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Thomas C Foster

Publications and source records attributed to Thomas C Foster.

14 recordsLinked to original sources
PubMed2026

Individual Differences in Cognitive Aging Rodent Datasets (ID-CARD): A collaborative platform for behavioral analysis across the lifespan.

Understanding cognitive aging requires approaches that capture individual variability while enabling integration across studies. In rodent models, behavioral data are central to this effort, yet cross-laboratory differences in experimental design limit comparability and constrain secondary analysis. To address this gap, we developed the Individual Differences in Cognitive Aging Rodent Datasets (ID-CARD), a first-of-its-kind collaborative repository aggregating trial-level Morris water maze data from multiple laboratories. ID-CARD is designed to support large-scale, integrative analyses and to facilitate secondary use of existing behavioral data in alignment with emerging data-sharing and transparency initiatives. Rather than imposing retrospective harmonization of experimental protocols, we implemented a normalization and modeling framework that enables comparison of learning trajectories while preserving meaningful variation across studies. Behavioral data from > 5000 rats spanning common strains, both sexes, and multiple ages were normalized in training and performance domains and fit with a logarithmic function to derive an error accumulation rate coefficient (EARC) as a measure of spatial learning. Age was strongly associated with increased EARC, indicating attenuated learning, even after adjusting for non-spatial cue performance. Analyses of goodness of fit revealed systematic structure in learning dynamics, where age was associated with reduced learning-curve conformity after accounting for overall performance. Inter-individual variability in spatial learning also increased with age, with strain-specific interactions. These findings demonstrate that integrated analysis of heterogeneous behavioral datasets can yield robust, individual-level insights into cognitive aging. ID-CARD provides a scalable resource and analytic framework to advance discovery in behavioral neuroscience by enabling reuse, integration, and comparative analysis of existing data.

Cognitive aging↗
PubMed2006

Biological markers of age-related memory deficits: treatment of senescent physiology.

In humans, age-related memory impairments begin in mid-life and cognitive weakening continues with advancing age. An important aspect of defining memory decline is the distinction between dementia as a result of neurological diseases, such as Alzheimer's disease, and memory loss not specifically associated with disease. Within the population of elderly without dementia, there is considerable variability in memory. This variability is likely to be a result of the interaction of genetic make-up and environment, which influences several processes for cell maintenance and repair including oxidative damage and cholesterol metabolism, leading to disruption of Ca(2+) homeostasis, and ultimately Ca(2+)-dependent processes that underlie memory. In humans, several methods have been employed to distinguish biological markers of aging that may predict cognitive decline. Memory deficits associated with normal aging and Alzheimer's disease have been linked to a decrease in the volume of brain structures, such as the hippocampus and to genetic markers, such as apolipoprotein E. In this regard, examination of CSF for biomarkers of disease can help in differentiating normal aging from Alzheimer's disease. Measures of oxidative stress and cholesterol in plasma correlate with memory deficits; research suggests that treatments that reduce oxidative stress or cholesterol through exercise, diet or the use of antioxidant vitamins may delay cognitive decline.Nevertheless, to date, very little treatment is available to reverse memory deficits in later life. In this regard it is important to identify individuals at risk for memory deficits in order to discriminate different mechanisms of brain aging and develop treatments. Considerable effort is driving research to develop accurate biological markers of brain aging. In turn, these markers will provide information on mechanisms of aging and cognitive decline and point to potential treatments. Accordingly, the effectiveness of treatment needs to be verified for both cognitive changes and biological markers that are specific for age-related memory deficits.

Aging↗
PubMed2005

Gene therapy restores vision-dependent behavior as well as retinal structure and function in a mouse model of RPE65 Leber congenital amaurosis.

Retinal pigment epithelium-specific protein 65 kDa (RPE65) is a protein responsible for isomerization of all-trans-retinaldehyde to its photoactive 11-cis-retinaldehyde and is essential for the visual cycle. RPE65 mutations can cause severe, early onset retinal diseases such as Leber congenital amaurosis (LCA). A naturally occurring rodent model of LCA with a recessive nonsense Rpe65 mutation, the rd12 mouse, displays a profoundly diminished rod electroretinogram (ERG), an absence of 11-cis-retinaldehyde and rhodopsin, an overaccumulation of retinyl esters in retinal pigmented epithelial (RPE) cells, and photoreceptor degeneration. rd12 mice were injected subretinally at postnatal day 14 with rAAV5-CBA-hRPE65 vector. RPE65 expression was found over large areas of RPE soon after treatment. This led to improved rhodopsin levels with ERG signals restored to near normal. Retinyl ester levels were maintained at near normal, and fundus and retinal morphology remained normal. All parameters of restored retinal health remained stable for at least 7 months. The Morris water maze behavioral test was modified to test rod function under very dim light; rd12 mice treated in one eye performed similar to normally sighted C57BL/6J mice, while untreated rd12 mice performed very poorly, demonstrating that gene therapy can restore normal vision-dependent behavior in a congenitally blind animal.

