Estradiol enhances DMP acquisition via a mechanism not mediated by turning strategy but which requires intact basal forebrain cholinergic projections

This study examined whether effects on turning strategy, use of an allocentric strategy, and/or short-term spatial memory account for the effects of estradiol treatment on acquisition of a delayed matching-to-position (DMP) T-maze task, in rats with and without basal forebrain cholinergic lesions. Ovariectomized rats received either 192IgG saporin (SAP) or saline injected into the medial septum. Two weeks later, half of each group received either continuous estradiol treatment (5-mm silastic capsule containing 17-beta-estradiol implanted s.c.) or implantation of an empty capsule. All rats were trained on the DMP task. Results show that estradiol enhanced, and SAP lesions impaired, learning on the DMP task. SAP lesions impaired learning primarily by increasing the use of a persistent turning strategy early on during training. In contrast, estradiol had no apparent effect on turning strategy, and enhanced learning only in non-lesioned rats. There was no evidence that any of these effects were due primarily to an effect on ultimate strategy selection (e.g., allocentric vs. egocentric, evaluated with a probe trial in which the maze was rotated 180 degrees), or on short-term spatial memory (evaluated by increasing the intertrial delay). We conclude that estradiol enhances DMP acquisition via a mechanism independent of effects on turning strategy and short-term memory, but nevertheless dependent on cholinergic neurons in the MS and VDB. We hypothesize that estradiol may affect the facility with which female rats are able to extract and incorporate extramaze information into an effective navigational strategy, and that this may be mediated by effects in prefrontal cortex.     

Timing, memory for intervals, and memory for untimed stimuli: The role of instructional ambiguity

Theories of animal timing have had to account for findings that the memory for the duration of a timed interval appears to be dramatically shorted within a short time of its termination. This finding has led to the subjective shortening hypothesis and it has been proposed to account for the poor memory that animals appear to have for the initial portion of a timed interval when a gap is inserted in the to-be-timed signal. It has also been proposed to account for the poor memory for a relatively long interval that has been discriminated from a shorter interval. I suggest here a simpler account in which ambiguity between the gap or retention interval and the intertrial interval results in resetting the clock, rather than forgetting the interval. The ambiguity hypothesis, together with a signal salience mechanism that determines how quickly the clock is reset at the start of the intertrial interval can account for the results of the reported timing experiments that have used the peak procedure. Furthermore, instructional ambiguity rather than memory loss may account for the results of many animal memory experiments that do not involve memory for time.     

Timing, memory for intervals, and memory for untimed stimuli: the role of instructional ambiguity

Theories of animal timing have had to account for findings that the memory for the duration of a timed interval appears to be dramatically shorted within a short time of its termination. This finding has led to the subjective shortening hypothesis and it has been proposed to account for the poor memory that animals appear to have for the initial portion of a timed interval when a gap is inserted in the to-be-timed signal. It has also been proposed to account for the poor memory for a relatively long interval that has been discriminated from a shorter interval. I suggest here a simpler account in which ambiguity between the gap or retention interval and the intertrial interval results in resetting the clock, rather than forgetting the interval. The ambiguity hypothesis, together with a signal salience mechanism that determines how quickly the clock is reset at the start of the intertrial interval can account for the results of the reported timing experiments that have used the peak procedure. Furthermore, instructional ambiguity rather than memory loss may account for the results of many animal memory experiments that do not involve memory for time.     

