Period Of Memory Consolidation Research Articles

Cognitive impairments in a Down syndrome model with abnormal hippocampal and prefrontal dynamics and cytoarchitecture

The Dp(10)2Yey mouse carries a ∼2.3-Mb intra-chromosomal duplication of mouse chromosome 10 (Mmu10) that has homology to human chromosome 21, making it an essential model for aspects of Down syndrome (DS, trisomy 21). In this study, we investigated neuronal dysfunction in the Dp(10)2Yey mouse and report spatial memory impairment and anxiety-like behavior alongside altered neural activity in the medial prefrontal cortex (mPFC) and hippocampus (HPC). Specifically, Dp(10)2Yey mice showed impaired spatial alternation associated with increased sharp-wave ripple activity in mPFC during a period of memory consolidation, and reduced mobility in a novel environment accompanied by reduced theta-gamma phase-amplitude coupling in HPC. Finally, we found alterations in the number of interneuron subtypes in mPFC and HPC that may contribute to the observed phenotypes and highlight potential approaches to ameliorate the effects of human trisomy 21.

Does Engaging in Acute Exercise Prior to Memory Encoding and During Memory Consolidation have an Additive Effect on Long-Term Memory Function?

Previous work has demonstrated that acute exercise prior to memory encoding may enhance long-term memory. Similarly, other work demonstrates that acute exercise during the memory consolidation period may also enhance long-term memory function. However, no study has evaluated whether long-term memory is enhanced when an acute bout of exercise occurs during both of these time periods, when compared to just prior to memory encoding. A within-subject randomized controlled intervention was employed. On separate laboratory visits, participants completed two main protocols, including (1) exercise before memory encoding and (2) exercise before and after memory encoding. Long-term memory was assessed, via a word-list task, from a 20-min delay period and a 24-h delay period. We observed a significant main effect for time, F(8, 176) = 529.5, P < 0.001, ηp2 = 0.96, but no significant main effect for condition, F(1, 22) = 0.08, P = 0.77, ηp2 = 0.004, or time by condition interaction, F(8, 176) = 0.19, P = 0.99, ηp2 = 0.009. In conclusion, there was no difference in long-term memory function when comparing acute exercise only prior to memory encoding vs. acute exercise both before and immediately after memory encoding.

The Temporal Effects of Acute Exercise on Episodic Memory Function: Systematic Review with Meta-Analysis.

Background: Accumulating research demonstrates that the timing of exercise plays an important role in influencing episodic memory. However, we have a limited understanding as to the factors that moderate this temporal effect. Thus, the purpose of this systematic review with meta-analysis was to evaluate the effects of study characteristics (e.g., exercise modality, intensity and duration of acute exercise) and participant attributes (e.g., age, sex) across each of the temporal periods of acute exercise on episodic memory (i.e., acute exercise occurring before memory encoding, and during memory encoding, early consolidation, and late consolidation). Methods: The following databases were used for our computerized searches: Embase/PubMed, Web of Science, Google Scholar, Sports Discus and PsychInfo. Studies were included if they: (1) Employed an experimental design with a comparison to a control group/visit, (2) included human participants, (3) evaluated exercise as the independent variable, (4) employed an acute bout of exercise (defined as a single bout of exercise), (5) evaluated episodic memory as the outcome variable (defined as the retrospective recall of information either in a spatial or temporal manner), and (6) provided sufficient data (e.g., mean, SD, and sample size) for a pooled effect size estimate. Results: In total, 25 articles met our inclusionary criteria and were meta-analyzed. Acute exercise occurring before memory encoding (d = 0.11, 95% CI: −0.01, 0.23, p = 0.08), during early memory consolidation (d = 0.47, 95% CI: 0.28, 0.67; p < 0.001) and during late memory consolidation (d = 1.05, 95% CI: 0.32, 1.78; p = 0.005) enhanced episodic memory function. Conversely, acute exercise occurring during memory encoding had a negative effect on episodic memory (d = −0.12, 95% CI: −0.22, −0.02; p = 0.02). Various study designs and participant characteristics moderated the temporal effects of acute exercise on episodic memory function. For example, vigorous-intensity acute exercise, and acute exercise among young adults, had greater effects when the acute bout of exercise occurred before memory encoding or during the early memory consolidation period. Conclusions: The timing of acute exercise plays an important role in the exercise-memory interaction. Various exercise- and participant-related characteristics moderate this temporal relationship.

