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PubMed2004

Multi-item working memory--a behavioral study.

Macaque monkeys were trained to recognize the repetition of one of the images already seen in a sequence of random length. On average, performance decreased with sequence length. However, this was due to a complex combination of factors, as follows: performance was found to decrease with the separation in the sequence of the test (repetition image) from the cue (its first appearance in the sequence), for trials with sequences of fixed length. In contrast, performance improved as a function of sequence length, for equal cue-test separations. Reaction times followed a complementary trend: they increased with cue-test separation and decreased with sequence length. The frequency of false positives (FPs) indicates that images are not always removed from working memory between successive trials, and that the monkeys rarely confuse different images. The probability of miss errors depends on number of intervening stimulus presentations, while FPs depend on elapsed time. A simple two-state stochastic model of multi-item working memory is proposed that guides the account for the main effects of performance and false positives, as well as their interaction. In the model, images enter WM when they are presented, or by spontaneous jump-in. Misses are due to spontaneous jump-out of images previously seen.

Animals↗
PubMed2005

Impairments in working memory and decision-taking processes in monkeys in a model of Alzheimer's disease.

Studies were performed on two groups of animals (three monkeys in each). Monkeys of group I received unilateral intracerebroventricular injections of the neurotoxin p75-saporin (the ribosomal toxin saporin bound to monoclonal antibody to the p75NTR receptor), which elicits irreversible degradation of cholinergic neurons in the basal nuclei of Meynert, along with the enzyme dopamine-beta-hydroxylase (DBH-saporin), which impairs the functioning of noradrenergic neurons in the locus ceruleus. Monkeys of group II received injections of sterile physiological saline (0.9% NaCI). Monkeys were trained to discriminate stimuli containing different types of information (spatial frequency grids, geometric figures with different colors, different spatial relationships between objects) and perform spatial selection. The characteristics of working memory were identified in delayed differentiation tasks in monkeys of both groups before and after injections. These studies provided the first evidence that the development of Alzheimer's disease in rhesus macaques is characterized by a deficiency of working memory, this being based on impairment of two components of these processes. Impairment of the first in monkeys of group I was minifest in delayed visual differentiation as a significant decrease in correct responses. The extent of decreases depended on the duration of the delay and the type of visual information. Impairment of the second component, associated with decision-taking processes, was characterized by an increase in refusals to take decisions and was independent of the duration of delays and the type of visual information. Monkeys given injections of physiological saline showed no significant differences in these characteristics. The features of impairments in these memory components resulting from the development of Alzheimer's disease demonstrate that the structural-functional organization of cholinergic and noradrenergic mechanisms responsible for sensory processing differ from those involved in decision-taking.

Alzheimer Disease↗
PubMed2006

Administration of raloxifene reduces sensorimotor and working memory deficits following traumatic brain injury.

Hormonal differences between males and females have surfaced as a crucial component in the search for effective treatments after experimental models of traumatic brain injury (TBI). Recent findings have shown that selective estrogen receptor modulators (SERMs) may have therapeutic benefit. The present study examined the effects of raloxifene, a SERM, on functional recovery after bilateral cortical contusion injury (bCCI) or sham procedure. Male rats received injections of raloxifene (3.0mg/kg, i.p.) or vehicle (1.0 ml/kg, i.p.) 15 min, 24, 48, 72, and 96 h after bCCI or sham procedure. Rats were tested on both sensorimotor (bilateral tactile removal and locomotor placing tests) and cognitive tests (reference and working memory in the Morris water maze). Raloxifene-treated animals showed a significant reduction in the initial magnitude of the deficit and facilitated the rate of recovery for the bilateral tactile removal test, compared to vehicle-treated animals. The raloxifene-treated animals also showed a significant improvement in the acquisition of working memory compared to vehicle-treated animals. However, raloxifene did not significantly improve the acquisition of reference memory or locomotor placing ability. Raloxifene treatment also did not result in a significant reduction in the size of the lesion cavity. Thus, the task-dependent improvements seen following raloxifene treatment do not appear to be the result of cortical neuroprotection. However, these results suggest that raloxifene improves functional outcome following bCCI and may present an interesting avenue for future research.

