Estradiol or diarylpropionitrile administration to wild type, but not estrogen receptor beta knockout, mice enhances performance in the object recognition and object placement tasks

Cognitive processes mediated by the hippocampus and cortex are influenced by estradiol (E₂); however, the mechanisms by which E₂ has these effects are not entirely clear. As such, studies were conducted to begin to address the role of actions at the β form of the intracellular estrogen receptor (ERβ) for E₂’s cognitive effects in adult female mice. We investigated whether E₂ improved performance of wild type (WT) and ERβ knockout (βERKO) mice in tasks considered to be mediated by the cortex and hippocampus, the object recognition and object placement tasks. WT and βERKO mice were ovariectomized (ovx) and E₂ (0.1 mg/kg), an ERβ selective ER modulator (SERM), diarylpropionitrile (DPN; 0.1 mg/kg), or oil vehicle was administered to mice following training in these tasks. We hypothesized that if E₂ has mnemonic effects, in part, due to its actions at ERβ, then WT mice administered E₂ or DPN would have improved performance compared to vehicle WT controls, which would not be different from βERKO mice administered vehicle, E₂ or DPN. Alternatively, activation of ERα (with E₂, which is a ligand for both ERα and ERβ) may produce opposing effects on cognition and/or the activation of ERα and ERβ vs. either receptor isoform alone may produce a different pattern of effects. Results obtained supported the hypothesis that ERβ activation is important for mnemonic effects. Ovx WT, but not βERKO, mice administered E₂ or DPN had a greater percentage of time exploring a novel object in the object recognition task and a displaced object in the object placement task. Thus, actions at ERβ may be important for E₂ or SERMs to enhance cognitive performance of female mice in the object recognition and placement tasks.     

Estrogens and progestins enhance spatial learning of intact and ovariectomized rats in the object placement task

Steroid modulation of cognitive function has focused on estrogen (E(2)), but progestins naturally co-vary with E(2) and may also influence cognitive performance. Spatial performance in the object placement task over endogenous hormonal states in which E(2) and progestins vary, and when E(2) and/or progestins were administered, was examined. Experiment 1: Rats in proestrus or estrus had significantly better performance in the object placement task than did diestrus rats. Experiment 2: Rats in the third trimester, post-partum, or lactation exhibited significantly better performance in the object placement task than did rats in the first trimester. Experiment 3: Ovariectomized (ovx) rats administered 17beta-estradiol (0.9 mg/kg), subcutaneously (sc), progesterone (P; 4 mg/kg, sc), or E(2) and P, immediately after training in the object placement task, performed significantly better when tested 4h later, than did control rats administered vehicle (sesame oil 0.2 cc). Experiment 4: ovx rats administered E(2) or P with a 1.5h delay after training in the object placement task, did not perform differently than vehicle-administered controls. Experiment 5: ovx rats administered post-training E(2), which has a high affinity for both E(2) receptor (ER)alpha and beta isoforms, or propyl pyrazole triol (PPT; 0.9 mg/kg, sc), which is more selective for ERalpha than ERbeta, had significantly better performance in the object placement task than did rats administered vehicle or diarylpropionitrile (DPN; 0.9 mg/kg, sc), an ERbeta selective ligand. Experiment 6: ovx rats administered P, or its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP; 4 mg/kg, sc), immediately post-training performed significantly better in the object placement task than did vehicle control rats. Thus, performance in the object placement task is better when E(2) and/or P are naturally elevated or when E(2), the ERalpha selective ER modulator PPT, P, or its metabolite, 3alpha,5alpha-THP, are administered post-training.     

Familiarity,Cued and Free Odor Identification and Their Association with Cognitive Functioning in Middle Aged and Older Adults

ABSTRACT

The aim of the present study was to examine the association between familiarity of odors, cued and free odor identification performance and cognitive function in elderly adults. It was further investigated how age affects performance on the various odor tasks. A third aim was to investigate the role of familiarity in explaining performance on the free identification task. One hundred and thirty-six participants (aged 45–79 years) with normal olfactory sensitivity were assessed with the Scandinavian Odor Identification Test (SOIT) and standardized tests of cognitive function. Familiarity did not correlate with any measure of cognitive function, while verbal identification performance was associated with several cognitive measures, although correlations were modest. In this sample, free odor identification was affected by increasing age to a marginally larger extent than cued identification performance and familiarity ratings. The results suggest that the different olfactory tasks involve different levels of cognitive processing.     

