Memory Retrieval In Mice Research Articles

Higher-order interactions between hippocampal CA1 neurons are disrupted in amnestic mice.

Across systems, higher-order interactions between components govern emergent dynamics. Here we tested whether contextual threat memory retrieval in mice relies on higher-order interactions between dorsal CA1 hippocampal neurons requiring learning-induced dendritic spine plasticity. We compared population-level Ca2+ transients as wild-type mice (with intact learning-induced spine plasticity and memory) and amnestic mice (TgCRND8 mice with high levels of amyloid-β and deficits in learning-induced spine plasticity and memory) were tested for memory. Using machine-learning classifiers with different capacities to use input data with complex interactions, our findings indicate complex neuronal interactions in the memory representation of wild-type, but not amnestic, mice. Moreover, a peptide that partially restored learning-induced spine plasticity also restored the statistical complexity of the memory representation and memory behavior in Tg mice. These findings provide a previously missing bridge between levels of analysis in memory research, linking receptors, spines, higher-order neuronal dynamics and behavior.

Comparing behaviours induced by natural memory retrieval and optogenetic reactivation of an engram ensemble in mice.

Memories are thought to be stored within sparse collections of neurons known as engram ensembles. Neurons active during a training episode are allocated to an engram ensemble ('engram neurons'). Memory retrieval is initiated by external sensory or internal cues present at the time of training reactivating engram neurons. Interestingly, optogenetic reactivation of engram ensemble neurons alone in the absence of external sensory cues is sufficient to induce behaviour consistent with memory retrieval in mice. However, there may exist differences between the behaviours induced by natural retrieval cues or artificial engram reactivation. Here, we compared two defensive behaviours (freezing and the syllable structure of ultrasonic vocalizations, USVs) induced by sensory cues present at training (natural memory retrieval) and optogenetic engram ensemble reactivation (artificial memory retrieval) in a threat conditioning paradigm in the same mice. During natural memory recall, we observed a strong positive correlation between freezing levels and distinct USV syllable features (characterized by an unsupervised algorithm, MUPET (Mouse Ultrasonic Profile ExTraction)). Moreover, we observed strikingly similar behavioural profiles in terms of freezing and USV characteristics between natural memory recall and artificial memory recall in the absence of sensory retrieval cues. Although our analysis focused on two behavioural measures of threat memory (freezing and USV characteristics), these results underscore the similarities between threat memory recall triggered naturally and through optogenetic reactivation of engram ensembles. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Self-Aggregating Tau Fragments Recapitulate Pathologic Phenotypes and Neurotoxicity of Alzheimer's Disease in Mice.

In tauopathy conditions, such as Alzheimer's disease (AD), highly soluble and natively unfolded tau polymerizes into an insoluble filament; however, the mechanistic details of this process remain unclear. In the brains of AD patients, only a minor segment of tau forms β-helix-stacked protofilaments, while its flanking regions form disordered fuzzy coats. Here, it is demonstrated that the tau AD nucleation core (tau-AC) sufficiently induced self-aggregation and recruited full-length tau to filaments. Unexpectedly, phospho-mimetic forms of tau-AC (at Ser324 or Ser356) show markedly reduced oligomerization and seeding propensities. Biophysical analysis reveal that the N-terminus of tau-AC facilitates the fibrillization kinetics as a nucleation motif, which becomes sterically shielded through phosphorylation-induced conformational changes in tau-AC. Tau-AC oligomers are efficiently internalized into cells via endocytosis and induced endogenous tau aggregation. In primary hippocampal neurons, tau-AC impaired axon initial segment plasticity upon chronic depolarization and is mislocalized to the somatodendritic compartments. Furthermore, it is observed significantly impaired memory retrieval in mice intrahippocampally injected with tau-AC fibrils, which corresponds to the neuropathological staining and neuronal loss in the brain. These findings identify tau-AC species as a key neuropathological driver in AD, suggesting novel strategies for therapeutic intervention.

Aerobic Glycolysis Is Required for Spatial Memory Acquisition But Not Memory Retrieval in Mice.