Analysis of Variance↗
PubMed2006

Continuous ASL perfusion fMRI investigation of higher cognition: quantification of tonic CBF changes during sustained attention and working memory tasks.

Arterial spin labeling (ASL) perfusion fMRI is an emerging method in clinical neuroimaging. Its non-invasiveness, absence of low frequency noise, and ability to quantify the absolute level of cerebral blood flow (CBF) make the method ideal for longitudinal designs or low frequency paradigms. Despite the usefulness in the study of cognitive dysfunctions in clinical populations, perfusion activation studies to date have been conducted for simple sensorimotor paradigms or with single-slice acquisition, mainly due to technical challenges. Using our recently developed amplitude-modulated continuous ASL (CASL) perfusion fMRI protocol, we assessed the feasibility of a higher level cognitive activation study in twelve healthy subjects. Taking advantage of the ASL noise properties, we were able to study tonic CBF changes during uninterrupted 6-min continuous performance of working memory and sustained attention tasks. For the visual sustained attention task, regional CBF increases (6-12 ml/100 g/min) were detected in the right middle frontal gyrus, the bilateral occipital gyri, and the anterior cingulate/medial frontal gyri. During the 2-back working memory task, significantly increased activations (7-11 ml/100 g/min) were found in the left inferior frontal/precentral gyri, the left inferior parietal lobule, the anterior cingulate/medial frontal gyri, and the left occipital gyrus. Locations of activated and deactivated areas largely concur with previous PET and BOLD fMRI studies utilizing similar paradigms. These results demonstrate that CASL perfusion fMRI can be successfully utilized for the investigation of the tonic CBF changes associated with high level cognitive operations. Increased applications of the method to the investigation of cognitively impaired populations are expected to follow.

Adult↗
PubMed2004

Effect of articulatory suppression on task-switching performance: implications for models of working memory.

In a series of experiments, we examine some effects of articulatory suppression in task switching. The results from Experiments 1a and 2a showed that switch costs in the articulatory suppression condition were larger than those in the control and tapping conditions when the switching cues were not provided. On the other hand, articulatory suppression did not have any effect on switch costs in Experiments 1b and 2b, where the switching cues were provided. In Experiment 3, using a computer-assisted experimentation, this pattern of data was replicated in a two-factor design with articulatory suppression and switching cues factors. The results indicate that a specific component in working memory, the phonological loop, might contribute to the performance in task switching, at least in situations where the external task cues were not available. The data reported here suggest that the phonological loop plays an important role in one of the executive control processes, and challenge the traditional idea that the slave systems are simply governed by the central executive in the working memory.

Adolescent↗
PubMed2006

Working memory and decision-making biases in young adults with a family history of alcoholism: studies from the Oklahoma family health patterns project.

BACKGROUND: Alcohol misuse is more common in persons with a family history of alcoholism (FH+) than in those with no such history (FH-). Among FH+, behavioral disinhibition and male sex seem to signal the presence of an increased risk. METHODS: This study examined cognitive and behavioral characteristics of 175 nonabusing 18- to 30-year-olds, 87 FH+ and 88 FH-, who were further characterized by their degree of behavioral disinhibition using the Sociability scale of the California Personality Inventory. Working memory and decision making were tested using the Stroop Color-Word Test and the Iowa Gambling Task, a simulated card game. RESULTS: Persons with a family history of alcoholism who were behaviorally disinhibited displayed significantly greater interference on the Stroop task than the other subgroups. On the Iowa Gambling Task, FH+ males, but not the females, were significantly more attentive to financial gains than other subgroups, and they had greater consistency in their choice behaviors. CONCLUSIONS: Persons with a family history of alcoholism, in combination with behavioral disinhibition, appears to signal working memory deficits and in combination with male sex indicates an attraction to the rewarding aspects of a risk-taking challenge. These findings are not secondary to heavy exposure to alcohol or other drugs, but instead reflect intrinsic risk-related familial and personal characteristics of the subjects.