Effects of progesterone administration and APPswe+PSEN1Deltae9 mutation for cognitive performance of mid-aged mice

Progesterone (P(4)) and its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) have trophic effects and may improve cognitive function. We investigated the role of progestins in a murine model of Alzheimer's Disease (AD) in which transgenic mice co-overexpress a mutant form of amyloid precursor protein (APPswe) and a deletion in presenilin 1 Delta exon 9 (APPswe+PSEN1Deltae9). We hypothesized that: (1) mice with the APPswe+PSEN1Deltae9 mutation would have performance deficits compared to wildtype mice and (2) long-term administration of P(4) would enhance cognitive performance and increase brain progestin levels over placebo. Mice were ovariectomized at 6 months of age and administered placebo or P(4) via subcutaneously implanted pellets. Mice were tested between 9 and 12 months of age for cognitive performance in the object placement, water maze, object recognition, and T-maze tasks and for motor behavior in an activity monitor and then tissues were collected for steroid measurement. P(4) administration increased progestin levels in cortex, diencephalon, midbrain, and cerebellum of wildtype and mutant mice, but increases in 3alpha,5alpha-THP levels in the hippocampus of APPswe+PSEN1Deltae9 mutant mice were attenuated compared to that observed in wildtype mice. APPswe+PSEN1Deltae9 mice showed poorer performance in hippocampus measures (object placement and water maze tasks). In the object recognition and T-maze task, which are mediated by the cortex and hippocampus, P(4) administration improved performance in both wildtype and APPswe+PSEN1Deltae9 mutant mice compared to placebo administration. Thus, APPswe+PSEN1Delta9 mice have deficits in hippocampal performance and capacity to form 3alpha,5alpha-THP in the hippocampus and both wildtype and APPswe+PSEN1Delta9 mice show beneficial effects of P(4) in cortical function and similar capacity to form 3alpha,5alpha-THP in the cortex.     

Life-long environmental enrichment differentially affects the mnemonic response to estrogen in young, middle-aged, and aged female mice

The present study was designed to examine whether life-long exposure to standard or enriched housing affects the ability of estrogen to improve spatial and object memory throughout the lifespan. Three-week-old female mice were maintained in standard or enriched housing up to and through ovariectomy and behavioral testing at 5, 17, or 22 months of age. Spatial memory was tested in the Morris water maze and object memory was tested using an object recognition task. Immediately after training each day, mice were injected intraperitoneally with vehicle or 0.2 mg/kg 17beta-estradiol. Among young females, object recognition was enhanced by estradiol alone, an effect that was reduced by enrichment. In contrast, spatial water maze performance was impaired by estradiol alone, but improved by the combination of both estradiol and enrichment. At middle-age, object recognition was enhanced by estradiol or enrichment alone, and the combination of both treatments. Spatial memory in the water maze was also improved by both treatments at middle-age, but the beneficial effects of estradiol were limited to standard-housed females. Finally, whereas enrichment in aged females significantly enhanced performance in both tasks, estradiol had no effect at this age in either task. In total, the data indicate that life-long enrichment can significantly alter the extent to which estradiol affects memory in mice throughout the lifespan. Importantly, the interaction between these treatments is highly dependent on age and type of memory tested.     