Animals↗
PubMed2005

Prodynorphin knockout mice demonstrate diminished age-associated impairment in spatial water maze performance.

Dynorphins, endogenous kappa-opioid agonists widely expressed in the central nervous system, have been reported to increase following diverse pathophysiological processes, including excitotoxicity, chronic inflammation, and traumatic injury. These peptides have been implicated in cognitive impairment, especially that associated with aging. To determine whether absence of dynorphin confers any beneficial effect on spatial learning and memory, knockout mice lacking the coding exons of the gene encoding its precursor prodynorphin (Pdyn) were tested in a water maze task. Learning and memory assessment using a 3-day water maze protocol demonstrated that aged Pdyn knockout mice (13-17 months) perform comparatively better than similarly aged wild-type (WT) mice, based on acquisition and retention probe trial indices. There was no genotype effect on performance in the cued version of the swim task nor on average swim speed, suggesting the observed genotype effects are likely attributable to differences in cognitive rather than motor function. Young (3-6 months) mice performed significantly better than aged mice, but in young mice, no genotype difference was observed. To investigate the relationship between aging and brain dynorphin expression in mice, we examined dynorphin peptide levels at varying ages in hippocampus and frontal cortex of WT 129SvEv mice. Quantitative radioimmunoassay demonstrated that dynorphin A levels in frontal cortex, but not hippocampus, of 12- and 24-month mice were significantly elevated compared to 3-month mice. Although the underlying mechanisms have yet to be elucidated, the results suggest that chronic increases in endogenous dynorphin expression with age, especially in frontal cortex, may adversely affect learning and memory.

Age Factors↗
PubMed2005

Intracellular calcium stores contribute to increased susceptibility to LTD induction during aging.

Release of Ca(2+) from intracellular Ca(2+) stores (ICS) is involved in age-related changes in the induction of long-term potentiation. However, the role of this Ca(2+) source for the increased susceptibility to long-term depression (LTD) with advanced age is unknown. Extracellular excitatory postsynaptic field potentials were recorded from CA3-CA1 synaptic contacts from hippocampal slices obtained from young (5-8 months) and aged (22-24 months) male Fischer 344 rats. Blockade of Ca(2+)-release from ICS by cyclopiazonic acid, thapsigargin, or ryanodine blocked LTD induction in aged rats. Impaired LTD was not simply due to a loss of a Ca(2+) source. The idea that ICS may play prominent role in regulating synaptic modifiability through regulation of cell excitability and the timing of pre and postsynaptic activity is discussed.

Aging↗
PubMed2005

Interaction of rapid signal transduction cascades and gene expression in mediating estrogen effects on memory over the life span.

Estrogen treatment during middle-age postpones memory impairments, which depend on the hippocampus. However, estrogen responsiveness diminishes with advanced age. The challenge remains to determine, which processes are important for delaying brain aging and the mechanisms for decreased sensitivity. Estrogen can influence transcription through estrogen receptors (e.g., ERalpha and ERbeta) and membrane effects on rapid signal transduction cascades ultimately influencing the phosphorylation state of transcription factors. In middle-aged animals, the membrane effects involve Ca2+ and G-protein cascades, which rapidly counteract senescent physiology. Moreover, estrogen induces transcription for elements of signal transduction cascades that decline with age. Together, the rapid and genomic influences promote synaptic transmission and cell growth. Thus, interruption of genomic/membrane interactions due to loss of ERs, disruption of the hormone cycle, or uncoupling of the hormone/receptor system associated with extended exposure to estrogen could contribute to a decline in these biological pathways during aging.

Aging↗
PubMed2004

Enhanced long-term potentiation during aging is masked by processes involving intracellular calcium stores.