昆明小鼠物体识别模型的建立及其在检测化学药物对记忆损伤中的应用

本研究的主要目的是建立昆明小鼠物体识别模型并评价该模型在安全药理学研究中的潜在应用价值。研究了昆明小鼠物体识别记忆随时间而减弱的特性,在训练结束后4h或1h,检测昆明小鼠的物体识别记忆,并评价了东莨胆碱对昆明小鼠物体识别记忆的影响。结果表明:1h间隔组昆明小鼠熟悉期探究物体的时间差和测试期探究物体的时间差存在显著差异(P<0.05),昆明小鼠在训练结束后1h记忆保持良好,可以进行物体识别;东莨胆碱组昆明小鼠熟悉期探究物体的时间差和测试期探究物体的时间差比较(P>0.05),没有显著性差异。因此,东莨胆碱损伤了昆明小鼠的物体识别记忆。用昆明小鼠建立的物体识别模型具有简单、快速、可靠等特点,在安全药理学研究中可用于检测化学药物对记忆的损伤。     

Features of the formation and dynamics of short-term image memory in the rat

Direct and indirect methods of delayed reactions showed that short-term image memory of rats elaborated on the basis of conditioned signals in poorly developed and its duration is not more than 1 s. While testing this memory, changes in the behaviour were seen, pointing to the development of "hard state" in the higher nervous activity of animals. Short-term image memory based on complex perception was shown to be well developed in rats, and by many characteristics it approximated to the memory of highly organized animals. The ability to reproduce the short-term image memory on the basis of conditioned signals is supposed to be a complex form of psychonervous activity of animals, and in rodents it appears to be at an initial stage of development.     

Social isolation improves working memory at reversal but not primary radial-arm maze learning in rats

Social isolation starting from the 21st day of birth affected neither a short-term nor a long-term memory in male rats at primary acquisition learning in an 8-arm radial maze. A number of the short-term and long-term memory errors were substantially decreased during primary learning but the difference between groups was not significant. Isolates were faster to start a search in an individual trial and took less time to finish offa trial. During the reversal learning, when baited and non-baited arms were reversed, the isolates outperformed of socially reared rats on working but not reference memory task. In overall they made twice less working memory errors than socially reared animals. During the reversal learning the isolates were also faster than non-isolates in initiation and completion of a trial. Maternal separation of rat's pups on the postnatal days 1-21 for 4 hr per day did not affect either working or reference memory on both primary and reversal learning. The data obtained are discussed on basis of influence of stress in early postnatal life on hypothalamo-pituitary axis and its effects on behavior of adult animals.     

Computer simulation of pigeons' performance on a spatial memory task

Delayed matching of key location is a useful paradigm for the study of pigeons' short-term memory for a spatial location. On each trial a randomly selected key from a matrix of keys is lit briefly as a sample and followed by a retention interval. During the ensuing choice period the sample and one of the non-sample keys are lit; choice of the sample is correct and rewarded whereas choice of the distractor key is not. The computer simulation of performance on this task is based on a simple model: We assume that the pigeon has knowledge of the location of the keys stored in a map-like reference memory. We also assume that short-term memory involves an attention focus or “pointer” that “drifts” on the surface of this map. The pointer migrates from a randomly determined position during the intertrial interval towards the location of the sample when this stimulus is presented. It wanders randomly from its previous position when this cue is no longer present in the retention interval. During the test for retention the bird selects the location (i.e., sample or distractor) closer to the location of the pointer on the map of the matrix. The simulation successfully reproduced several of the phenomena observed in delayed matching of location experiments and provided an account of some hitherto perplexing results. As well, the model successfully predicted some new empirical data.     

DNA methylation mediates the discriminatory power of associative long-term memory in honeybees

Memory is created by several interlinked processes in the brain, some of which require long-term gene regulation. Epigenetic mechanisms are likely candidates for regulating memory-related genes. Among these, DNA methylation is known to be a long lasting genomic mark and may be involved in the establishment of long-term memory. Here we demonstrate that DNA methyltransferases, which induce and maintain DNA methylation, are involved in a particular aspect of associative long-term memory formation in honeybees, but are not required for short-term memory formation. While long-term memory strength itself was not affected by blocking DNA methyltransferases, odor specificity of the memory (memory discriminatory power) was. Conversely, perceptual discriminatory power was normal. These results suggest that different genetic pathways are involved in mediating the strength and discriminatory power of associative odor memories and provide, to our knowledge, the first indication that DNA methyltransferases are involved in stimulus-specific associative long-term memory formation.     