Adolescent↗
PubMed2002

Perirhinal cortex neuronal activity is actively related to working memory in the macaque.

Lesion studies suggest that the perirhinal cortex plays a role in object recognition memory. To analyze its role, we recorded the activity of single neurons in the perirhinal cortex in a rhesus monkey (Macaca mulatta) performing a delayed matching-to-sample task with up to four intervening stimuli. Certain neurons (40 of 90 analyzed) showed a smaller response to an image when it was shown the second time within a trial (as a match image) than when it had been shown (as a sample image) the first time. A new finding was that the perirhinal cortex neurons were actively reset between trials: when a particular image was shown as a sample on a succeeding trial, the response was much larger than when it had been shown as a match image a short time previously on the previous trial. This resetting between trials appears to reflect the operation of an active working memory process rather than a passive temporal decay in a neuronal response. The results thus provide evidence that the perirhinal cortex plays an active role in visual working memory, perhaps in association with other brain areas such as the prefrontal cortex.

Animals↗
PubMed2002

Early-onset alcoholism with conduct disorder: go/no go learning deficits, working memory capacity, and personality.

BACKGROUND: Two studies were conducted to investigate the disinhibitory mechanisms that (1) discriminate early-onset alcoholism (EOA) with conduct disorder (CD; antisocial EOA) from a non-antisocial subtype of EOA and (2) are associated with novelty-seeking and low harm avoidance. METHODS: Young adults with antisocial EOA (n = 96), with non-antisocial EOA (without CD; n = 80), with CD alone (n = 50), and controls (n = 125) were given two go/no go tasks (one with monetary loss and the other with shock punishment), the Digit Span test (working memory capacity), and personality measures of harm avoidance, novelty-seeking/impulsivity, excitement-seeking, and negative affectivity. RESULTS: Study 1 revealed that antisocial EOA subjects had poor behavioral inhibition compared with non-antisocial EOAs and controls on both go/no go tasks and with the CD-alone group on the monetary-loss task. Low Digit Span scores accentuated poor inhibition in antisocial EOAs on the monetary loss, but not the shock task. EOA with low Digit Span was associated with higher hit rates on the shock task. Study 2 revealed that antisocial EOAs had high novelty-seeking/impulsivity and low harm avoidance compared with both non-antisocial EOAs and controls. Low harm avoidance was associated with poor inhibition with shock punishment, and this association was mediated by CD. For subjects with low Digit Span scores, novelty-seeking/impulsivity was associated with poor inhibition to monetary-loss punishment and higher hit rates to shock punishment. CONCLUSIONS: The results suggest two disinhibitory mechanisms that distinguish antisocial from non-antisocial EOA: an increased sensitivity to reward in nonaversive contexts associated with novelty-seeking/impulsivity and a decreased sensitivity to punishment in aversive contexts associated with low harm avoidance. Results also suggest that EOA and novelty-seeking/impulsivity are associated with a greater response to rewards in those with low working memory capacity.

Adolescent↗
PubMed2003

Frontal cortex BDNF levels correlate with working memory in an animal model of Down syndrome.