Effect of Short‐Term Theta Frequency Stimulation of the Vagus Nerve on Cognition among Patients with Refractory Epilepsy: A Pilot Study

ObjectiveThe purpose of this investigation is to collect preliminary data on the effect of theta frequency vagus nerve stimulation on cognitive measures, including memory retention, in patients with refractory epilepsy.BackgroundVagus nerve stimulation (VNS) was approved by the FDA in 1997 as an adjunctive treatment for medically refractory epilepsy. VNS provides intermittent high frequency stimulation to the left vagus nerve, resulting in retrograde stimulation to centers in the brainstem. Research interest into alternative uses of VNS has increased in popularity over the past decade, including its effect on cognition.Initial short‐term studies (3–24 hours of stimulation) have provided information on how it may be working to alter cognitive function. Two pre‐clinical studies showed that rats displayed increased memory retention after 24 hours of VNS. Clinical studies have also demonstrated a significant increase in cognitive performance when VNS is administered during the memory consolidation period of a list learning task.The nucleus of the solitary tract (NST) in the brain stem is the primary relay station for afferent vagal nerve fibers. The NST has numerous projections to various areas of the forebrain and brain stem, including the hippocampus. Stimulation of the vagus nerve has been shown to alter the electrophysiological and metabolic profiles of the hippocampus, an area that plays a critical role in learning and memory functions. The hippocampus generates and maintains high amplitude oscillations in the theta frequency range (4–8 Hz), which play an important role in memory tasks. Furthermore, there is pre‐clinical evidence that theta oscillations are depressed in rodent models with temporal lobe epilepsy, and that reduced theta activity correlates with memory deficits. We hypothesize that theta frequency VNS will have a positive effect on memory retention.MethodsPatients with implanted VNS devices were identified in the medical records, consented, and screened via the Beck Depression Inventory (excluded if score &gt; 20) and the Montreal Cognitive Assessment (excluded if score &lt; 24). Participants then practiced cognitive tasks for 30 minutes, followed by three rounds of neurocognitive testing with different VNS settings (Figure 1). Only VNS frequency (theta: 5 Hz, beta: 25–30 Hz, and control: 0 Hz) was altered. Each round of neurocognitive testing included two tasks. The first was a memory encoding/retrieval task (California Verbal Learning Test, CVLT). The second was an executive function task administered between the encoding and retrieval portions of CVLT. Both participants and test administrators were blinded to VNS parameters.Results &amp; DiscussionOver the course of one year, data was only collected from one patient. This was due to a combination of factors, including stringent exclusion criteria, difficult patient recruitment, and an understaffed research team. However, this patient did display a 23% increase in delayed free recall performance when treated with theta frequency stimulation (Figure 2). Furthermore, accuracy and reaction time decreased by 5% and &gt;15% for both beta and theta stimulation (as compared to the control) during the executive function task (Stroop test). While generalizable conclusions are impossible to draw from this data, the preliminary results support our hypothesis. While we are in the process of collecting more data, we hope that this study can serve as a platform for researchers to build from.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory

BackgroundThere are many contradictory findings about the role of the hormone ghrelin in aversive processing, with studies suggesting that ghrelin signaling can both inhibit and enhance aversion. Here, we characterize and reconcile the paradoxical role of ghrelin in the acquisition of fearful memories. MethodsWe used enzyme-linked immunosorbent assay to measure endogenous acyl-ghrelin and corticosterone at time points surrounding auditory fear learning. We used pharmacological (systemic and intra-amygdala) manipulations of ghrelin signaling and examined several aversive and appetitive behaviors. We also used biotin-labeled ghrelin to visualize ghrelin binding sites in coronal brain sections of amygdala. All work was performed in rats. ResultsIn unstressed rodents, endogenous peripheral acyl-ghrelin robustly inhibits fear memory consolidation through actions in the amygdala and accounts for virtually all interindividual variability in long-term fear memory strength. Higher levels of endogenous ghrelin after fear learning were associated with weaker long-term fear memories, and pharmacological agonism of the ghrelin receptor during the memory consolidation period reduced fear memory strength. These fear-inhibitory effects cannot be explained by changes in appetitive behavior. In contrast, we show that chronic stress, which increases both circulating endogenous acyl-ghrelin and fear memory formation, promotes profound loss of ghrelin binding sites in the amygdala and behavioral insensitivity to ghrelin receptor agonism. ConclusionsThese studies provide a new link between stress, a novel type of metabolic resistance, and vulnerability to excessive fear memory formation and reveal that ghrelin can regulate negative emotionality in unstressed animals without altering appetite.

