetically stimulating and inhibiting BLA activity immediately after training on an inhibitory avoidance task enhances and impairs retention, respectively. The BLA of male Sprague-Dawley rats was transduced to express either ChR2(E123A) or archaerhodopsin-3 from the Halorubrum sodomense strain TP009 (ArchT). Immediately after inhibitory avoidance training, rats received optical stimulation or inhibition of the BLA, and 2 d later, rats' retention was tested. Stimulation of ChR2(E123A)-expressing neurons in the BLA using trains of 40-Hz light pulses enhanced retention, consistent with recording studies suggesting the importance of BLA activity at this frequency. Light pulses alone given to control rats had no effect on retention. Inhibition of ArchT-expressing neurons in the BLA for 15 min, but not 1 min, significantly impaired retention. Again, illumination alone given to control rats had no effect on retention, and BLA inhibition 3 h after training had no effect. These findings provide critical evidence of the importance of specific frequency patterns of activity in the BLA during consolidation and indicate that optogenetic manipulations can be used to alter activity after a learning event to investigate the processes underlying memory consolidation.

Glucocorticoid receptors recruit the CaMKIIα-BDNF-CREB pathways to mediate memory consolidation

Emotionally important events are well remembered. Although memories of emotional experiences are known to be mediated and modulated by the stress hormones glucocorticoids, little is known about the underlying molecular mechanisms. Here we show that the hippocampal glucocorticoid receptors critically engaged during the formation of long–term inhibitory avoidance memory in rats are coupled to the activation of CaMKIIα, TrkB, ERK, Akt, PLCγ and CREB, as well as a significant induction of Arc and synaptic GluA1. Most of these changes, which are initiated by a non–genomic effect of glucocorticoid receptors, are also downstream of the activation of brain–derived neurotrophic factor (BDNF). Hippocampal administration of BDNF, but not other neurotrophins, selectively rescues both the amnesia and the molecular impairments produced by glucocorticoid receptor inhibition. Hence, glucocorticoid receptors mediate long–term memory formation by recruiting the CaMKIIα–BDNF–CREB–dependent neural plasticity pathways.

Involvement of the ventral tegmental area in the inhibitory avoidance memory in rats

The ventral tegmental area (VTA) is a neural structure that sends strong efferent projections to the hippocampus. Output from the VTA can affect hippocampal-dependent neural processes that are critical for learning and memory, including long term potentiation and theta activity. However, no study to date has elucidated what role the VTA plays in mediating the different stages of learning and memory. Therefore, the current study was designed to assess how reversible inactivation of the VTA may affect the acquisition, consolidation and retrieval of memory in rats using an inhibitory avoidance (IA) task. In this experiment, rats with chronically implanted cannulae aimed at the VTA were trained on an inhibitory avoidance task. They received intra-VTA infusions of lidocaine or saline immediately before training, after training or before a memory retention test. The results indicate that inactivation of the VTA prior to the first acquisition session increased the number of trials rats required to reach the acquisition criterion. Similarly, inactivation of the VTA after acquisition training decreased the step-through latency and increased the amount of time spent in the dark compartment relative to the saline-treated group. However, inactivation of the VTA immediately prior to the memory retention test failed to alter either step-through latency or the amount of time spent in the dark compartment. Overall, these results suggest the VTA facilitates the acquisition and consolidation of IA learning and memory.

Sevoflurane impairs memory consolidation in rats, possibly through inhibiting phosphorylation of glycogen synthase kinase-3β in the hippocampus