The contribution of Ca(2+) release from intracellular Ca(2+) stores (ICS) for regulation of synaptic plasticity thresholds during aging was investigated in hippocampal slices of old (22-24 mo) and young adult (5-8 mo) male Fischer 344 rats. Inhibition of Ca(2+)-induced Ca(2+) release by thapsigargin, cyclopiazonic acid (CPA), or ryanodine during pattern stimulation near the threshold for synaptic modification (5 Hz, 900 pulses) selectively induced long-term potentiation (LTP) to CA1 Schaffer collateral synapses of old rats. Increased synaptic strength was specific to test pathways and blocked by AP-5. Intracellular recordings demonstrated that ICS plays a role in the augmentation of the afterhyperpolarization (AHP) in old rats. The decrease in the AHP by ICS inhibition was reversed by the L-channel agonist, Bay K8644. Under conditions of ICS inhibition and a Bay K8644-mediated enhancement of the AHP, pattern stimulation failed to induce LTP, consistent with the idea that the AHP amplitude shapes the threshold for LTP induction. Finally, ICS inhibition was associated with an increase in the N-methyl-d-aspartate (NMDA) receptor component of synaptic transmission in old animals. This increase in the synaptic response was blocked by the calcineurin inhibitor FK506. The results reveal an age-related increase in susceptibility to LTP-induction that is normally inhibited by ICS and suggest that the age-related shift in Ca(2+) regulation and Ca(2+)-dependent synaptic plasticity is coupled to changes in cell excitability and NMDA receptor function through ICS.

Aging↗
PubMed2003

Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment.

Gene expression microarrays provide a powerful new tool for studying complex processes such as brain aging. However, inferences from microarray data are often hindered by multiple comparisons, small sample sizes, and uncertain relationships to functional endpoints. Here we sought gene expression correlates of aging-dependent cognitive decline, using statistical profiling of gene microarrays in well powered groups of young, mid-aged, and aged rats (n = 10 per group). Animals were trained on two memory tasks, and the hippocampal CA1 region of each was analyzed on an individual microarray (one chip per animal). Aging- and cognition-related genes were identified by testing each gene by ANOVA (for aging effects) and then by Pearson's test (correlating expression with memory). Genes identified by this algorithm were associated with several phenomena known to be aging-dependent, including inflammation, oxidative stress, altered protein processing, and decreased mitochondrial function, but also with multiple processes not previously linked to functional brain aging. These novel processes included downregulated early response signaling, biosynthesis and activity-regulated synaptogenesis, and upregulated myelin turnover, cholesterol synthesis, lipid and monoamine metabolism, iron utilization, structural reorganization, and intracellular Ca2+ release pathways. Multiple transcriptional regulators and cytokines also were identified. Although most gene expression changes began by mid-life, cognition was not clearly impaired until late life. Collectively, these results suggest a new integrative model of brain aging in which genomic alterations in early adulthood initiate interacting cascades of decreased signaling and synaptic plasticity in neurons, extracellular changes, and increased myelin turnover-fueled inflammation in glia that cumulatively induce aging-related cognitive impairment.

Aging↗
PubMed2003

Interaction of age and chronic estradiol replacement on memory and markers of brain aging.

The current study examined effects of chronic estradiol replacement on cognition and biomarkers of aging. Young, middle-aged, and aged rats were ovariectomized and implanted with blank capsules, or capsules containing high or low doses of estradiol benzoate (EB). Three weeks later, animals were tested on inhibitory avoidance and cue and spatial discrimination on the Morris water maze. High plasma estradiol levels were associated with slower swim speed and impaired retention of inhibitory avoidance. No effect of EB treatment was observed for acquisition of the spatial discrimination task, however, a dose by age interaction was observed for retention of spatial discrimination such that higher retention scores were observed for young, middle-aged and aged animals under blank, low and high dose conditions, respectively. EB treatment reversed several hippocampal markers of age-related memory impairment, blocking induction of long-term depression and decreasing cytosolic calcineurin activity. Results indicate that the level of chronic hormone replacement interacts with age to influence hippocampal function.

Aging↗
PubMed2003

The neurotoxicity induced by ethanol withdrawal in mature organotypic hippocampal slices might involve cross-talk between metabotropic glutamate type 5 receptors and N-methyl-D-aspartate receptors.