Differential effects of estrogen on hippocampal- and striatal-dependent learning

Estrogen's role in learning and memory may be to predispose animals to use specific cognitive strategies (Korol & Kolo, 2002). Specifically, estrogen may facilitate hippocampal-dependent learning, while at the same time attenuate striatal-dependent learning. As a stringent test of this hypothesis, place or response learning on an eight-arm radial maze was compared between ovariectomized (OVX) female Long-Evans rats and rats with chronic estrogen replacement (OVX+E; 5mg 17-beta estradiol 60-day release tablet). Reference and working memory errors were monitored separately for both place and response learning tasks. OVX+E rats learned the place task significantly faster than the response task, and faster than OVX rats. OVX rats required fewer days to reach criterion on the response task than OVX+E rats. Estrogen selectively enhanced reference memory performance, but only during place learning. The specific pattern of estrogen effects on learning suggests that future studies include verification of cognitive strategies used by animals.     

Estradiol decreases anxiety behavior and enhances inhibitory avoidance and gestational stress produces opposite effects

Although there is evidence that estradiol has effects in women and in animal models to reduce anxiety and depressive behavior and enhance performance in some cognitive tasks, this is not seen among all individuals. Given the interaction between estradiol and hypothalamic-pituitary-adrenal function, we hypothesized that an individual's prior exposure to stress may mitigate some of the subsequent effects of estradiol. To address this, rats were exposed to gestational stress, or not, to determine if stress exposure during development alters behavioral responses to estradiol in adulthood. If estradiol's effects on anxiety and cognitive behavior are modulated by prior stress experience, then gestationally-stressed rats administered estradiol should have decreased anti-anxiety (open field, elevated plus maze) behavior and cognitive performance in the inhibitory avoidance task. Offspring of dams that were exposed to restraint stress daily on gestational days 14-20, or no such manipulation, were used as adults either intact in behavioral estrus (high estradiol) or diestrus (low estradiol), or ovariectomized (OVX) with empty or estradiol-containing silastic implants. Rats were used for blood collection to determine plasma corticosterone and estradiol concentrations, or were used for behavioral testing. Compared with rats in diestrus or OVX and vehicle-replaced, rats in behavioral estrus and OVX rats with estradiol implants had higher estradiol concentrations, entered more central squares in an open field, spent more time on the open arms of the plus maze, and had a longer latency to crossover to the dark, shock-associated side of the inhibitory avoidance chamber. Gestational stress increased plasma corticosterone but not estradiol levels, decreased plus maze open arm time in cycling rats, and decreased inhibitory avoidance performance. Thus, estradiol and gestational stress can have opposite effects on anxiety and inhibitory avoidance performance.     

Posttraining androgens' enhancement of cognitive performance is temporally distinct from androgens' increases in affective behavior

Steroid hormone-induced variations in spatial learning and memory tasks have been reported. In this study, androgens’ effects in various cognitive and affective tasks were investigated in order to determine whether any observed differences in cognitive performance could be due to affective changes produced by the hormones. Ovariectomized rats (N = 72) received 0.0, 3.0, or 7.5 mg/kg subcutaneously, of testosterone (T), dihydrotestosterone (DHT), or 5α-androstane-3α, 17β-diol (3a-Diol) suspended in 10% ethanol/sesame oil v/v. For the cognitive tasks (Y maze, inhibitory avoidance, and object recognition), subjects were injected after training trials. For the affective tasks (open field, elevated plus maze, and tailflick), subjects were injected 1 or 24 h before testing. Posttraining injections that produced physiological concentrations of androgens - T, DHT, and 3α-Diol - 1 h later increased the percentage of correct choices in the Y maze, the latencies to cross to the shock-associated side of the inhibitory avoidance chamber, and percentage of time exploring novel objects 24 h later, when androgen levels were no longer increased. Administration of T, DHT, and 3α-Diol also increased the number of entries into the center squares of a brightly lit open field, open-arm time in the elevated plus maze, and tailflick latencies 1 but not 24 h following administration. These findings suggest that these androgens, when administered following training, can enhance cognitive performance in the tasks investigated 24 h later when androgen levels nadir, but overt changes in the affective behaviors examined occurred at the time of physiological concentrations 1 h but not 24 h following androgen administration. These findings suggest posttraining androgens can enhance consolidation and cognitive performance, independent of their anxiolytic actions.     