Sevoflurane administration impairs memory processes in both humans and animals. Increasing evidence suggests that enhancement of the phosphorylation state of glycogen synthase kinase-3β (GSK-3β), as a result of acute administration of lithium chloride (LiCl), may enhance memory consolidation. The current experiments examined whether GSK-3β phosphorylation was involved in mediating the memory impairing effects of posttraining sevoflurane on inhibitory avoidance (IA) retention. In experiment 1, adult male Sprague–Dawley rats were exposed to sevoflurane (0.5%, 1%, or 2%) for 2 h immediately after training in a continuous multiple-trail IA paradigm. Sevoflurane (2% inspired) induced significant impairment of retention performance on a 24-h test and inhibited phosphorylation of GSK-3β in the hippocampus 2 h after training. In experiment 2, administration of LiCl (100 mg/kg, intraperitoneally) 30 min before IA training not only blocked the sevoflurane-induced impairment of consolidation, but also reversed the inhibitory effect of sevoflurane on GSK-3β phosphorylation in the hippocampus. Collectively, these findings support the hypothesis that sevoflurane exposure can impair consolidation of IA memory in rats. Sevoflurane-induced amnesia may be due, at least in part, to suppression of GSK-3β phosphorylation in the hippocampus.

Temporary inactivation of the dorsal hippocampus induces a transient impairment in retrieval of aversive memory

The reconsolidation hypothesis, which predicts that consolidated memories become labile and sensitive to amnestic agents upon reactivation, has been one of the most debated topics in memory research over recent years. One of the main criticisms to this hypothesis is the fact that some studies have shown the effects of “reconsolidation blockade” to be transient. Here we show that muscimol inactivation of the dorsal hippocampus following memory reactivation produces a reversible impairment of step-down inhibitory avoidance memory in rats. Moreover, we show that the reversal of this effect is dependent on the passage of time, and not on repeated testing. The implications of the findings to the interpretation of the phenomenon of transient retrieval impairment induced by post-reactivation pharmacological interventions on memory systems are discussed.

Inhibition of PKC in basolateral amygdala and posterior parietal cortex impairs consolidation of inhibitory avoidance memory

Hippocampal α- and βI/βII protein kinase C (PKC) are crucial for the formation of different types of memory in several species, including that for a one trial inhibitory avoidance (IA) task in rats. Many studies, however, have shown that other brain structures besides the hippocampus, notably the basolateral amygdala (BLA) and posterior parietal cortex (PC) are also necessary for memory consolidation. Here, we examine the role of α- and βI/βII PKC in the BLA and PC on the consolidation of the memory for IA in rats. The selective inhibitor of α- and βI/βII-PKC Gö 6976 and the nonselective PKC inhibitor Gö 7874 were administered into these structures at different times after training at concentrations known to inhibit PKC and to produce retrograde amnesia when given into the hippocampus. Gö 7874 blocked consolidation of IA memory when infused into BLA immediately and 30 min or into PC 180 to 360 min posttraining. Gö 6976 caused amnesia when given into the BLA also immediately or 30 min posttraining but in the PC hindered memory retention only when infused 270 and 360 min after the training session. Our data indicate that α- and βI/βII-PKC are critical for consolidation of IA memory shortly after training in BLA and that, first other isoforms and subsequently the α- and βI/βII PKC are required 3 or more hours after training in the PC. The findings on BLA are similar to those previously reported in the hippocampus, but those on PC suggest an entirely different molecular dynamics for memory formation in that area.

Differential involvement of hippocampal and amygdalar NMDA receptors in contextual and aversive aspects of inhibitory avoidance memory in rats

Adult male rats bilaterally implanted with guide canullae aimed either at the dorsal hippocampus (dHIP) or the basolateral nucleus of the amygdala (BLA) were trained in a step-down inhibitory avoidance task (IA) and tested for retention 24 h after training. Immediately after training, animals were given a bilateral infusion of the N-methyl- d-aspartate (NMDA) glutamate receptor antagonist d, l-2-amino-5-phosphonopentanoic acid (AP5) (5.0 μg) into the dHIP or the BLA. Both intrahippocampal and intraamygdala infusions of AP5 blocked IA retention. Preexposure to the training box, but not to a different environment 24 h prior to training prevented the impairing effect of intrahippocampal infusion of AP5 on retention. Preexposure did not affect the retention impairment induced by intraamygdala infusion of AP5. These data suggest that hippocampal NMDA receptors might be involved in the contextual and spatial aspects, while amygdalar NMDA receptors might be involved in the aversive aspects of memory for IA.