Individuals with Down syndrome (DS) develop most neuropathological hallmarks of Alzheimer's disease early in life, including loss of cholinergic markers in the basal forebrain. Ts65Dn mice, an animal model of DS, perform poorly on tasks requiring spatial memory and also exhibit basal forebrain pathology beginning around 6 months of age. We evaluated memory as well as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) protein levels in basal forebrain, frontal cortex, hippocampus, and striatum in Ts65Dn mice at the age when cholinergic degeneration is first observed, and compared values to normosomic controls. Six-month-old Ts65Dn mice exhibited impairments in working and reference memory as assessed on a water radial-arm maze. The working memory deficit was related to the inability of Ts65Dn mice to successfully sustain performance as the working memory load increased. Coupled with cognitive performance deficiencies, Ts65Dn mice also exhibited lower frontal cortex BDNF protein levels than controls. Further, BDNF levels were negatively correlated with working memory errors during the latter portion of testing in Ts65Dn mice, thereby suggesting that lower BDNF protein levels in the frontal cortex may be associated with the observed working memory impairment.

Animals↗
PubMed2000

Event-related brain potentials and working memory function in healthy humans after single-dose and prolonged intranasal administration of adrenocorticotropin 4-10 and desacetyl-alpha-melanocyte stimulating hormone.

Neuropeptides of the adrenocorticotropin/melanocorticotropin (ACTH/MSH) family are most potent modulators of cognitive function. Their neurobehavioral activity is principally encoded in the 4-10 fragment of the ACTH/MSH molecule; in humans, it has been shown to pertain primarily to functions of attentive stimulus/response processing. The aims of this study were (1) to examine the effects of ACTH 4-10 on event-related brain potentials (ERPs) and behavioral indicators of stimulus encoding within the working memory; (2) to compare the effects after a single dose and after prolonged treatment with ACTH 4-10; and (3) to compare the effects of ACTH 4-10 with those of desacetyl-alpha-MSH (i.e., ACTH 1-13 amide), which, like ACTH 4-10, binds to the known brain melanocortin receptors (MC-Rs) but with distinctly higher affinity. Double-blind, placebo-controlled experiments were performed in 60 healthy control subjects. The authors monitored ERPs and reaction times while these subjects performed an auditory vigilance task ("oddball"). Recall was tested on a verbal short-term memory task including different word categories (neutral, rare, food, sex). After a single (1 mg) as well as prolonged intranasal administration (1 mg/day over a period of 6 weeks), ACTH 4-10 enhanced the positive slow wave in ERPs to target stimuli of the vigilance task (p < 0.05), but left classic P3 unaffected. Moreover, single-dose and prolonged administration of ACTH 4-10 increased the rate of false responses during vigilance (p < 0.01). In the short term, ACTH 4-10 also impaired recall of neutral words (p < 0.05). Equimolar doses of desacetyl-alpha-MSH did not influence ERPs, neither after a single dose nor after prolonged treatment. Similar to ACTH 4-10, desacetyl-alpha-MSH increased the error rate during vigilance and acutely impaired the recall of neutral words. The increase in ERP slow-wave positivity, in conjunction with behavioral impairments after treatment with ACTH 4-10, complemented previous results of inferior focusing of attention and a less concise structure of thought after administration of ACTH 4-10. The changes indicated an impairment in differential processing of relevant versus irrelevant contents within the working memory, and, in this regard, might mimic aspects of psychopathologic disturbances of attention and thought processes. Their persistence after prolonged treatment with ACTH 4-10 suggests an activation of mechanisms subserving the consolidation of the peptide's effects. The poor efficacy of desacetyl-alpha-MSH suggests that the known MC-Rs may be irrelevant for mediating cognitive effects of this neuropeptide family.

Administration, Intranasal↗
PubMed2005

Working memory and inhibitory control among manic and euthymic patients with bipolar disorder.

Bipolar disorder (BPD) is a severe psychiatric illness that is characterized by episodes of extreme mood states. The affective components of bipolar disorder have been studied extensively, but only recently have investigators begun to systematically examine its cognitive concomitants. Although executive dysfunction has been reported in this population, especially while patients are manic, the tasks administered in many previous studies have made it difficult to determine the specific executive abilities that were compromised. The present study examined 15 patients with bipolar disorder who were manic, 18 who were euthymic, and 18 healthy participants. Tests were selected to evaluate two specific aspects of executive functioning in these participants. The Object Alternation Task was given as a measure of inhibitory control, and the Delayed Response Task was included as a measure of spatial delayed working memory. All groups performed similarly on the Delayed Response Task. On the Object Alternation Task, however, the manic and euthymic patients committed significantly more perseverative errors than healthy participants. These results indicated that patients in the present sample had relatively normal working memory abilities, but had a deficit in behavioral self-regulation, which was evident across mood states.

