Strain-dependent differences in LTP and hippocampus-dependent memory in inbred mice

Many studies have used "reverse" genetics to produce "knock-out" and transgenic mice to explore the roles of various molecules in long-term potentiation (LTP) and spatial memory. The existence of a variety of inbred strains of mice provides an additional way of exploring the genetic bases of learning and memory. We examined behavioral memory and LTP expression in area CA1 of hippocampal slices prepared from four different inbred strains of mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms-+(Ter?)/J. We found that LTP induced by four 100-Hz trains of stimulation was robust and long-lasting in C57BL/6J and DBA/2J mice but decayed in CBA/J and 129/SvEms-+(Ter?)/J mice. LTP induced by one 100-Hz train was significantly smaller after 1 hr in the 129/SvEms-+(Ter?)/J mice than in the other three strains. Theta-burst LTP was shorter lasting in CBA/J, DBA/2J, and 129/SvEms-+(Ter?)/J mice than in C57BL/6J mice. We also observed specific memory deficits, among particular mouse strains, in spatial and nonspatial tests of hippocampus-dependent memory. CBA/J mice showed defective learning in the Morris water maze, and both DBA/2J and CBA/J strains displayed deficient long-term memory in contextual and cued fear conditioning tests. Our findings provide strong support for a genetic basis for some forms of synaptic plasticity that are linked to behavioral long-term memory and suggest that genetic background can influence the electrophysiological and behavioral phenotypes observed in genetically modified mice generated for elucidating the molecular bases of learning, memory, and LTP.     

Strain-dependent modulation of memory by stress in mice

The effects of immobilization stress were investigated in Swiss Webster (Swiss), DBA/2 (DBA), and C57BL/6 (C57) mice, tested in a passive avoidance situation. Retention performance was impaired in Swiss and DBA mice, and improved in C57 mice, immobilized immediately, but not 2 hr, after training. These effects lasted for less than 7 days in DBA and Swiss mice, while they were still present, in the C57 strain, 14 days after training. The naloxone antagonism of the effects observed was also demonstrated. The results are discussed in terms of the possible role of endogenous opioids, stress hormones, and genetic makeup in the stress-induced modulation of memory processes in the mouse.     

Hemispheric processing differences revealed by differential conditioning and reaction time performance.

Two different experimental procedures were used to examine (a) information-processing differences between two groups of subjects (Cs versus Vs) identified by the form of their conditioned eyeblinks; (b) information-processing differences between the right and left cerebral hemispheres; and (c) parallels between hypothesized C-V differences and right-left hemisphere differences. In the first experiment, the evocative command words BLINK and DON'T BLINK served as positive and negative conditioned stimuli. It was found that Vs gave more conditioned eyeblinks than Cs and that differential eyelid conditioning of Vs more than Cs was influenced by the semantic content of the stimuli. More importantly, the conditioning performance of Cs was more influenced by the semantic attributes of the stimuli when they were presented directly to the right visual field (left hemisphere) than when they were presented directly to the left visual field (right hemisphere). In contrast, the conditioning performance of Vs was equally influenced by the semantic attributes regardless of which hemisphere received direct stimulation. A second experiment was designed to determine whether such hemisphere-of-presentation differences for Cs versus Vs could also be obtained in a very different task. Subjects classified as Cs or Vs during a differential eyelid conditioning task then performed two same-different reaction time (RT) tasks that required discrimination of complex polygons in one case and the names of letters in another. On each RT trial both stimuli of a pair appeared briefly either in the center, left, or right visual field. For both Cs and Vs RTs to complex polygon pairs averaged 20 msec faster on left visual field trials than on right visual field trials, consistent with current hypotheses about right-hemisphere specialization for visuospatial processing. In contrast, the results for letter pairs generally confirmed the C-V differences found in Experiment 1. That is, the right visual field (left-hemisphere) advantage for these verbal stimuli was once again larger for Cs than for Vs. The present results suggest that the two groups of subjects (Cs versus Vs) differ qualitatively in the modes of information processing that they typically employ. The results also suggest that these different modes of processing are related to aspects of cerebral hemisphere organization and that even right-handed individuals may differ from each other in the extent to which each cerebral hemisphere is mobilized for a given experimental task. Such individual differences must be incorporated into both models of classical eyelid conditioning and models of cerebral hemisphere specialization.     