Reliability, Distribution, and Validity of Age-Related Cognitive Deficits in the Morris Water Maze

In the present study, F-344 rats throughout 1.5 to 26 months of age were tested in the reference memory version, a moving-platform repeated acquisition version, and in a cued platform version of the Morris water maze. The results suggest that: (1) performance in the water maze declines continuously, beginning at the earliest age, and very closely fits a linear function; (2) there are robust, reliable differences between individuals in terms of their performance in the Morris water maze, but chronological age accounts for only a fraction of the variance between individuals; (3) there is no evidence of a bimodal distribution among aged rats—there is no distinct subgroup of individuals that performs so poorly that they are qualitatively different from the majority of the population, and distinctions between “impaired” and “unimpaired” subjects must be based on arbitrary criteria that may not be consistent from one study to the next; (4) age-related deficits in the Morris water maze may not be restricted to learning and memory, but may also include deficits in attention, the ability to process spatial information, and/or the ability to develop efficient spatial search strategies; and (5) swim distance is the most appropriate measure of cognitive function in the Morris water maze, but the relationship between this measure and other measures of noncognitive function make it clear that swim distance may not be a pure measure of cognitive function. Although the Morris water maze remains a valuable preclinical test with better validity and specificity than many other behavioral tests, measures of performance in the Morris water maze should not be considered synonymous with cognitive function.     

Acute Ethanol Administration Impairs Spatial Performance While Facilitating Nonspatial Performance in Rats

Acute ethanol administration produces learning and memory impairments similar to those found following lesions to the hippocampal system in rats. For example, both ethanol and hippocampal lesions impair performance on spatial learning and memory tasks while sparing performance on many nonspatial learning and memory tasks. Lesions to the hippocampal system can also alter the nature of the information that the animal uses to guide its behavior, from using spatial information to using individual cues. In the present experiment, rats were trained, while sober, to navigate on an eight-arm radial arm maze to a specific arm for food reward. During training, the rewarded arm was always in the same specific location and contained well-defined cues. After the rat learned the task, a memory test was conducted under different doses of ethanol (0.0 g/kg [saline control], 1.0, 1.5, or 2.0 g/kg, intraperitoneal). On the test day the maze was rotated so that the cued arm was 90 degrees to the right of its original position. During testing, intact rats showed a significant bias to approach the place where they had been previously rewarded, even though the cue was no longer located there. Acute ethanol administration dose dependently reduced approaches to the rewarded place. However, ethanol administration did not result in increases in random choices; rather, it resulted in a dose-dependent increase in approaches to the cued arm, now in a new location. These results extend previous research showing that acute ethanol administration and lesions to the hippocampal system produce similar effects on learning and memory in rats.     

A multicomponent investigation of the interaction of generalized anxiety and phobia

Forty female undergraduates forming four groups, high or low trait anxiety with or without a specific fear (rats), participated in a psychophysiological assessment of their response to the phobic object, a neutral object (rabbit), and to a general anxiety-induction procedure (threat of shock). Subjects also completed a number of tasks requiring sustained attention. Blood samples were drawn to determine thyroid hormone (T3 and T4) levels. Trait anxiety was found to interact with specific fear in response to the feared object. The high-trait anxious/high-fear group was most physiologically responsive to the rat. Trait- anxious subjects were more responsive to the threat of shock and showed performance deficits on reaction time, vigilance, and backward digit span tasks. These subjects also had significantly higher T3 and T4 levels. The findings are discussed with regard to the role of general anxiety in the etiology and/or maintenance of specific fears and the role of thyroid hormones in accentuating physiological response to feared stimuli.     