Adolescent↗
PubMed2001

A retinoic acid receptor antagonist suppresses brain retinoic acid receptor overexpression and reverses a working memory deficit induced by chronic ethanol consumption in mice.

BACKGROUND: Chronic ethanol consumption induces disorders in the biosynthesis of retinoic acid, an active derivative of vitamin A. Recent evidence suggests that an alteration in the retinoic acid signaling pathway leads to impairments in learning and memory in adult mice. We have previously shown that chronic ethanol consumption in mice produces an increased expression of the brain retinoic acid receptor beta (RARbeta) mRNA. These results prompted us to examine whether suppressing the overexpression of retinoid receptors in alcohol-treated mice by RAR antagonist administration would reverse their cognitive impairment. METHODS: After 10 months of ethanol consumption (12% v/v in drinking water), C57BL/6 mice were submitted to a working memory task in a T-maze. Then, mice of the control and the ethanol-treated groups received an RARbeta antagonist (CD2665 0.6 mg/kg) for 22 days. The behavioral effect of CD2665 administration was evaluated on a spontaneous alternation task and the neurochemical effect was measured by quantifying the mRNA expression of RARalpha, RARbeta, retinoid X receptor (RXRbeta/gamma) and tissue transglutaminase (tTG; a retinoic acid-target gene). RESULTS: Mice submitted to ethanol treatment exhibited a progressive decrease in spontaneous alternation rates over successive trials. Moreover, these mice displayed an increased expression of brain RARbeta and RXRbeta/gamma mRNA, together with an increased level of tTG mRNA and enzymatic activity. The administration of CD2665 to alcohol-treated mice totally reversed the working memory deficit and suppressed the overexpression of brain RARbeta, RXRbeta/gamma and tTG mRNA, whereas the same treatment in control mice decreased only the RARbeta mRNA level without affecting memory performance. CONCLUSION: These data point to the potential role of the retinoid signaling pathway in memory processes and suggest that the overexpression of brain RARbeta and RXRbeta/gamma could be responsible, at least in part, for some memory impairments observed during chronic ethanol consumption.

Alcohol Drinking↗
PubMed1999

Adult ontogeny of rat working memory of social interactions.

BACKGROUND: Social memory has features that may make it uniquely appropriate for studying normal aging. We used a cross-section experimental design with an animal model to survey the lifetime adult ontogeny of memory of a brief social interaction. METHODS: Groups of healthy adult male rats representing young adulthood (5 months), middle age (10 months), or old age (19-27 months) were tested weekly over a month in two paradigms. Basic social memory and social interference memory were quantified by differences between investigation times of a juvenile rat during a 5-min interaction (acquisition trial) and a second exposure (recall testing), with interexposure intervals (IEI) ranging from 15 min to 24 h. RESULTS: Although basic social memory of all age groups was similar at the brief or longer IEI, there were memory declines at intermediate IEI delays in older males, especially the oldest groups. Decrements to working memory appeared as early as middle-age when an unfamiliar juvenile was inserted between acquisition and recall testing. Nonetheless, our healthy old animals retained a robust ability to recall identity of a conspecific that a minute by minute comparison suggested involves similar behavioral means of gathering social information. CONCLUSIONS: Normative aging of working social memory in male rats can be characterized as being more fragile, beginning at middle age but without significant further decline until near the end of the life span. Functional impact of these age-dependent changes in social memory, on the other hand, may be minimal for all but the very oldest animals in the social group.