Epicatechin, a component of dark chocolate, enhances memory formation if applied during the memory consolidation period

ABSTRACTEpicatechin (Epi), a flavanol found in foods such as dark chocolate has previously been shown to enhance memory formation in our model system, operant conditioning of aerial respiration in Lymnaea. In those experiments snails were trained in Epi. Here we ask whether snails exposed to Epi before training, during the consolidation period immediately following training, or 1 h after training would enhance memory formation. We report here that Epi is only able to enhance memory if snails are placed in Epi-containing pond water immediately after training. That is, Epi enhances memory formation if it is applied during the memory consolidation period as well as if snails are trained in Epi-containing pond water.

Motivated encoding selectively promotes memory for future inconsequential semantically-related events

Neurobiological models of long-term memory explain how memory for inconsequential events fades, unless these happen before or after other relevant (i.e., rewarding or aversive) or novel events. Recently, it has been shown in humans that retrospective and prospective memories are selectively enhanced if semantically related events are paired with aversive stimuli. However, it remains unclear whether motivating stimuli, as opposed to aversive, have the same effect in humans. Here, participants performed a three phase incidental encoding task where one semantic category was rewarded during the second phase. A memory test 24h after, but not immediately after encoding, revealed that memory for inconsequential items was selectively enhanced only if items from the same category had been previously, but not subsequently, paired with rewards. This result suggests that prospective memory enhancement of reward-related information requires, like previously reported for aversive memories, of a period of memory consolidation. The current findings provide the first empirical evidence in humans that the effects of motivated encoding are selectively and prospectively prolonged over time.

Stress-free automatic sleep deprivation using air puffs

BackgroundSleep deprivation via gentle handling is time-consuming and personnel-intensive. New methodWe present here an automated sleep deprivation system via air puffs. Implanted EMG and EEG electrodes were used to assess sleep/waking states in six male Sprague-Dawley rats. Blood samples were collected from an implanted intravenous catheter every 4h during the 12-h light cycle on baseline, 8h of sleep deprivation via air puffs, and 8h of sleep deprivation by gentle handling days. ResultsThe automated system was capable of scoring sleep and waking states as accurately as our offline version (∼90% for sleep) and with sufficient speed to trigger a feedback response within an acceptable amount of time (1.76s). Manual state scoring confirmed normal sleep on the baseline day and sleep deprivation on the two manipulation days (68% decrease in non-REM, 63% decrease in REM, and 74% increase in waking). No significant differences in levels of ACTH and corticosterone (stress hormones indicative of HPA axis activity) were found at any time point between baseline sleep and sleep deprivation via air puffs. Comparison with existing methodThere were no significant differences in ACTH or corticosterone concentrations between sleep deprivation by air puffs and gentle handling over the 8-h period. ConclusionsOur system accurately detects sleep and delivers air puffs to acutely deprive rats of sleep with sufficient temporal resolution during the critical 4–5h post learning sleep-dependent memory consolidation period. The system is stress-free and a viable alternative to existing sleep deprivation techniques.

Administration of nicotinic receptor antagonists during the period of memory consolidation affects passive avoidance learning and modulates synaptic efficiency in the CA1 region in vivo

We examined whether a non-selective antagonist of nAChRs mecamylamine and selective antagonists of α4β2-containing nAChRs dihydro-β-erythroidine (DHβE) and α7-containing nAChRs methyllycaconitine (MLA) affect learning performance and synaptic efficiency in the CA1 area of the hippocampus of freely moving rats during the memory consolidation period. Adult male Wistar rats received mecamylamine (0.5mg/kg), DHβE (1mg/kg), MLA (2mg/kg) or saline immediately after training in a passive avoidance task. Memory retention was examined 24h after the training. The changes in the latency of the first entry into a dark compartment of a test chamber were chosen as a criterion of learning. The ability of nAChRs antagonists to induce changes in the basal level of focal potentials (fEPSP, field excitatory postsynaptic potential) was estimated before training (baseline), 90min after the training (consolidation period) and 24h after the training (retention period). We found that in untrained rats mecamylamine, DHβE and MLA diminished the amplitude of fEPSP within the first 90min after the injection; similar effect was observed in DHβE- and MLA-treated trained animals. These suppressive effects of DHβE and MLA were associated with memory loss. In contrast, mecamylamine, when applied to trained animals, tended to increase latency to enter the dark chamber and did not influence fEPSP during first 90min after injection. Thus, the nAChRs antagonists with different selectivity induced different changes in fEPSP and behavior which suggests that nAChRs with different subunit composition are diversely involved in memory consolidation.