Memory of a choice direction in a T maze as measured by spontaneous alternation in mice: Effects of intertrial interval and reward

Spontaneous alternation in a T maze was studied as a one trial learning paradigm in mice of the BALB/c strain. In the first experiment the combined effects of time interval between the first and second trial (intertrial interval: ITI), food deprivation and feeding given during the first trial, were shown to affect performance. Thus, on the one hand, the percentage of spontaneous alternation decreased as ITI increased; on the other hand, food reward dramatically improved spontaneous alternation for the 24-h ITI, but had no significant effect for 30-sec and 1-h ITI. Since the effect of feeding might be due either to an increase of arousal, thus favoring input of informations associated with the first choice, or to an improvement in memory consolidation, a second experiment was aimed at testing the effect of food given after the first trial. It was shown that, as in the first experiment, post-trial feeding improved spontaneous alternation on the second trial given 24 hours later with a temporal gradient of effect less than 30 min. These results clearly showed that the reinforcement of run to one side (first trial) increased the tendency to go to the other side 24 hours later. It is concluded that reinforcement might have two distinct effects: (i) according to SR theory, reinforcement increases conditioned responses and (ii), as shown here, acts on memory processes by preventing memory traces from fading. The fact that this last effect was only observed for long ITI suggests that short-term or transient memory and long-term memory are two relatively independent processes.     

Influence of partial intraspecies deprivation on short-term image-driven memory in rats

Behavior and short-term memory function were studied in adult rats risen under conditions of partial intraspecies social deprivation. Testing of delayed responses (and emotional state) showed that the partial deprivation of intraspecies communication at the early stage of postnatal ontogeny led not only to disorders of short-term memory in the adult rats, but also to behavioral alterations, which may be due to impaired development of the regulatory mechanisms of motivation and emotions.     

Alpha1-adrenergic receptor antagonist tamsulosin ameliorates aging-induced memory impairment by enhancing neurogenesis and suppressing apoptosis in the hippocampus of old-aged rats

Age-related memory decline is closely associated with decreased neurogenesis and increased apoptosis in the hippocampus. Noradrenaline exerts its effect by selectively binding to and activating adrenergic receptors (ARs). Tamsulosin, α₁-AR antagonist, is reported to have access to the brain and interact with α₁-AR. In this study, the effects of tamsulosin on short-term and spatial learning memory in terms of neurogenesis and apoptosis were investigated using rats. Step-down avoidance test for short-term memory and radial 8-arm maze test for spatial learning memory were conducted. Neurogenesis was detected by 5-bromo-2’-deoxyuridine (BrdU) immunohistochemistry and apoptosis was evaluated by caspase-3 immunohistochemisty and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNE) staining. Western blot for protein kinase C (PKC), cAMP-responsive element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), tyrosine kinase B (TrkB), phosphatidylinositol 3-kinase (PI 3-kinase), Akt, Bcl-2, and Bax was conducted. In the aged rats, short-term and spatial learning memory was declined. Hippocampal nerogenesis was suppressed and hippocampal apoptosis was enhanced in the aged rats. In addition, phosphorylation of PKCα, CREB, PI-3 kinase, and Akt was decreased in the hippocampus of old-aged rats. Tamsulosin activated PKC/CREB and PI-3 kinase/Akt pathways. With these pathways, BDNF-TrkB signaling enhanced hippocampal neurogenesis and suppressed apoptosis in the old-aged rats. As the results, tamsulosin improved performance of short-term and spatial learning memory in the aged rats.     