Aging↗
PubMed2000

Effects of intraseptal zolpidem and chlordiazepoxide on spatial working memory and high-affinity choline uptake in the hippocampus.

Injection of GABA(A)/benzodiazepine receptor ligands into the medial septum (MS) alters the activity of cholinergic neurons that innervate the hippocampus and can produce bidirectional modulation of spatial memory. Recent evidence suggests that two subtypes of the GABA(A) receptor are differentially localized to either GABAergic (alpha(1)/beta(2)/gamma(2)) or cholinergic (alpha(3)/beta(3)/gamma(2)) neurons within the MS. The present studies characterized the dose-related behavioral and neurochemical effects of intraseptal infusions of two benzodiazepine (BDZ) agonists that appear to exhibit different profiles of pharmacological specificity for these receptor subtypes. Male Sprague-Dawley rats were cannulated and then artificial CSF, chlordiazepoxide (CDP: 8 or 12 microg), or zolpidem (4, 8, or 12 microg) was injected into the MS. Spatial working memory was assessed in a delay radial-arm maze task and the activity of cholinergic neurons in the MS was evaluated by high-affinity choline uptake (HA-ChU) in the hippocampus. Intraseptal injection of either CDP or zolpidem produced dose-related impairments in spatial working memory and decreases in hippocampal HAChU. Both BDZ agonists were found to produce retrograde memory deficits and a decrease in HAChU following the highest dose tested (12 microg). However, intraseptal injection of 8 microg of zolpidem produced a behavioral deficit comparable to the high dose of CDP, but did not alter HAChU within the HPC. Although the cholinergic component of the septohippocampal pathway has been shown to be important in modulating hippocampal physiology and spatial memory processes, data from the present experiments suggest that the GABAergic component may also play an important role in the behavioral functions of the septohippocampal pathway.

Animals↗
PubMed2003

Working memory and fear conditioning.

Previous studies of associative learning implicate higher-level cognitive processes in some forms of classical conditioning. An ongoing debate is concerned with the extent to which attention and awareness are necessary for trace but not delay eye-blink conditioning [Clark, R. E. & Squire, L. R. (1998) Science 280, 77-81; Lovibond, P. F. & Shanks, D. (2002) J. Exp. Psychol. Anim. Behav. Processes 28, 38-42]. In trace conditioning, a short interval is interposed between the termination of the conditioned stimulus (CS) and the onset of the unconditioned stimulus (US). In delay conditioning, the CS and US overlap. We here investigate the extent to which human classical fear conditioning depends on working memory. Subjects had to carry out an n-back task, requiring tracking an item 1 or 2 back in a sequentially presented list of numbers, while simultaneously being tested for their ability to associate auditory cues with shocks under a variety of conditions (single-cue versus differential; delay versus trace; no task versus 0-, 1-, and 2-back). Differential delay conditioning proved to be more resilient than differential trace conditioning but does show a reduction due to task interference similar in slope to that found in trace conditioning. Explicit knowledge of the stimulus contingency facilitates but does not guarantee trace conditioning. Only the single-cue delay protocol shows conditioning during the more difficult working memory task. Our findings suggest that the larger the cognitive demands on the system, the less likely conditioning occurs. A postexperimental questionnaire showed a positive correlation between conditioning and awareness for differential trace conditioning extinction.

Adolescent↗
PubMed1996

Deficits of spatial learning and working memory in spontaneously hypertensive rats.

