Evidence for hippocampal role in place avoidance other than merely memory storage

Spatial navigation is used as a popular animal model of higher cognitive functions in people. The data suggest that the hippocampus is important for both storing spatial memories and for performing spatial computations necessary for navigation. Animals use multiple behavioral strategies to solve spatial tasks often using multiple memory systems. We investigated how inactivation of the rat hippocampus affects performance in a place avoidance task to determine if the role of the hippocampus in this task could be attributed to memory storage/retrieval or to the computations needed for navigation. Injecting tetrodotoxin (TTX) into both hippocampi impaired conditioned place avoidance, but after injecting only one hippocampus, the rats learned the place avoidance as well as without any injections. Retention of the place avoidance learned with one hippocampus was not impaired when the injection was switched to the hippocampus that had not been injected during learning. The result suggests that during learning, the hippocampus did not store the place avoidance memory.     

Interaction of stereotypic behavior in mice and effects of activation of presynaptic dopaminergic receptors in extinction and amnesia

Using the methods of agonistic confrontations of C57BL/6J mice for formation of aggressive and submissive types of behavior and passive avoidance training we investigated the influence of activation of dopamine presynaptic receptors on retention of a memory trace during extinction and amnesia. Autoreceptor agonist (+)3PPP (2 mg/kg, intraperitoneal injection) impaired learning and retention of a memory trace during extinction and strengthened the amnestic influence of animal detention in a dangerous compartment on the training day only in aggressive mice. In submissive mice, (+) 3PPP improved the retrieval of passive avoidance during extinction but did not change the development of amnesia. This work was the first to demonstrate that the effects of dopamine autoreceptor activation on the passive avoidance retrieval depend on behavioral stereotype (aggressive or submissive). It is suggested that different basic states of the dopaminergic system in aggressive and submissive mice are responsible for different (+) 3PPP effects.     

Neural dynamics of the cognitive map in the hippocampus

The rodent hippocampus has been thought to represent the spatial environment as a cognitive map. In the classical theory, the cognitive map has been explained as a consequence of the fact that different spatial regions are assigned to different cell populations in the framework of rate coding. Recently, the relation between place cell firing and local field oscillation theta in terms of theta phase precession was experimentally discovered and suggested as a temporal coding mechanism leading to memory formation of behavioral sequences accompanied with asymmetric Hebbian plasticity. The cognitive map theory is apparently outside of the sequence memory view. Therefore, theoretical analysis is necessary to consider the biological neural dynamics for the sequence encoding of the memory of behavioral sequences, providing the cognitive map formation. In this article, we summarize the theoretical neural dynamics of the real-time sequence encoding by theta phase precession, called theta phase coding, and review a series of theoretical models with the theta phase coding that we previously reported. With respect to memory encoding functions, instantaneous memory formation of one-time experience was first demonstrated, and then the ability of integration of memories of behavioral sequences into a network of the cognitive map was shown. In terms of memory retrieval functions, theta phase coding enables the hippocampus to represent the spatial location in the current behavioral context even with ambiguous sensory input when multiple sequences were coded. Finally, for utilization, retrieved temporal sequences in the hippocampus can be available for action selection, through the process of reverting theta rhythm-dependent activities to information in the behavioral time scale. This theoretical approach allows us to investigate how the behavioral sequences are encoded, updated, retrieved and used in the hippocampus, as the real-time interaction with the external environment. It may indeed be the bridge to the episodic memory function in human hippocampus.     