Participation of muscarinic receptors in memory consolidation in passive avoidance learning.

It is well-known that the cholinergic system and the muscarinic cholinergic receptors are associated with cognitive functions. Here we examined whether a non-selective muscarinic receptor antagonist scopolamine affects learning performance and/or synaptic plasticity during the memory consolidation period. Adult male Wistar rats (250-300 g) were injected with scopolamine (2 mg/kg) or saline immediately after training in a "passive avoidance" task. Memory retention test was conducted 24 h after training. The changes in the latency of the first entry into a dark compartment of a test chamber was chosen as a criterion of learning. The efficacy of synaptic transmission was estimated by the changes in the basal level of focal potentials (fEPSP amplitude and slope ratio) before training (baseline), 90 min after the training (consolidation period), and 24 hour after the training (retention period). We found that foot-shock presentation by itself had no effect on fEPSP within the first 90 min after training, but in 24 hour fEPSPs were decreased. In untrained rats administration of scopolamine had no effect on the fEPSP amplitude within the first 90 min after the injection, but in 24 h we observed an increase in the fEPSP amplitude. In trained animals, scopolamine decreased the fEPSP amplitude in the hippocampal CA1 area during first 1.5 h after the injection. However, the drug had no effect on the memory retention in the passive avoidance task. Taken together our data suggest that scopolamine modifies the synaptic placticity of the hippocampal network but does not induce significant changes in the retention of the passive avoidance skill.

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.

Circadian Oscillations within the Hippocampus Support Memory Formation and Persistence

The ability to sustain memories over long periods of time, sometimes even a lifetime, is one of the most remarkable properties of the brain. Much knowledge has been gained over the past few decades regarding the molecular correlates of memory formation. Once a memory is forged, however, the molecular events that provide permanence are as of yet unclear. Studies in multiple organisms have revealed that circadian rhythmicity is important for the formation, stability, and recall of memories (Gerstner et al., 2009).The neuronal events that provide this link need to be explored further. This article will discuss the findings related to the circadian regulation of memory-dependent processes in the hippocampus. Specifically, the circadian-controlled mitogen-activated protein kinase (MAPK) and cAMP signal transduction pathway plays critical roles in the consolidation of hippocampus-dependent memory. A series of studies have revealed the circadian oscillation of this pathway within the hippocampus, an activity that is absent in memory-deficient, transgenic mice lacking Ca2+-stimulated adenylyl cyclases. Interference with these oscillations proceeding the cellular memory consolidation period impairs the persistence of hippocampus-dependent memory. These data suggest that the persistence of long-term memories may depend upon reactivation of this signal transduction pathway in the hippocampus during the circadian cycle. New data reveals the dependence of hippocampal oscillation in MAPK activity on the suprachiasmatic nucleus, again underscoring the importance of this region in maintaining the circadian physiology of memory. Finally, the downstream ramification of these oscillations in terms of gene expression and epigenetics should be considered, as emerging evidence is pointing strongly to a circadian link between epigenetics and long-term synaptic plasticity.