The consolidation of newly formed memories and their retrieval are energetically demanding processes. Aerobic glycolysis (AG), also known as the Warburg effect, consists of the production of lactate from glucose in the presence of oxygen. The astrocyte neuron lactate shuttle hypothesis posits that astrocytes process glucose by AG to generate lactate, which is used as a fuel source within neurons to maintain synaptic activity. Studies in mice have demonstrated that lactate transport between astrocytes and neurons is required for long-term memory formation, yet the role of lactate production in memory acquisition and retrieval has not previously been explored. Here, we examined the effect of dichloroacetate (DCA), a chemical inhibitor of lactate production, on spatial learning and memory in mice using the Morris water maze (MWM). In vivo hyperpolarized 13C-pyruvate magnetic resonance spectroscopy revealed decreased conversion of pyruvate to lactate in the mouse brain following DCA administration, concomitant with a reduction in the phosphorylation of pyruvate dehydrogenase. DCA exposure before each training session in the MWM impaired learning, which subsequently resulted in impaired memory during the probe trial. In contrast, mice that underwent training without DCA exposure, but received a single DCA injection before the probe trial exhibited normal memory. Our findings indicate that AG plays a key role during memory acquisition but is less important for the retrieval of established memories. Thus, the activation of AG may be important for learning-dependent synaptic plasticity rather than the activation of signaling cascades required for memory retrieval.

Effect of sevoflurane on memory retrieval in mice: the role of hippocampal PSD95 and AMPA receptor

Objective To evaluate the effect of sevoflurane on memory retrieval in mice and the role of hippocampal PSD95 and amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor. Methods Sixty-four healthy pathogen-free Kuming mice of both sexes, aged 2-3 months, weighing 30-35 g, were divided into control group (n=32) and sevoflurane group (n=32) in a stratified randomized block design.The ability of memory retrieval was evaluated using dark avoidance test.After setting up the memory of dark avoidance, the mice inhaled 40% oxygen for 2 h in control group and 3.3% sevofluane in 40% oxygen for 2 h in sevoflurane group.Dark avoidance test was performed at 12, 24, 48 and 72 h after the end of oxygen or sevoflurane inhalation (T1-4), and the test results and development of amnesia were recorded.The animals were sacrificed after behavior test at each time point, and brains were removed and cut into sections which were stained with haematoxylin and eosin for examination of the pathological changes of hippocampal CA1 area (under a light microscope) and for determination of the expression of PSD95 and AMPA receptors in hippocampi (using immunohistochemistry and Western blot). Results Compared with control group, the step-in latency and test results of error times were significantly decreased, the expression of PSD95 and AMPA receptors in hippocampus was down-regulated, and the incidence of amnesia was increased at T1 and T2 in sevoflurane group (P 0.05), and the step-in latency and test results of error times were significantly decreased at T1 and T2 in sevoflurane group (P<0.05). Apoptosis in pyramidal cells was not found in sevoflurane group. Conclusion Sevoflurane can inhibit the ability of memory retrieval transiently in mice, and the mechanism is related to inhibiting the expression of hippocampal PSD95 and AMPA receptors. Key words: Anesthetics, inhalation; Memory disorders; Membrane proteins; Receptors, AMPA

Interactive effects of morphine and dopamine receptor agonists on spatial recognition memory in mice.

Both opiates and dopamine play important roles in learning and memory. Although synergistic action between these two neurotransmitters has been found, their functional roles remain unclear. Here, low dose morphine (2.5mg/kg) and low dose dopamine receptor agonists (apomorphine 0.05mg/kg; SKF38393 0.01mg/kg; bromocriptine 0.05mg/kg), which have no effects on spatial recognition memory, were injected intraperitoneally into mice 30minutes before a memory test in a two-trial recognition Y-maze. The Y-maze is based on the innate tendency of rodents to explore novel environments and is therefore suitable for exploring the effects of morphine on learning and memory. Our results showed that both D1-like and D2-like dopamine receptor agonists dose-dependently impaired the retrieval of spatial recognition memory in the Y-maze, and co-administration of memory ineffective doses of apomorphine (0.05mg/kg), SKF38393 (0.01mg/kg), or bromocriptine (0.05mg/kg) and of morphine (2.5mg/kg) resulted in impaired spatial recognition memory retrieval in mice. These findings suggest the existence of interactions between morphine and dopamine receptor agonists in memory processing and that activation of the dopamine system might contribute to morphine-induced impairment of memory, which could provide insight into human addiction.

Memory Retrieval in Mice and Men.