RNA interference in hippocampus demonstrates opposing roles for CREB and PP1α in contextual and temporal long-term memory

We injected small interfering RNAs (siRNAs) directly into the hippocampus of wild-type mice, knocking down expression of cyclic AMP responsive element-binding protein (CREB) and disrupting long-term, but not short-term, memory after both contextual and trace fear conditioning. In contrast, similar knockdown of siRNA for protein phosphatase 1 (PP1) was sufficient to enhance contextual and temporal memory formation, thereby demonstrating with such a gain-of-function effect a lack of any general deleterious effect for this method of RNAi-mediated gene knockdown. Our findings clearly confirm that contextual memory formation involves CREB and PP1 as positive and negative regulators, respectively, and show for the first time that temporal memory formation shares this mechanism. More generally, we establish that direct injection of siRNA into identified adult brain regions yields specific gene knockdowns, which can be used to validate in vivo candidate genes involved in behavioral plasticity.     

Effects of the neurogenesis stimulator Ro 25-6981 upon formation of spatial skill in adult rats depend on the term of its administration and the animals' ability to learn

Effect of administration of selective N-methyl-D-aspartate (NMDA) receptor antagonist Ro 25-6981 on learning and memory in a dose which is known to stimulate neoneurogenesis was assessed in adult rats with different abilities to formation of spatial skills in different time periods after the antagonist injection. Wistar male rats were trained to find hidden platform in the Morris water maze for 5 consecutive days. Rats' learning ability for spatial skill formation was evaluated depending on platform speed achievements. In re-training sessions (cues and platform location changed), it was found that all rats received Ro 25-6981 13 days before the re-training demonstrated impaired spatial memory. At the same time the inhibitor injected 29 days before re-training selectively facilitated the formation of spatial skill in animals with initially low learning abilities.     

Effect of sexual steroids and androgen sterilization on avoidance and exploratory behaviour in the rat

The effect on avoidance and exploratory behavior of large doses of sexual steroids or of changes in ovarian steroid secretion induced by gonadotropin treatment or androgen sterilization was studied in female R-Amsterdam rats. Estrogen, progesterone, testosterone, androgen sterilization, and human chorionic gonadotropin (HCG) effects were tested and evaluated. Estrogen in castrated female rats delayed extinction of the conditioned avoidance response from Day 8 of extinction and increased intertrial activity during extinction. Estrogen treatment applied from extinction was ineffective. Progesterone treatment of castrated female rats applied from the first days of conditioning delayed extinction from Day 12. If the treatment was begun at extinction, this was delayed after Day 8. Intertrial activity was also higher between Day 8 and Day 15 of extinction. Testosterone treatment of castrated male rats increased intertrial activity during acquisition. In the animals treated from extinction, a delay was observed from Day 9, and intertrial activity was increased simultaneously. In androgen-sterilized female rats, extinction was facilitated. HCG treatment of intact female rats delayed the extinction. The steroids used failed to affect the exploratory activity of castrated rats, indicating that, under the conditions tested, general activity and exploratory activity are not motivated by the same mechanism.     

The Role of non-NMDA-Receptors in the Process of Associative Learning in the Honeybee Apis mellifera

Pharmacological parameters of non-NMDA-receptors and their participation in the associative learning in the honeybee Apis mellifera L. have been studied using the method of conditional reflexes and pharmacological analysis. The effect of 1-amino-3-hydroxy-5-methyl, 4-isoxazolprpionate (AMPA), kainate, domoate, antagonist of AMPA-receptors NS-257 HCl and modulator of AMPA-receptors cyclothiazide was studied on retention of the elaborated conditional reflex in short- and long-term memory. It was shown that AMPA-receptors, but not kainate receptors, are involved in the process of formation of short-term memory and are characterized by pharmacological profile similar with that in molluscs. Coactivation of AMPA- and NMDA-receptors is considered as one of possible mechanisms of formation of short-term memory in the honeybee.     