Long-term accelerated forgetting of verbal and non-verbal information in temporal lobe epilepsy

IntroductionWe investigated whether pre-surgical patients with temporal lobe epilepsy (TLE) forget verbal and non-verbal material faster than healthy controls over retention intervals of an hour and 6 weeks, and whether any observed memory loss was associated with structural changes to the hippocampus and/or seizure frequency. MethodsA mixed factorial design compared the performance of 27 patients with TLE and 22 healthy control participants, matched for IQ, age and gender, on tests of story recall and complex figure recall at three delays: immediate, 1h and 6 weeks. Performance of the patient and control groups was matched at the immediate delay, which enabled comparisons of forgetting rate over the longer delays. ResultsWe found that TLE can affect the acquisition and retention of new memories over a relatively short delay of 1h. This deficit was associated with structural hippocampal abnormality, with a material-specific effect that was particularly evident for the verbal task. We also found evidence of accelerated long-term forgetting in both patient groups, for the verbal and non-verbal tasks. It was demonstrated most strongly on the verbal task by the patients with right lateralized hippocampal sclerosis whose verbal recall was normal at the 1-h delay. Accelerated long-term forgetting was not associated with hippocampal pathology, but was associated with the frequency of epileptic seizures. DiscussionThe findings from the verbal task in particular provide evidence consistent with an extended period of memory consolidation that can be disrupted by both left and right TLE. The material-specific effects at the 1-h delay only, suggest that the initial consolidation of verbal and non-verbal, information depends on the integrity of the left and right hippocampus, respectively.

A critical role for IGF-II in memory consolidation and enhancement

We report that, in the rat, administering insulin-like growth factor II (IGF-II) significantly enhances memory retention and prevents forgetting. Inhibitory avoidance learning leads to an increase in hippocampal expression of IGF-II, which requires the transcription factor CCAAT enhancer binding protein β and is essential for memory consolidation. Furthermore, injections of recombinant IGF-II into the hippocampus after either training or memory retrieval significantly enhance memory retention and prevent forgetting. To be effective, IGF-II needs to be administered within a sensitive period of memory consolidation. IGF-II-dependent memory enhancement requires IGF-II receptors, new protein synthesis, the function of activity-regulated cytoskeletal-associated protein and glycogensynthase kinase 3 (GSK3). Moreover, it correlates with a significant activation of synaptic GSK3β and expression of GluR1 a-amino-3-hydroxy-5-methyl-4-isoxasoleproprionic acid receptor subunits. In hippocampal slices, IGF-II promotes IGF-II receptor-dependent, persistent long-term potentiation after weak synaptic stimulation. Thus, IGF-II may represent a novel target for cognitive enhancement therapies.

Intraventricular infusions of anti–NCAM PSA impair the process of consolidation of both avoidance conditioning and spatial learning paradigms in Wistar rats

Processing of information for long-term storage requires specific patterns of activity that lead to modification of synapse structure and eventual change in neural connectivity pattern. Morphological change associated with memory consolidation is reliant on neural cell adhesion molecule (NCAM) function and that of its polysialylated variant (NCAM PSA). Across species and paradigms, a transient frequency increase of polysialylated neurons in the hippocampal dentate has been found necessary for memory consolidation, however, recent studies suggest that NCAM PSA may serve to suppress memory formation in certain paradigms. As intraventricular infusions of NCAM blocking antibodies have been used successfully to demonstrate its time-dependent role at the 6 h post-training period of memory consolidation, we employed the same procedure to demonstrate a functional requirement for NCAM PSA in the consolidation of two commonly used behavioral paradigms: avoidance conditioning and spatial learning in Wistar rats. Anti-PSA was found to significantly induce amnesia of the passive avoidance response when infused at the 10 h post-training time, a period coincident with the learning-associated increase in dentate polysialylated cell frequency. Moreover, the amnesia became apparent at the 48 h recall time and was not apparent at the 24 h post-training time, suggesting a possible role in memory reconsolidation. A similar anti-PSA action was observed following water maze training in aged animals but was not apparent in young animals, an effect suggested to be due to inadequate antibody saturation of the polysialylated cell population. These studies confirm the requirement for NCAM PSA in memory consolidation and separate it from that of NCAM.

Circadian oscillation of hippocampal MAPK activity and cAMP: implications for memory persistence

The mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate (cAMP) signal transduction pathways have critical roles in the consolidation of hippocampus-dependent memory. We found that extracellular regulated kinase 1/2 MAPK phosphorylation and cAMP underwent a circadian oscillation in the hippocampus that was paralleled by changes in Ras activity and the phosphorylation of MAPK kinase and cAMP response element-binding protein (CREB). The nadir of this activation cycle corresponded with severe deficits in hippocampus-dependent fear conditioning under both light-dark and free-running conditions. Circadian oscillations in cAMP and MAPK activity were absent in memory-deficient transgenic mice that lacked Ca2+ -stimulated adenylyl cyclases. Furthermore, physiological and pharmacological interference with oscillations in MAPK phosphorylation after the cellular memory consolidation period impaired the persistence of hippocampus-dependent memory. These data suggest that the persistence of long-term memories may depend on reactivation of the cAMP/MAPK/CREB transcriptional pathway in the hippocampus during the circadian cycle.