Retrieval, the use of learned information, was until recently mostly terra incognita in the neurobiology of memory, owing to shortage of research methods with the spatiotemporal resolution required to identify and dissect fast reactivation or reconstruction of complex memories in the mammalian brain. The development of novel paradigms, model systems, and new tools in molecular genetics, electrophysiology, optogenetics, in situ microscopy, and functional imaging, have contributed markedly in recent years to our ability to investigate brain mechanisms of retrieval. We review selected developments in the study of explicit retrieval in the rodent and human brain. The picture that emerges is that retrieval involves coordinated fast interplay of sparse and distributed corticohippocampal and neocortical networks that may permit permutational binding of representational elements to yield specific representations. These representations are driven largely by the activity patterns shaped during encoding, but are malleable, subject to the influence of time and interaction of the existing memory with novel information.

Projections from neocortex mediate top-down control of memory retrieval.

Top-down prefrontal cortex inputs to the hippocampus have been hypothesized to be important in memory consolidation, retrieval, and the pathophysiology of major psychiatric diseases; however, no such direct projections have been identified and functionally described. Here we report the discovery of a monosynaptic prefrontal cortex (predominantly anterior cingulate) to hippocampus (CA3 to CA1 region) projection in mice, and find that optogenetic manipulation of this projection (here termed AC-CA) is capable of eliciting contextual memory retrieval. To explore the network mechanisms of this process, we developed and applied tools to observe cellular-resolution neural activity in the hippocampus while stimulating AC-CA projections during memory retrieval in mice behaving in virtual-reality environments. Using this approach, we found that learning drives the emergence of a sparse class of neurons in CA2/CA3 that are highly correlated with the local network and that lead synchronous population activity events; these neurons are then preferentially recruited by the AC-CA projection during memory retrieval. These findings reveal a sparsely implemented memory retrieval mechanism in the hippocampus that operates via direct top-down prefrontal input, with implications for the patterning and storage of salient memory representations.

Acute stress blocks the caffeine-induced enhancement of contextual memory retrieval in mice

This study investigated in mice the dose-effect of caffeine on memory retrieval in non-stress and stress conditions. C57 Bl/6 Jico mice learned two consecutive discriminations (D1 and D2) in a four-hole board which involved either distinct contextual (CSD) or similar contextual (SSD) cues. All mice received an i.p. injection of vehicle or caffeine (8, 16 or 32mg/kg) 30min before the test session. Results showed that in non-stress conditions, the 16mg/kg caffeine dose induced a significant enhancement of D1 performance in CSD but not in SSD. Hence, we studied the effect of an acute stress (electric footshocks) administered 15min before the test session on D1 performance in caffeine-treated mice.Results showed that stress significantly decreased D1 performance in vehicle-treated controls and the memory-enhancing effect induced by the 16mg/kg caffeine dose in non-stress condition is no longer observed. Interestingly, whereas caffeine-treated mice exhibited weaker concentrations of plasma corticosterone as compared to vehicles in non-stress condition, stress significantly increased plasma corticosterone concentrations in caffeine-treated mice which reached similar level to that of controls. Overall, the acute stress blocked both the endocrinological and memory retrieval enhancing effects of caffeine.

Short-term sleep deprivation reinstates memory retrieval in mice: The role of corticosterone secretion

While the effects of sleep deprivation (SD) on the acquisition and consolidation phases of memory have been extensively characterized, its effects on memory retrieval remain overlooked. SD alone is a stressor, and stress-activated glucocorticoids promote bimodal effects on memory. Because we have recently demonstrated that 72h SD impairs memory retrieval in the plus-maze discriminative avoidance task (PM-DAT) in mice, this study investigated whether shorter SD periods would facilitate retrieval. In Experiment I, the temporal forgetting curve of the PM-DAT was determined and an interval between training/testing in which retrieval was no longer present was used in all subsequent experiments. In Experiments II and III, retrieval performance and corticosterone concentration, respectively, were quantified in mice that were sleep deprived for 12 or 24h before testing. In Experiments IV and V, the effects of the corticosterone synthesis inhibitor metyrapone were evaluated on 12h SD-induced retrieval reinstatement and corticosterone concentration enhancement, respectively. Experiment VI determined whether pre-test acute administration of exogenous corticosterone would mimic the facilitatory effects of 12h SD on retrieval. Thirty days after training, mice presented poor performance of the task; however, SD for 12h (but not for 24) before testing reinstated memory retrieval. This facilitatory effect was accompanied by increased corticosterone concentration, abolished by metyrapone, and mimicked by pre-test acute corticosterone administration. Collectively, short-term SD can facilitate memory retrieval by enhancing corticosterone secretion. This facilitatory effect is abolished by longer periods of SD.