Voluntary exercise impairs initial delayed spatial alternation performance in estradiol treated ovariectomized middle-aged rats

Estrogens differentially modulate behavior in the adult female rodent. Voluntary exercise can also impact behavior, often reversing age associated decrements in memory processes. Our research group has published a series of papers reporting a deficit in the acquisition of an operant working memory task, delayed spatial alternation (DSA), following 17β-estradiol treatment to middle-aged ovariectomized (OVX) rats. The current study examined if voluntary exercise could attenuate the 17β-estradiol induced deficits on DSA performance. OVX 12-month old Long–Evans rats were implanted with a Silastic capsule containing 17β-estradiol (10% in cholesterol: low physiological range) or with a blank capsule. A subset of the 17β-estradiol and OVX untreated rats were given free access to a running wheel in their home cage. All rats were tested for 40 sessions on the DSA task. Surprisingly, we found running wheel access to impair initial acquisition of the DSA task in 17β-estradiol treated rats, an effect not seen in OVX untreated rats given running wheel access. This deficit was driven by an increase in perseverative responding on a lever no longer associated with reinforcement. We also report for the first time a 17β-estradiol induced impairment on the DSA task following a long intertrial delay (18-sec), an effect revealed following more extended testing than in our previous studies (15 additional sessions). Overall, running wheel access increased initial error rate on the DSA task in 17β-estradiol treated middle-aged OVX rats, and failed to prevent the 17β-estradiol induced deficits in performance of the operant DSA task in later testing sessions.     

The dynamics of neuronal,autonomic and movement parameters in animals during the reproduction of a learned habit

Data by the authors, as well as from other laboratories, show that the intertrial responses correlated with accuracy of avoidance or feeding behaviour. Moreover our previously data demonstrated the definite changes of neuronal activity, heart rate and respiration during intertrial responses. In this study we investigated the time-course of intertrial response appearance, the pattern of neurophysiological parameters during intertrial periods, and the types of intertrial responses. Experiment 1 showed that different environmental stimuli influenced the level of intertrial responses and successfulness of the avoidance learning. In experiment 2, in which learning and extinction procedures were presented in rabbit passive-avoidance conditioning, two types of intertrial responses were observed; the first type repeated the pain reinforcement, the second one imitated the conditioned reaction of neuronal activity, heart rate, respiration, and moving. These investigations suggest that the processes of intertrial eliciting of avoidance effector programs may be one of the mechanisms of fixation in memory and play an important role in acquisition of more effective results.     

The influence of combinations of encoded amino acids on associative learning in the honeybee <Emphasis Type="Italic">Apis mellifera</Emphasis> L.

This study addresses the influence of combinations of two encoded amino acids with opposite, memory-inhibiting and memory-enhancing, effects on short-term and long-term memory formation in the honeybee. Experimentation was based on the classical proboscis extension response conditioning by a single-trial exposure to clove odor with a sucrose solution reward. The presence of the acquired conditioned response was tested 1 min (short-term memory) and 180 min (long-term memory) after the learning trial. The data obtained suggest a stimulatory (memory-enhancing) effect of the combination of two amino acids, individual effects of which are opposite. The stimulatory amino acid was present in the mixture in all the trials (8 combinations) at a subthreshold concentration, i.e. it did not influence memory formation. In some trials, the stimulatory effect of an amino acid mixture (for example, stimulatory aspartic acid combined with inhibitory lysine or serine) significantly exceeded that of a single stimulatory amino acid applied at a threshold concentration. Interestingly, the effect of amino acid combinations on memory formation in honeybees resembles their effect on cell proliferation in rat tissue explants of various origin.     

Intrahippocampal infusion of the bombesin/gastrin-releasing peptide antagonist RC-3095 impairs inhibitory avoidance retention

Bombesin (BN)-like peptides regulate cell proliferation and cancer growth as well as neuroendocrine and neural functions. We evaluated the effects of the BN/gastrin-releasing peptide (GRP) antagonist RC-3095 on memory formation. Male Wistar rats were given a bilateral infusion of saline or RC-3095 (0.2, 1.0 or 5.0 microg) into the dorsal hippocampus either immediately or 2 h after training in an inhibitory avoidance (IA) task. Retention test trials were carried out 1.5 h (short-term memory) and 24 h (long-term memory) after training. RC-3095 impaired both short- and long-term retention only when given immediately after training. The results suggest that the hippocampal BN/GRP receptor system modulates IA memory formation.