Deficits in trace cued fear conditioning in galanin-treated rats and galanin-overexpressing transgenic mice

Galanin inhibits the release of several neurotransmitters and produces performance deficits in a variety of spatial and aversive learning and memory tasks. The experiments in this study investigated the role galanin has in emotional learning and memory using a standard delay cued and contextual fear conditioning task. Rats were administered galanin into the lateral ventricles before training, and scored for freezing behavior in the same context and in a novel context with and without an auditory cue (CS) that had been paired previously with an aversive stimulus (US). Galanin-overexpressing transgenic mice were tested in an identical behavioral protocol. The galanin-administered rats and the transgenic mice were not significantly different from their respective controls on this task. A more challenging trace cued and contextual fear conditioning procedure was administered to separate groups of galanin-treated rats and galanin-overexpressing transgenic mice. Subjects were trained with the same CS and US, however, a 2.5-sec delay was inserted between CS offset and US onset. Following the trace conditioning, rats administered galanin and mice overexpressing galanin both exhibited significantly less freezing to the CS in the novel context as compared with their control groups. These results indicate that the observed disruption of cued fear conditioning was specific to the more difficult trace conditioning task. These findings are the first demonstration that galanin impairs performance on an emotional memory task and support the hypothesis that galanin-induced deficits are specific to more difficult cognitive tasks.     

Retro-cue benefits in working memory without sustained focal attention

In working memory (WM) tasks, performance can be boosted by directing attention to one memory object: When a retro-cue in the retention interval indicates which object will be tested, responding is faster and more accurate (the retro-cue benefit). We tested whether the retro-cue benefit in WM depends on sustained attention to the cued object by inserting an attention-demanding interruption task between the retro-cue and the memory test. In the first experiment, the interruption task required participants to shift their visual attention away from the cued representation and to a visual classification task on colors. In the second and third experiments, the interruption task required participants to shift their focal attention within WM: Attention was directed away from the cued representation by probing another representation from the memory array prior to probing the cued object. The retro-cue benefit was not attenuated by shifts of perceptual attention or by shifts of attention within WM. We concluded that sustained attention is not needed to maintain the cued representation in a state of heightened accessibility.     

Differential induction of c-Jun and Fos-like proteins in rat hippocampus and dorsal striatum after training in two water maze tasks

Research examining the neuroanatomical bases of memory in mammals suggests that the hippocampus and dorsal striatum are parts of independent memory systems that mediate "cognitive" and stimulus-response "habit" memory, respectively. At the molecular level, increasing evidence indicates a role for immediate early gene (IEG) expression in memory formation. The present experiment examined whether acquisition of cognitive and habit memory result in differential patterns of IEG protein product expression in these two brain structures. Adult male Long-Evans rats were trained in either a hippocampal-dependent spatial water maze task, or a dorsal striatal-dependent cued water maze task. Ninety minutes after task acquisition, brains were removed and processed for immunocytochemical procedures, and the number of cells expressing Fos-like immunoreactivity (Fos-like-IR) and c-Jun-IR in sections from the dorsal hippocampus and the dorsal striatum were counted. In the dorsal hippocampus of rats trained in the spatial task, there were significantly more c-Jun-IR pyramidal cells in the CA1 and CA3 regions, relative to rats that had acquired the cued task, yoked controls (free-swim), or na?ve (home cage) rats. Relative to rats receiving cued task training and control conditions, increases in Fos-like IR were also observed in the CA1 region of rats trained in the spatial task. In rats that had acquired the cued task, patches of c-Jun-IR were observed in the posteroventral striatum; no such patches were evident in rats trained in the spatial task, yoked-control rats, or na?ve rats. The results demonstrate that IEG protein product expression is up-regulated in a task-dependent and brain structure-specific manner shortly after acquisition of cognitive and habit memory tasks.     

Estrogen abolishes latent inhibition in ovariectomized female rats

Estrogen is frequently prescribed as a method of birth control and as hormone replacement therapy for post-menopausal women with varied effects on cognition. Here the effects of estrogen on attention were examined using the latent inhibition (LI) behavioral paradigm. Ovariectomized (OVX) female rats were given either estrogen benzoate (EB, 10 or 100 microg/ml/kg; SC) or sesame oil vehicle. Males and OVX females receiving vehicle displayed normal LI. In contrast, LI was abolished in OVX females receiving EB. The lack of LI in OVX females receiving EB was a result of low suppression ratios, reflecting strong conditioning between the tone and the shock in these subjects even if they were pre-exposed to the tone. Thus, estrogen impaired the ability of OVX females to ignore irrelevant stimuli. Since different cognitive tasks vary in their required ability to ignore irrelevant stimuli, these results may account for some of the variations in the current literature on estrogen and cognition.     