The effects of green Ocimum basilicum hydroalcoholic extract on retention and retrieval of memory in mice

The purpose of this study was evaluation of green Ocimum basilicum (sweet basil) hydroalcoholic extract on memory retention and retrieval of mice by using passive avoidance apparatus. For this purpose, after weighting, coding and classifying the mice, they were grouped (n = 8) as follow as: test groups (electric shock plus sweet basil extract by doses: 100, 200, 400 and 800 mg/kg, i.p.), control group (Only electric shock) and blank group (electric shock plus normal saline). In all mentioned groups delay time of leaving the platform for both retention and retrieval test of memory was measured. In retention test, sweet basil extract was administered immediately after receiving electric shock and in retrieval test it was administered 24 hours after receiving electric shock. The results indicated that hydroalcoholic extract of green Ocimum basilicum significantly (P < 0.05) increased memory retention. The best response was achieved with 400 mg/Kg of the extract. Also, results showed that sweet basil extract significantly (P < 0.05) increased memory retrieval and the best result was achieved with 400 mg/Kg too. It can be concluded that memory enhancing effects of green Ocimum basilicum is because of antioxidant activity of flavonoids, tannins and terpenoids.

Performance of PAC1-R Heterozygous Mice in Memory Tasks-II

An involvement of pituitary adenylate cyclase activating polypeptide-specific receptor type 1 (PAC1-R) in behavioral performance of retrieval of memory upon the stimulation of perception of sensory modality was investigated in mice. Eighteen heterozygous (-/+) transgenic mutant PAC1-R-deficient mice ((-/+) mice) and 18 wild-type (+/+) mice of littermates ((+/+) mice) as a control were used. No homozygous (-/-) transgenic mutant PAC1-R-deficit mouse was bred in our colony. It was observed that; (1) changing a single alley in the multiple mazes interfered with retrieval of memory in both (-/+) mice and (+/+) mice, and they made considerable errors; (2) a rotation of the multiple mazes for 180 degrees in relation to the geomagnetic field made also considerable errors, but in only (+/+) mice and not in (-/+) mice; and (3) an exposure for perception of fear signals made also considerable errors, but in only (+/+) mice and not in (-/+) mice. It is inferred that PAC1-R may play a gating role in passage permitting through perception of geomagnetic orientation and fear signals, but not perception of visual orientation, and it regulates behavioral performance in retrieval of memory in mice.

Effects of nicotine on memory retrieval in mice

The effect of nicotine was tested on retrieval 24 h after training on a passive avoidance task. Intraperitoneal (i.p.) injection of nicotine (0.25–1.5 mg/kg) increased the step-down latency in mice dose dependently. Pretreatment with the nicotinic receptor antagonist mecamylamine (0.5–1 mg/kg) decreased, whereas pretreatment with the dopamine D 1 receptor antagonist SCH 23390 ( R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1 H-3-benzazepine-7-ol maleate) (0.01, 0.05 and 0.1 mg/kg) and the β-adrenoreceptor antagonist propranolol (10 mg/kg) increased the nicotine response. The dopamine receptor D 2 receptor antagonist sulpiride (5–10 mg/kg), the anti-muscarinic agent atropine (2.5–10 mg/kg), the peripheral nicotinic receptor antagonist hexamethonium (0.01–0.5 mg/kg), the α-adrenoceptor antagonist phenoxybenzamine (1 and 10 mg/kg) and the peripheral dopamine D 2 receptor antagonist domperidone (5 and 10 mg/kg) did not change the response induced by nicotine. Single administration of the antagonists did not cause response; however, a high dose of domperidone (10 mg/kg) and propranolol alone increased the step-down latencies. It may be concluded that a nicotinic receptor mechanism is involved in the nicotine-induced improvement of memory retrieval.

Beneficial effects of S-113m, a novel herbal prescription, on learning impairment model in mice.