Sex differences in chronic stress effects on memory in rats

Recent studies in rodent models and in humans have shown that the status of both the gonadal and adrenal axes (hypothalamic-pituitary-gonadal, HPG and hypothalamic-pituitary-adrenal, HPA, respectively) can influence learning and memory function. In this article, the effects of activating the HPA axis (stress) on performance of memory tasks in rats are reviewed. More importantly, results are presented which show that chronic stress has a different impact on performance of these tasks depending upon the sex of the rat. These observations are novel and potentially important since few studies, animal or human, have utilized females as subjects in studies of the stress response. Sex differences in the effects of chronic stress on memory were investigated in rats using an object recognition task and two spatial memory tasks, radial arm maze and object location. Given the same chronic stress--21 days of restraint for 6 h each day--males were impaired in all of the memory tests while females showed enhanced performance of the spatial memory tasks and no changes in object recognition performance. Levels of neurotransmitters and metabolites were measured in brain areas important for cognition in the subjects in order to determine neural systems that may respond to stress and mediate the cognitive responses. These results show that responses of monoamine and amino acid containing neural systems may contribute to or underlie sex differences in stress effects on cognition. Stress decreased dopaminergic activity in the frontal cortex and amygdala of males but not females; whereas, in CA3 of the hippocampus, stress increased levels of 5-HT and norepinephrine in females, but not males, and increased GABA in males, but not females. Finally, a possible role for estradiol in mediating sexually differentiated responses to stress was examined. Behavioral and neurochemical evaluations in ovariectomized, stressed females, with or without estrogen replacement, suggest that sex differences in response to stress are influenced by both the organizing and activating effects of estradiol. A few, recent studies in humans, that show sexually dimorphic relationships between chronic stress and cognition, are also highlighted. These results in humans are consistent with the pattern of results in rats. Clearly, further studies are necessary to substantiate sex differences in stress effects on memory function in humans and to understand mechanisms whereby estrogen may influence the stress response in rats. Nonetheless, recent studies show sexually differentiated cognitive responses to chronic stress and underline the importance of considering the sex/gender of subjects when studying the stress response.     

Catecholamine depletion in mice upon reexposure to stress: mediation of the escape deficits produced by inescapable shock

Immediately following exposure to 60 inescapable shocks, Swiss-Webster mice had significantly reduced hypothalamic norepinephrine (NE). Within 24 hr NE levels returned to control values. Reexposure to as few as 10 shocks 24 hr after initial stress exposure resulted in a significant decline of hypothalamic NE. Moreover, at this interval after inescapable shock, escape performance was severely disrupted, with a large proportion of mice exhibiting numerous failures to escape shock. Increasing brain dopamine (DA) and NE by L-dopa treatment prior to inescapable shock prevented the escape deficits. Conversely, pairing five inescapable shocks with NE depletion by FLA-63, or both DA and NE depletion by alpha-methyl-p-tyrosine, disrupted escape performance 24 hr later. Residual drug effects, state dependence, or sustained amine turnover could not account for the behavioral changes observed. Data are discussed in terms of catecholamine mediation of escape performance through variations in response maintenance abilities. Furthermore, it is suggested that the long-term effects of inescapable shock may be due to sensitization effects or conditioned amine depletion.     

Individual differences in components of reaction time distributions and their relations to working memory and intelligence

The authors bring together approaches from cognitive and individual differences psychology to model characteristics of reaction time distributions beyond measures of central tendency. Ex-Gaussian distributions and a diffusion model approach are used to describe individuals' reaction time data. The authors identified common latent factors for each of the 3 ex-Gaussian parameters and for 3 parameters central to the diffusion model using structural equation modeling for a battery of choice reaction tasks. These factors had differential relations to criterion constructs. Parameters reflecting the tail of the distribution (i.e., tau in the ex-Gaussian and drift rate in the diffusion model) were the strongest unique predictors of working memory, reasoning, and psychometric speed. Theories of controlled attention and binding are discussed as potential theoretical explanations.     