BACKGROUND: We recently reported that the sodium salt of acamprosate (Na-acamprosate) demonstrates the characteristics of an antagonist at metabotropic glutamate type 5 receptors (mGluR5s) rather than at N-methyl-d-aspartate receptors (NMDARs). Because mGluR5s are able to enhance the function of NMDARs, this interplay may be involved in the dysregulation of glutamatergic transmission during ethanol withdrawal. The following studies use organotypic hippocampal slice cultures at a mature age to investigate the potential for this interplay in the neurotoxicity associated with withdrawal from long-term ethanol exposure. METHODS: At 25 days in vitro, organotypic hippocampal slice cultures prepared from male and female 8-day-old rats were exposed to an initial concentration of 100 mM ethanol for 10 days before undergoing a 24-hr period of withdrawal. The effects of Na-acamprosate; 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at mGluR5s; 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, a noncompetitive antagonist at mGluR1s; dizocilpine (MK-801), a noncompetitive NMDAR antagonist; and staurosporine on the neurotoxicity induced by ethanol withdrawal were assessed by determining differences in propidium iodide uptake. Polypeptide levels of mGluR5s and the NR1 and NR2B subunits of NMDARs were also determined via Western blot analyses after 10 days of ethanol exposure. RESULTS: Significant neurotoxicity was always evident in the CA1 hippocampal region after a 24-hr withdrawal period. This spontaneous neurotoxicity resulted from intrinsic changes induced by the long-term presence of ethanol. Na-acamprosate (200-1000 microM), SIB-1893 (200-500 microM), MK-801 (20 microM), and staurosporine (200 nM) were all neuroprotective. The polypeptide levels of mGluR5s and NR1 and NR2B subunits of NMDARs were all increased after ethanol exposure; however, the increase in mGluR5s did not achieve statistical significance. CONCLUSIONS: From this model of long-term ethanol exposure and withdrawal, the functional interplay between mGluR5s and NMDARs might represent a novel target for the prevention of neurotoxicity associated with ethanol withdrawal.

Animals↗
PubMed2002

Calcineurin as a potential contributor in estradiol regulation of hippocampal synaptic function.

Estradiol influences Ca(2+) regulation and Ca(2+)-dependent synaptic plasticity, suggesting estrogenic effects on Ca(2+)-dependent enzymes that regulate synaptic plasticity may mediate hormonal influences on cognition. In ovariectomized female rats, injections of estradiol benzoate (EB, 10 microg) reduced hippocampal cytosolic activity of serine/threonine protein phosphatases, calcineurin and protein phosphatase 1 (PP1). The decreased activity was rapid and recovered substantially over a 24-h period. Decreased calcineurin activity was associated with a decreased level of calcineurin in the cytosol. In contrast, expression of PP1 was not altered suggesting that the level of calcineurin activity regulated PP1 activity. EB application to hippocampal slices rapidly decreased cytosolic phosphatase activity, which was not blocked by the estrogen receptor antagonist, ICI 182780. Decreased phosphatase activity was associated with an increase in CA3-CA1 synaptic transmission. In addition, EB application shifted synaptic plasticity, blocking the induction of long-term depression and facilitating the establishment of long-term potentiation. The reduction in calcineurin activity and shift in synaptic plasticity were mimicked to a lesser extent by 17-alpha-estradiol. From these results we suggest that EB can act to rapidly influence Ca(2+) signaling pathways including the activity of Ca(2+)-regulated phosphatases involved in synaptic plasticity.

Animals↗
PubMed2002

17beta-estradiol benzoate decreases the AHP amplitude in CA1 pyramidal neurons.

Disruption of Ca(2+) homeostasis is hypothesized to mediate several electrophysiological markers of brain aging. Recent evidence indicates that estradiol can rapidly alter Ca(2+)-dependent processes in neurons through nongenomic mechanisms. In the current study, electrophysiological effects of 17beta-estradiol benzoate (EB) on the Ca(2+)-activated afterhyperpolarization (AHP) were investigated using intracellular sharp electrode recording in hippocampal slices from ovariectomized Fischer 344 female rats. The AHP amplitude was enhanced in aged (22-24 mo) compared with young (5-8 mo) rats and direct application of EB (100 pM) reduced the AHP in aged rats. The age-related difference was due, in part, to the increased AHP amplitude of aged animals, since an EB-mediated decrease in the AHP could be observed in young rats when the extracellular Ca(2+) was elevated to increase the AHP amplitude. In aged rats, bath application of EB occluded the ability of the L-channel blocker, nifedipine (10 microM), to attenuate the AHP. The results support a role for EB in modifying hippocampal Ca(2+)-dependent processes in a manner diametrically opposite that observed during aging, possibly through L-channel inhibition.

Aging↗
PubMed2002

Calcium dysregulation in the aging brain.

The idea that age-related cognitive decline is associated with disruption of calcium (Ca2+) homeostasis has been investigated over the past two decades. Much of this work has focused on the hippocampus because hippocampal-dependent memory is age sensitive. It is now well established that Ca(2+)-dependent processes such as susceptibility to neurotoxicity, the afterhyperpolarization amplitude, induction of synaptic plasticity, and long-term potentiation and long-term depression are altered with age. Recent work has identified changes in Ca2+ signaling pathways that may underlie the development of these biological markers of aging. This review considers recent findings concerning interactions between the various Ca(2+)-dependent processes, with special emphasis on the role of altered Ca2+ regulation and disruption of Ca2+ signaling pathways in mediating the expression of biological and behavioral markers of brain aging.

Aging↗