Effects of methoxsalen from Poncirus trifoliata on acetylcholinesterase and trimethyltin-induced learning and memory impairment

Previously, we identified methoxsalen (8-methoxy-2',3',6,7-furocoumarin) as the bioactive compound probably responsible for acetylcholinesterase (AchE) inhibition achieved by feeding crude extract of Poncirus trifoliate. To confirm the activity of methoxsalen, Institute of Cancer Research (ICR) mice were fed a control or a methoxsalen-supplemented diet for 4 weeks, and then learning and memory enhancing effects with respect to trimethyltin (TMT)-induced neurotoxicity were evaluated. The brain tissues of ICR mice were dissected after completion of the behavioral tests for biochemical analysis. Methoxsalen effectively reversed TMT-induced memory impairment on both Y-maze and passive avoidance tests. Brain AchE activity was inhibited by the oral consumption of all concentrations of methoxsalen. Moreover, the level of oxidative stress was significantly ameliorated in the groups on methodsalen containing diets. This is the first in vivo study conducted with methoxsalen in the field of AD research, and it indicates that further investigation of methoxsalen is warranted.     

An analysis of D-amphetamine produced facilitation of avoidance acquisition in rats and performance changes subsequent to drug termination

In Experiment I rats were trained on a discriminated Y-maze active avoidance task following administration of saline or one of three dosages (.75, 1.50 or 3.0 mg/kg) of d-amphetamine. The six measures recorded simultaneously during each session indicated that the avoidance facilitation produced by d-amphetamine was due to attenuation of shock-induced behavioral suppression resulting in a behavioral baseline more compatible with the animal's associating running with shock avoidance. Results from Experiment II showed that the avoidance decrement following drug termination is dependent on training dosage and whether the drug is abruptly or gradually withdrawn. This experiment further suggested that the disruption is due to dissociation between the drug and non-drug states and could be attenuated by gradually withdrawing the drug over training sessions.     

Effects of Methoxsalen from Poncirus trifoliata on Acetylcholinesterase and Trimethyltin-Induced Learning and Memory Impairment

Previously, we identified methoxsalen (8-methoxy-2′,3′,6,7-furocoumarin) as the bioactive compound probably responsible for acetylcholinesterase (AchE) inhibition achieved by feeding crude extract of Poncirus trifoliate. To confirm the activity of methoxsalen, Institute of Cancer Research (ICR) mice were fed a control or a methoxsalen-supplemented diet for 4 weeks, and then learning and memory enhancing effects with respect to trimethyltin (TMT)-induced neurotoxicity were evaluated. The brain tissues of ICR mice were dissected after completion of the behavioral tests for biochemical analysis. Methoxsalen effectively reversed TMT-induced memory impairment on both Y-maze and passive avoidance tests. Brain AchE activity was inhibited by the oral consumption of all concentrations of methoxsalen. Moreover, the level of oxidative stress was significantly ameliorated in the groups on methodsalen containing diets. This is the first in vivo study conducted with methoxsalen in the field of AD research, and it indicates that further investigation of methoxsalen is warranted.     

Features of rat behavior associated with alternative choice in Y-maze and their interpretation in terms of complex probability amplitudes

The two-way alternative avoidance of a weak electric shock by male Wistar rats in Y-maze was studied. The following behavioral characteristics of a rat were determined in each test series: total time of an arm choice (going away into one of two safe maze arms), number and sequence of alternate turnings to the outlets in the process of choice, time of immobility in the Y-maze center, and "freezing" reaction. Rat behavior of choice of safe arms in Y-maze be interpreted on the basis of the rules of summation of complex probability amplitudes, which characterize a predictive estimation of achievement by a rat of its relative safety. With the need to avoid an electric shock, rat's estimations of suitabilities of two different avoidance ways can interfere. This makes it difficult for an animal to take a choice decision (if both pathways are equally acceptable for a rat). After entering a safe arm, sometimes a rat can leave it for another arm, such passages occur quasiperiodically.     