Genetic differences in response to novelty and spatial memory using a two-trial recognition task in mice

A two-trial memory task, based on a free-choice exploration paradigm in a Y-maze, was previously developed to study recognition processes in Sprague-Dawley rats. Because this paradigm avoids the use of electric shock or deprivation that may have nonspecific effects and does not require learning of a rule, it may be particularly useful for studying memory in mice. Four inbred strains (Balb/cByJ, DBA/2J, C57BL/6J, and SJL/J), an F1 hybrid (C57BL/6 x SJL/J), and one outbred strain (CD1) were used to validate this task in mice and to characterize a strain distribution in response to novelty and working memory. Exploration was measured with a short (2 min) intertrial interval (ITI) between acquisition and retrieval, while memory was examined with longer intervals (30 min, 1 h, and 2 h). A study of the time course of the response to novelty revealed varying degrees of preference and/or habituation to novelty among the different strains, with CD1 exhibiting a very high response to novelty and others showing lower (C57 x SJL hybrids) to complete absence (SJL) of exploration of novelty. Memory span, assessed with increasing ITIs, varied widely among strains from 30 min (C57 x SJL hybrids) to at least 2 h (C57 and BALB). Such demonstrated sensitivity to a wide range of behavioral phenotypes supports the use of this spatial memory task as an effective tool for the study of genetic influences on the response to novelty and recognition processes in mice.     

The impact of cortisol reactivity to acute stress on memory: sex differences in middle-aged people

Stress has been identified as a main factor involved in the cognitive changes that occur during the aging process. This study investigated sex differences in the relationship between the magnitude of the acute stress-induced salivary cortisol response and memory performance among middle-aged people. To this end, 16 men and 16 women (aged 54-72 years) were exposed to the Trier Social Stress Test and a control condition in a crossover design. Afterwards their memory performance was measured using a standardized memory test (Rey's Auditory Verbal Learning Test). Only among women, there was an acute impact of stress on memory performance and a significant relationship between a higher cortisol response to the stressor and poorer memory performance in both the stress and control conditions. Additionally, a poorer memory performance was related to earlier timing of sexual maturation (age at menarche), which was also marginally related to higher cortisol reactivity to stress. These results confirm that sex is a critical factor in the relationship between cortisol and poor memory performance. Furthermore, the findings emphasize a strong link between the individual cortisol response to stress and memory functioning among postmenopausal women.     

Gender differences in episodic memory

The relationship between gender and memory has been largely neglected by research, despite occasional studies reporting gender differences in episodic memory performance. The present study examined potential gender differences in episodic memory, semantic memory, primary memory, and priming. Five hundred thirty women and 470 men, randomly sampled from the city of Umeå, Sweden, 35–80 years of age, participated in the study. There were no differences between men and women with regard to age or education, or on a measure of global intellectual functioning. As has been demonstrated previously, men outperformed women on a visuospatial task and women outperformed men on tests of verbal fluency. In addition, the results demonstrated that women consistently performed at a higher level than did men on the episodic memory tasks, although there were no differences between men and women on the tasks assessing semantic memory, primary memory, or priming. The women’s higher level of performance on the episodic memory tasks could not be fully explained by their higher verbal ability.     

Age differences in recognition memory

It is generally believed that short-term memory (STM) performance decreases from maturity to old age, but the present paper questions the generality of this conclusion. The first experiment reported is a short-term recognition probe study—no significant age differences were found in either acquisition or the rate of forgetting. It is suggested that age decrements in STM are limited to situations where attention is divided at input or where the material must be manipulated during storage. Experiment II confirmed previous findings of minimal age losses in secondary memory word recognition. The results of this second study support the conclusion that there is poorer accessibility to stored verbal material with advancing age.     

Intra-list differences in short-term memory

Subjects attempted to recall lists of nine consonants immediately after presentation. Using various recall orders it was found that recall of part of a list interfered with retention of the other parts, memory for items presented early in a list being less affected by such interference than was that for later items. Since this result was not obtained when rate of presentation was increased, it is suggested that rehearsal contributed to the greater stability of early items.     

Age differences in memory span

Five-year-olds recalled fewer items than adults in memory-span tasks involving both familiar and unfamiliar faces. This occurred even though the use of rehearsal and recoding strategies was minimized for adults. This residual age difference may be partially accounted for by two further processing limitations in children. The five-year-olds needed more time than adults to name a face (Experiment 1) and to encode a face (Experiment 2). In order to test whether limitations in children's initial recognition and stimulus-identification processes could account for recall performance, Experiment 3 reduced adults' exposure duration in the memory-span task. This led to a drastic reduction in the age difference. Other factors contributing to remaining age differences included adults' adaptability in using various alternative encoding and retrieval strategies which elevated their recall performance.     