The effects of S-113m, a novel herbal prescription consisting of Biota orientalis, Panax ginseng and Schisandra chinensis, were studied regarding learning and memory performance in the step-down and lever-press tests in normal, as well as in learning-impaired, mice. The prescription had no effect on memory registration, consolidation and retrieval processes or on motor activity in normal mice. However, a single oral administration of S-113m at doses of 250 and 500 mg/kg reduced the ethanol-induced and scopolamine-induced impairment of memory registration in the step-down test. The preparation also improved the electroconvulsive shock-induced impairment of memory consolidation in the same test. S-113m did not, however, attenuate the ethanol-induced impairment of memory retrieval. These suggest that S-113M has a preferential beneficial effect on the impairment of memory registration and memory consolidation rather than on memory retrieval in mice, through direct action on the learning and memory process.

Effect of the calcium channel blocker amlodipine on memory in mice

Five experiments were performed to investigate the effects of amlodipine, a calcium channel antagonist of the 1,4-dihydropyridine class, on consolidation and retrieval of memory in mice. In a single-trial passive avoidance task, amlodipine was administered pretraining, posttraining, or pretesting. Results of temporal and dose-response studies showed that memory enhancement (significant increase in step-through latency) occurred when amlodipine (5, 7, 9, 15, and 30 mg/kg) was given either immediately post-training or (15 mg/kg) 15 min pretesting. Using a conditioned emotional response task, tone was paired with shock using Pavlovian conditioning procedures. Strength of conditioning was assessed by measuring suppression of drinking in the presence of a tone. Amlodipine (7 mg/kg) given immediately following both high- and low-intensity shock significantly enhanced conditioned suppression. In the third experiment thirsty mice were trained on a spatial discrimination task in a linear maze. Correct choices were reinforced with liquid reinforcement. Amlodipine (10 mg/kg) injected immediately after the training session produced a significant enhancement of discrimination performance on a 24-h retention test. In the fourth experiment mice were given 25 training trials in a two-way active avoidance task and were treated with either amlodipine (10 mg/kg) or saline after training. Amlodipine-treated mice made significantly more avoidances on the test session than control animals. The final experiment demonstrated that the deficit in approach-avoidance behavior seen in 18-month-old mice could be reversed by amlodipine treatment after the training session. These studies suggest that amlodipine can facilitate memory consolidation and retrieval.

Effect of D-1 or D-2 receptor stimulation on memory retrieval in mice

Mice were trained in one-way active avoidance procedure and retention was tested at 4, 8, 16 and 24 h after training of animals and compared with non-shocked or untrained animals. The effect of drugs was tested on retrieval 24 h after training in other groups of mice. High doses of apomorphine or bromocriptine impaired, while low doses of the drugs improved, retrieval of avoidance. High doses of sulpiride reversed the impairment induced by high doses of these dopamine agonists. Low doses of sulpiride antagonized the improvement of retrieval induced by low doses of apomorphine. SKF 38393 treatment of animals also improved the retrieval. The retrieval impairment induced by higher doses of apomorphine or the improvement induced by different doses of SKF 38393 was antagonized by SCH 23390 pre-treatment. Single administration of SCH 23390 or low doses of sulpiride also impaired retrieval. It is concluded that stimulating post-synaptic D-2 dopamine receptors impairs retrieval whilst activation of pre-synaptic D-2 or post-synaptic D-1 receptors improves memory retrieval.

Vasopressin modulates the activity of nicotinic cholinergic mechanisms during memory retrieval in mice

Lysine vasopressin (0.03 micrograms/kg, sc) enhanced retention test performance on a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 20 min before the retention test. Tests were done 48 h following training. A low dose of the vasopressin antagonist AAVP (0.01 microgram/kg, sc, 20 min prior to testing) did not significantly affect retention test performance, whereas a higher dose (0.03 microgram/kg, sc) impaired it. Neither lysine vasopressin nor AAVP when given prior to testing modified latencies to step-through of mice that had not received a footshock during training. The simultaneous administration of AAVP (0.01 microgram/kg, sc) prevented the enhancement of retention test performance induced by lysine vasopressin. The influence of lysine vasopressin on retention test performance was antagonized by the simultaneous administration of mecamylamine (5 mg/kg, sc) but not by hexamethonium (5 mg/kg, sc), atropine (0.5 mg/kg, sc), or methylatropine (0.5 mg/kg, sc). A modulatory role of vasopressin on the activity of central cholinergic nicotinic mechanisms which probably operate at the time of testing is suggested.