Blockage of glucocorticoid receptors during memory acquisition, retrieval and reconsolidation prevents the expression of morphine-induced conditioned place preferences in mice

Association between the reward caused by consuming drugs and the context in which they are consumed is essential in the formation of morphine-induced conditioned place preference (CPP). Glucocorticoid receptor (GRs) activation in different regions of the brain affects reward-based reinforcement and memory processing. A wide array of studies have demonstrated that blockage of GRs in some brain areas can have an effect on reward-related memory; however, to date there have been no systematic studies about the involvement of glucocorticoids (GCs) in morphine-related reward memory. Here, we used the GR antagonist RU38486 to investigate how GRs blockage affects the sensitization and CPP behavior during different phases of reward memory included acquisition, retrieval and reconsolidation. Interestingly, our results showed RU38486 has the ability to impair the acquisition, retrieval and reconsolidation of reward-based memory in CPP and sensitization behavior. But RU38486 by itself cannot induce CPP or conditioned place aversion (CPA) behavior. Our data provide a much more complete picture of the potential effects that glucocorticoids have on the reward memory of different phases and inhibit the sensitization behavior.     

Effect of forced swimming on the memory track retention in mice with various behavioral stereotypes

The effects of forced swimming on retrieval of the passive avoidance during its extinction were found to depend on aggressive and submissive behavior. In mice without generated behavioral stereotypes, swim stress applied before or after training stabilized retention of the memory trace retrieval. The similar improved influence of forced swimming on memory storage is revealed in submissive, but not aggressive mice. The increase of resistance against extinction under the swim stress can be connected to facilitation of emotional processes.     

长期注射吗啡对戒断后小鼠Y－迷宫空间识别记忆的影响

使用急性成瘾性药物会影响大脑功能,随着药物使用时间的延长,这种影响更加广泛、持久,并且在药物戒断后的很长时间内依然存在。实验表明,急性及短期吗啡给予小鼠和戒断均损伤了其Y迷宫空间识别记忆能力,但这种损伤短暂且可逆。本实验小鼠被连续注射吗啡（40 mg/kg•day,i p）或生理盐水21天,利用Y迷宫来检测长期吗啡给予后在戒断第2、9和19天,吗啡对小鼠空间识别记忆的影响。结果表明, 连续吗啡给予21天后,在戒断第2、9和19天,小鼠Y迷宫空识别记忆能力均受到损伤,提示长期给予小鼠吗啡会导致其空间识别记忆能力的长期损伤。     

Slow Potentials in the Rhinal Region of the Cat Brain Cortex Related to Visual Recognition Memory

We examined correlation between the development of slow potentials in the rhinal cortical region of cats and results of behavioral testing of visual recognition memory of these animals in the “delayed nonmatching-to-sample” (DNMS) selection version. Among different types of cognitive memory, the recognition memory occupies a special position because the process of taking off (retrieval) of a memory trace from the “stores” can be completely and effectively controlled by the experimenter (this process is initiated only after repetitive presentation of a stimulus identical to that whose trace should be subjected to retrieval or after presentation of an absolutely new stimulus whose trace had not been formed earlier). Recording of the field potentials was performed from the surface of the rhinal cortex using stereotaxically implanted mono- or bipolar Ag-AgCl electrodes after the experimental animals reached a sufficiently high level of successful performance of the test for recognition memory. Analysis of relations between negative slow potentials in the rhinal cortex and the correctness of performance (according to Spearman’s nonparametric test) demonstrated the existence of significant correlation between the electrophysiological and behavioral indices of visual recognition memory only within a late portion (final 10 sec but not initial 10 ones) of the retention interval for memorizing the trace of single presentation of a visual stimulus. The data obtained are interpreted as a confirmation of the existence of correlation between generation of negative slow potentials in the rhinal cortical region and the process of retrieval of the sample from the visual memory stores.     

Comparative analysis of haloperidol effects on passive avoidance retention in aggressive and submissive mice

The effects of haloperidol on retention of avoidance during its extinction in C57BL/6J mice were shown to depend on a behavioral stereotype (aggressive or submissive). In submissive mice, haloperidol (0.5 mg/kg) injected an hour before training stabilized retrieval of the conditioned reflex in repeated testings (up to 17 days) as compared to its fast extinction in control animals. In aggressive mice, on the contrary, haloperidol reduced the retention of the memory trace retrieval. It is suggested that divergent haloperidol effects on extinction of passive avoidance in mice with alternative behavioral strategies are determined by the features of organization of the mesolimbico-cortical dopaminergic system and emotional state, in particular, anxiety.     