It is possible that behavioral dysfunction, including cognitive, perceptual and psychomotor impairments in hypertensive subjects, can be the result of the high blood pressure. The aim of this study was to evaluate the performance of the spontaneously hypertensive rats (SHR) in the acquisition and execution of tasks in an 8-arm radial maze. Male Wistar normotensive rats (CON, n = 11) and SHR (n = 12), 3 months old, were first submitted to a series of training sessions to enter each of the 8 arms once in a given session (task acquisition), and errors (revisiting an arm in the same session) were computed. Errors before and after two delay intervals (5 s and 1 h, introduced between the fourth and fifth arm choice) were measured. These delayed tests allowed us to evaluate the working memory in different terms. It was observed that the SHR group made slightly more errors during the acquisition sessions and in the execution of the post-delay of 5-s interval tests, and significantly in the execution of the post-delay of 1-h interval tests compared to the CON. These results show that the SHR has a deficiency in the performance of the radial maze, suggestive of impairment of learning and working memory, mainly for a long-term memory, corroborating the hypothesis about the possible behavioral consequences of hypertension.

Animals↗
PubMedDate not supplied

Estradiol, but not raloxifene, improves aspects of spatial working memory in aged ovariectomized rhesus monkeys.

Estrogen replacement therapy (ERT) alleviates many postmenopausal symptoms but whether it also benefits cognitive function remains controversial. Further, since estrogen increases the risk of breast and uterine cancers, a new class of compounds, called selective estrogen receptor modulators (SERMs) is being considered as possible alternative to ERT. The SERM raloxifene is particularly interesting because, like estrogen, it improves lipid metabolism and reduces bone loss, without adverse effects on the breast or uterus. Little is known, however, about its effect upon cognitive function. We used a rhesus monkey model of human menopause to examine the effects of ERT and raloxifene on cognitive function. We tested 5 aged females (21-24 years old) ovariectomized long-term (10-16 years) on a battery of age-sensitive tasks, including the Delayed Response (DR), the Delayed Non-Matching-to-Sample-10 min (DNMS-10 min) and the spatial-Delayed Recognition Span Test (DRST). Monkeys were tested 5 days a week on each task for 9 consecutive months, while undergoing treatments with placebo, ethinyl estradiol (EE(2)), and raloxifene in alternating 28-days blocks. EE(2) transiently enhanced the working memory component of the spatial-DRST, but did not affect performance on the other tasks of the battery. Raloxifene had no effect on cognitive performance. These findings indicate that estradiol is able to enhance some aspects of spatial working memory in aged monkeys despite many years of estrogenic deprivation. Further, they suggest that raloxifene does not affect cognitive function after long-term ovarian hormone deprivation.

Aging↗
PubMed2005

Estradiol replacement enhances working memory in middle-aged rats when initiated immediately after ovariectomy but not after a long-term period of ovarian hormone deprivation.

The goal of the present study was to explore the effects of long-term hormone deprivation on the ability of subsequent estrogen replacement to affect cognition. Female rats, 12 months of age, underwent ovariectomies (n = 30) or sham surgeries (n = 10). Intact rats and 20 ovariectomized rats received cholesterol implants. Ten ovariectomized rats received implants containing 25% estradiol. Five months later, implants were replaced. Half of the ovariectomized rats with cholesterol implants received estradiol implants and half received new cholesterol implants. Rats with estradiol implants received new estradiol implants. Intact rats were ovariectomized and given estradiol implants. Beginning 1 wk later, working memory performance was assessed in an eight-arm radial maze across 24 d of acquisition and during eight additional trials in which a 2.5-h delay was imposed between the fourth and fifth arm choices. Estradiol replacement initiated immediately after ovariectomy at either 12 or 17 months of age significantly improved performance during acquisition and delay trials, compared with control treatment. When estradiol replacement was initiated at 17 months of age, 5 months after ovariectomy, no enhancements were evident. Uteri of rats that experienced delayed estradiol replacement weighed significantly more than uteri of ovariectomized controls but significantly less than uteri of rats that received immediate estradiol replacement. Uterine weight negatively correlated with mean errors during acquisition. These results indicate that whereas chronic estradiol replacement regimens positively affect working memory in middle-aged animals when initiated immediately after ovariectomy, estradiol replacement is not effective when initiated after long-term hormone deprivation.

Aging↗