Hippocampal activity, but not plasticity, is required for early consolidation of fear conditioning with a short trace interval

The dorsal hippocampus is required for explicit cue fear conditioning only when a temporal gap is inserted between conditioned stimulus (CS) termination and unconditioned stimulus (US) onset (trace fear conditioning). To examine the role of the dorsal hippocampus in associating temporally discontiguous stimuli and to minimize the potential contribution of contextual cues, fear conditioning was conducted using a relatively short (3-s) trace interval. Inactivation of the dorsal hippocampus using the AMPA receptor antagonist NBQX (3 microg/hemisphere) or the GABA(A) agonist muscimol (5 microg/hemisphere) disrupted trace fear conditioning when conducted immediately following training. Trace conditioning was not disrupted significantly when NBQX was infused either before or 2 h after training. Similarly, NBQX infusions were not effective when the CS and US overlapped (delay conditioning). Moreover, trace conditioning was not impaired by intrahippocampal infusion of either the NMDA receptor antagonist AP5 (5 microg/hemisphere) or the L-type voltage-gated calcium channel (VGCC) blocker diltiazem (20 or 40 microg/hemisphere). These data suggest that the involvement of the dorsal hippocampus in short trace interval fear conditioning is largely restricted to the early period of memory consolidation, during which time it mediates the storage of long-term memory in other brain regions.

Covalent Modification of DNA Regulates Memory Formation

DNA methylation is a covalent chemical modification of DNA catalyzed by DNA methyltransferases (DNMTs). DNA methylation is associated with transcriptional silencing and has been studied extensively as a lifelong molecular information storage mechanism put in place during development. Here we report that DNMT gene expression is upregulated in the adult rat hippocampus following contextual fear conditioning and that DNMT inhibition blocks memory formation. In addition, fear conditioning is associated with rapid methylation and transcriptional silencing of the memory suppressor gene PP1 and demethylation and transcriptional activation of the synaptic plasticity gene reelin, indicating both methyltransferase and demethylase activity during consolidation. DNMT inhibition prevents the PP1 methylation increase, resulting in aberrant transcription of the gene during the memory-consolidation period. These results demonstrate that DNA methylation is dynamically regulated in the adult nervous system and that this cellular mechanism is a crucial step in memory formation.

Methylene blue restores spatial memory retention impaired by an inhibitor of cytochrome oxidase in rats

Cytochrome oxidase is the mitochondrial enzyme that catalyzes the utilization of oxygen for the electron transport chain during cellular respiration. Chronic subcutaneous infusion of sodium azide, an inhibitor of cytochrome oxidase, produced a spatial memory retention deficit in rats in a holeboard maze. Methylene blue, which has been shown to increase oxygen consumption in vitro, was used to restore mitochondrial electron transport in order to facilitate memory consolidation. Administration of 1 mg/kg methylene blue after training, during the memory consolidation period, completely restored the memory retention impaired by the inhibitor of cytochrome oxidase. This suggests that methylene blue may compensate for impaired mitochondrial respiration and improve spatial memory retention. Memory retention deficits found in some neurodegenerative diseases may be improved by drugs targeting impaired mitochondrial respiration.

Post-training reversible inactivation of hippocampus reveals interference between memory systems.

A post-training reversible lesion technique was used to examine the effects of neural inactivation of the dorsal hippocampus on place and response learning. Male Long-Evans rats trained in one of two versions of a water plus-maze task received post-training intra-hippocampal infusions of the local anesthetic drug bupivacaine (0.75% solution, 0.5 microl), or saline. Post-training intra-hippocampal infusions of bupivacaine attenuated acquisition of the place task and enhanced acquisition of the response task. Delayed (2-h) post-training infusions of bupivacaine did not affect retention in either task. The findings demonstrate (1) enhanced learning after reversible hippocampal lesions that is independent of treatment influences on non-mnemonic factors, and (2) inactivation of the dorsal hippocampus during the post-training memory consolidation period is sufficient to enhance response learning.