Nicotine-induced memory impairment by increasing brain oxidative stress

Male Wistar rats were subjected to chronic nicotine treatment (0.3 mg/kg; 7 continuous days) and their memory performance was studied by means of Y-maze and multi-trial passive avoidance tasks. Nicotine significantly decreased spontaneous alternation in Y-maze task and step-through-latency in the multi-trial passive avoidance task, suggesting effects on both short-term memory and long-term memory, respectively. In addition, nicotine induced neuronal apoptosis, DNA fragmentation, reduced antioxidant enzymes activity, and increased production of lipid peroxidation and reactive oxygen species, suggesting pro-oxidant activity. Our results provide further support that nicotine-induced memory impairment is due to an increase in brain oxidative stress in rats.     

Task and content modulate amygdala-hippocampal connectivity in emotional retrieval

The ability to remember emotional events is crucial for adapting to biologically and socially significant situations. Little is known, however, about the nature of the neural interactions supporting the integration of mnemonic and emotional information. Using fMRI and dynamic models of effective connectivity, we examined regional neural activity and specific interactions between brain regions during a contextual memory retrieval task. We independently manipulated emotional context and relevance of retrieved emotional information to task demands. We show that retrieval of emotionally valenced contextual information is associated with enhanced connectivity from hippocampus to amygdala, structures crucially involved with encoding of emotional events. When retrieval of emotional information is relevant to current behavior, amygdala-hippocampal connectivity increases bidirectionally, under modulatory influences from orbitofrontal cortex, a region implicated in representation of affective value and behavioral guidance. Our findings demonstrate that both memory content and behavioral context impact upon large scale neuronal dynamics underlying emotional retrieval.     

Typological features of behavior and memory in Norway rats selected for absence of aggression toward a man

Features of behavior and retrieval of passive conditioned avoidance on a new and forgotten stimuli were compared in Wistar rats and Norway rats bred for the absence of aggression toward a man. As distinct from white rats, grey rats were characterized by low anxiety and high locomotor exploratory activity in the elevated plus maze and dark-light chamber. Norway rats demonstrated better avoidance performance with active defensive behavioral strategy than Wistar rats. Latent inhibition during conditioning with a previously forgotten situational stimulus was the same in both rat strains. The results are discussed in terms of the use of grey rats as a model for an in-depth analysis of the mechanisms of memory optimization.     

Behavioral determination of stimulus pair discrimination of auditory acoustic and electrical stimuli using a classical conditioning and heart-rate approach

Acute animal preparations have been used in research prospectively investigating electrode designs and stimulation techniques for integration into neural auditory prostheses, such as auditory brainstem implants and auditory midbrain implants. While acute experiments can give initial insight to the effectiveness of the implant, testing the chronically implanted and awake animals provides the advantage of examining the psychophysical properties of the sensations induced using implanted devices. Several techniques such as reward-based operant conditioning, conditioned avoidance, or classical fear conditioning have been used to provide behavioral confirmation of detection of a relevant stimulus attribute. Selection of a technique involves balancing aspects including time efficiency (often poor in reward-based approaches), the ability to test a plurality of stimulus attributes simultaneously (limited in conditioned avoidance), and measure reliability of repeated stimuli (a potential constraint when physiological measures are employed). Here, a classical fear conditioning behavioral method is presented which may be used to simultaneously test both detection of a stimulus, and discrimination between two stimuli. Heart-rate is used as a measure of fear response, which reduces or eliminates the requirement for time-consuming video coding for freeze behaviour or other such measures (although such measures could be included to provide convergent evidence). Animals were conditioned using these techniques in three 2-hour conditioning sessions, each providing 48 stimulus trials. Subsequent 48-trial testing sessions were then used to test for detection of each stimulus in presented pairs, and test discrimination between the member stimuli of each pair. This behavioral method is presented in the context of its utilisation in auditory prosthetic research. The implantation of electrocardiogram telemetry devices is shown. Subsequent implantation of brain electrodes into the Cochlear Nucleus, guided by the monitoring of neural responses to acoustic stimuli, and the fixation of the electrode into place for chronic use is likewise shown.     