Androgens' performance-enhancing effects in the inhibitory avoidance and water maze tasks may involve actions at intracellular androgen receptors in the dorsal hippocampus

Androgens can have performance-enhancing effects in some cognitive tasks, but the mechanism of these effects has not been established. Experiments examined whether androgens' actions to bind to intracellular androgen receptors (ARs) in the hippocampus are necessary to enhance cognitive performance in the inhibitory avoidance and water maze tasks. If androgens' binding at ARs are essential, then blocking them through intrahippocampal administration of flutamide, an AR receptor antagonist, should attenuate androgens' performance-enhancing effects in the inhibitory avoidance and water maze tasks. In Experiments 1 and 2, flutamide was administered through intrahippocampal inserts to intact male rats immediately pre- and post-training in the inhibitory avoidance and water maze tasks. Both pre- and post-training administration of flutamide to the dorsal hippocampus, but not missed sites, produced significantly poorer performance in the inhibitory avoidance and water maze tasks, without influencing control measures such as flinch/jump threshold or swim speed. In Experiment 3, flutamide administration to the hippocampus was delayed two hours following training in the inhibitory avoidance and water maze tasks. There was no significant effect of delayed administration of flutamide on performance in either of these tasks. Together, these findings suggest that blocking ARs in the dorsal hippocampus with flutamide administration immediately pre- or post-training can produce decrements in cognitive performance, which implies that androgens' performance-enhancing effects may occur, in part, through binding at intracellular androgen receptors in the dorsal hippocampus.     

Coantagonism of glutamate receptors and nicotinic acetylcholinergic receptors disrupts fear conditioning and latent inhibition of fear conditioning

The present study investigated the hypothesis that both nicotinic acetylcholinergic receptors (nAChRs) and glutamate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs) and N-methyl-d-aspartate glutamate receptors (NMDARs)) are involved in fear conditioning, and may modulate similar processes. The effects of the nAChR antagonist mecamylamine administered alone, the AMPAR antagonist NBQX administered alone, and the NMDAR antagonist MK-801 administered alone on cued fear conditioning, contextual fear conditioning, and latent inhibition of cued fear conditioning were examined. In addition, the effects of coadministration of either mecamylamine and NBQX or mecamylamine and MK-801 on these behaviors were examined. Consistent with previous studies, neither mecamylamine nor NBQX administered alone disrupted any of the tasks. However, coadministration of mecamylamine and NBQX disrupted both contextual fear conditioning and latent inhibition of cued fear conditioning. In addition, coadministration of mecamylamine with a dose of MK-801 subthreshold for disrupting either task disrupted both contextual fear conditioning and latent inhibition of cued fear conditioning. Coadministration of mecamylamine and NBQX, and coadministration of mecamylamine with a dose of MK-801 subthreshold for disrupting fear conditioning had little effect on cued fear conditioning. These results suggest that nAChRs and glutamate receptors may support similar processes mediating acquisition of contextual fear conditioning and latent inhibition of fear conditioning.     

Rules and more rules: The effects of multiple tasks, extensive training, and aging on task-switching performance

Task-switching performance was assessed in young and older adults as a function of the number of task sets to be actively maintained in memory (varied from 1 to 4) over the course of extended training (5 days). Each of the four tasks required the execution of a simple computational algorithm, which was instantaneously cued by the color of the two-digit stimulus. Tasks were presented in pure (task set size 1) and mixed blocks (task set sizes 2, 3, 4), and the task sequence was unpredictable. By considering task switching beyond two tasks, we found evidence for a cognitive control system that is not overwhelmed by task set size load manipulations. Extended training eliminated age effects in task-switching performance, even when the participants had to manage the execution of up to four tasks. The results are discussed in terms of current theories of cognitive control, including task set inertia and production system postulates.