Individual differences in sentence memory

Results from an experiment with two parts are presented in this paper. In part one, participants listened to sentences containing two, three, four, or five clauses, and were asked questions about the content of the sentences. The results of part one demonstrate that an important unit of representation in sentence memory is the clause, and not some other component of discourse structure. In part two, the same group of participants performed eight different short-term storage/working memory tasks. A composite complex span score was computed for each participant based on three working memory tasks closely based on Daneman & Carpenter's (1980) reading span task. This working memory measure was significantly correlated with the participants' performance on the sentence memory task in part one. A second working memory measure—N-back—was also significantly correlated with the participants' performance on the sentence memory task, and there was no correlation between their performance on the complex span task and the N-back task. It is therefore concluded that (i) working memory consists of a number of dissociable components; and (ii) memory for sentences taps into more than one of these working memory components. Furthermore, the high correlations of sentence memory with the complex span and the N-back tasks (neither of which are language processing tasks) suggests that memory for sentences is not simply a result of linguistic experience; rather, it is likely that an independent working memory component contributes to participants' performance on the sentence memory task.     

Sex differences in working memory

In two separate studies, sex differences in modal-specific elements of working memory were investigated by utilizing words and pictures as stimuli. Groups of men and women performed a free-recall task of words or pictures in which 20 items were presented concurrently and the number of correct items recalled was measured. Following stimulus presentation, half of the participants were presented a verbal-based distraction task. On the verbal working-memory task, performance of men and women was not significantly different in the no-distraction condition. However, in the distraction condition, women's recall was significantly lower than their performance in the no-distraction condition and men's performance in the distraction condition. These findings are consistent with previous research and point to sex differences in cognitive ability putatively resulting from functional neuroanatomical dissimilarities. On the visual working-memory task, women showed significantly greater recall than men. These findings are inconsistent with previous research and underscore the need for further research.     

Inter-event differences in action memory

Two experiments examined the effect of verb-noun connectivity on recall of simple action phrases, under motor and nonmotor encoding conditions. Connectivity, measured by associative overlap and rated belongingness, was found to make a difference. High-connectivity pairs are better recalled than low-connectivity pairs. Primacy effects are absent with low-connectivity pairs, but generally present with high-connectivity pairs—irrespective of encoding conditions. Inter-item action phrase differences thus influence the effects studied in action memory research. The results were discussed in terms of strategic and nonstrategic conceptions of memory for actions.     

Latency differences to monochromatic stimuli measured by disjunctive reaction time.

Two studies were done in order to assess the effects of wavelength on visual perceptual latency as measured in a disjunctive RT paradigm. The results of the first study, though not statistically significant, suggested a trend toward shorter RT to longer wavelength stimuli. In the second study, using well-practiced subjects, significant differences were found between disjunctive RT to red and green stimuli. The results suggest that latency differences as a function of wavelength are demonstrable in an experimental situation in which the subject must react to chromatic information, as differentiated from brightness information.     

Sex differences in memory for landmark arrays in C57BL/J6 mice

The most robust sex differences in cognition across polygynous mammalian species are the sex-specific patterns of the use of spatial cues during encoding and orientation. In laboratory rats, wild rodents, and humans, females orient preferentially to the features and arrangement of local landmarks, while males preferentially attend to distant landmarks. Yet this sex-specific pattern is often absent or reversed in the laboratory mouse, a species representing a major laboratory model of neural mechanisms. We explored sex differences in the C57BL/J6 strain of laboratory mouse by employing tasks that were motivated by the natural patterns of exploration. We predicted that such tasks would unmask the predicted default polygynous patterns of cue use by females and males. We used two standard tasks, a novel object recognition task and a five-stage serial object dishabituation task. On the first task, the results showed a female advantage in detecting the novel object, as predicted by prior results from other polygynous species. In the second task, we found, also as predicted, a male advantage in performance when the polarization of the array was distorted and a female advantage in performance when the local array was re-arranged. The pattern of sex-specific advantages in performance in C57BL/J6 mouse is thus concordant with that found in other polygynous mammals.