Influence of D1 dopamine receptor activation on extinction of passive avoidance and amnesia in aggressive and submissive mice

In mice with aggressive and submissive behavioral stereotypes, passive avoidance retrieval in extinction and amnesia was shown to be differently dependent on the activation of D1 dopamine receptors. In extinction, agonist of D1 receptors SKF 38393 injected before training or on 12-th day of testing in a dose of 5 mg/kg impaired the retrieval of a conditioned habit in aggressive mice and improved the retrieval in submissive mice. The opposite effects of D1 receptor activation depending on stereotype were also observed in a procedure of amnesia. In aggressive mice, SKF 38393 essentially reduced the resistance to amnesic effects characteristic of this stereotype. In submissive mice, SKF 38393 attenuated the amnesic effect of a detention in a dangerous compartment and restored the amnesic memory trace. Possible mechanisms of selective involvement of D1 receptors in retention of memory trace of aversive stimuli during extinction and amnesia in mice with different stereotypes of behavior are discussed.     

Effects of air ions on some aspects of learning and memory of rats and mice

When submitted to a single avoidance task male mice showed different behavioral responses if previously treated with opposite aeroionization polarities. Whereas negative air ions tend to improve learning, positive ions have disturbing effects. Male rats submitted to a single — trial inhibitory avoidance step-through task showed that retention processes may also be influenced by air ions. The positive air-ion-treated animals exhibit signs of impaired short and long term memory. The slightly impaired score of negative air-ion-treated animals seems only dependent upon the simultaneously increased locomotor activity. A separate experiment supported this hypothesis showing conspicuous differential effects of air ion polarity on spontaneous activity of male rats. On the basis of these findings and the results of other studies in biological air ion dependence field, the behavioral significance of aero-ionization in learning and memory processes is discussed in relation to serotonin metabolism and other neuroendocrine mechanisms.     

Forgetting, reminding, and remembering: the retrieval of lost spatial memory

Retrograde amnesia can occur after brain damage because this disrupts sites of storage, interrupts memory consolidation, or interferes with memory retrieval. While the retrieval failure account has been considered in several animal studies, recent work has focused mainly on memory consolidation, and the neural mechanisms responsible for reactivating memory from stored traces remain poorly understood. We now describe a new retrieval phenomenon in which rats' memory for a spatial location in a watermaze was first weakened by partial lesions of the hippocampus to a level at which it could not be detected. The animals were then reminded by the provision of incomplete and potentially misleading information—an escape platform in a novel location. Paradoxically, both incorrect and correct place information reactivated dormant memory traces equally, such that the previously trained spatial memory was now expressed. It was also established that the reminding procedure could not itself generate new learning in either the original environment, or in a new training situation. The key finding is the development of a protocol that definitively distinguishes reminding from new place learning and thereby reveals that a failure of memory during watermaze testing can arise, at least in part, from a disruption of memory retrieval.     

From spreading depression to spatial cognition

The Laboratory of Neurophysiology of Memory started its existence in 1954 by systematic research into spreading depression of EEG activity of laboratory rodents and by the use of this remarkable phenomenon as a functional ablation method in behavioral research. Its main contributions were in the study of memory formation and consolidation, interhemispheric transfer, motor learning, conditioned taste aversion and spatial orientation and navigation. In the last five years it concentrated on navigation of rats in multiple reference frames, on electrophysiological evidence for the role of hippocampal place cells support of behavior in such dissociated frames, on the analysis of idiothetic and allothetic forms of navigation and on the mathematical methods allowing assessment of the contribution of goal directed locomotion to place cell activity. The methods used in spatial memory research in rats were used for examination of human subjects in a laboratory equipped with a tracking system for humans in the hospital Homolka. Animal models of Alzheimer disease were studied in transgenic mice with the human gene for the beta amyloid precursor protein.