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D K Ingram

Publications and source records attributed to D K Ingram.

190 records · Page 11Linked to original sources

Complex maze learning in rodents as a model of age-related memory impairment.

Research is reviewed concerning the age-related learning deficit observed in a 14-unit T-maze (Stone maze). Rats and mice of several strains representing different adult age groups are first trained to criterion in one-way active avoidance in a straight runway. Then training in the Stone maze is conducted which involves negotiation of five maze segments to avoid footshock. Results indicate a robust age-related impairment in acquisition observed in males and females, and in outbred, inbred, and hybrid strains. Pharmacological studies using the muscarinic antagonist, scopolamine, in young and aged rats indicate cholinergic involvement for accurate encoding during acquisition of this task. Retention aspects of storage and retrieval do not appear to be affected by scopolamine treatment. Bilateral electrolytic lesions to the fimbria-fornix of young rats also produce an acquisition deficit to implicate involvement of the septo-hippocampal cholinergic system in Stone maze learning. A salient feature of Stone maze performance is the tendency to demonstrate an alternation strategy in solving the maze. This strategy is exacerbated by impairment of cholinergic neurotransmission with either scopolamine treatment or fimbria-fornix lesions. Various models of hippocampal function are applied toward the psychological characterization of the Stone maze task without complete success. Future research is outlined to provide more thorough psychological characterization of maze performance, to analyze the specificity of cholinergic involvement in the task, and to test possible therapeutic interventions for alleviating the age-related impairments observed.

Aging↗

Individual differences in aging: behavioral and neurobiological correlates.

The goal of this experiment was to determine the correlations among different behavioral and neurobiological measures in aged rats. Aged Sprague-Dawley rats were given a battery of cognitive and sensorimotor tests, followed by electrophysiological assessment of sleep and biochemical measurements of various neurotransmitter systems. The behavioral tests included the following: Activity level in an open field; short-term and long-term memory of a spatial environment as assessed by habituation: spatial navigation, discrimination reversal, and cue learning in the Morris water pool; spatial memory in a T-maze motivated by escape from water; spatial memory and reversal on the Barnes circular platform task; passive avoidance; motor skills. Sleep was assessed by electrographic cortical records. The following neurotransmitter markers were examined: Choline acetyltransferase; the density of nicotinic, benzodiazepine and glutamine receptors in the cortex and caudate nucleus; endogenous levels of norepinephrine, dopamine, and serotonin in the cortex and hippocampus. The duration of bouts of paradoxical sleep was strongly correlated with several cognitive measures and selected serotonergic markers. This finding suggests that changes in sleep patterns and brain biochemistry contribute directly to deficits in learning and memory, or that the same neurobiological defect contributes to age-related impairments in sleep and in learning and memory.

Age Factors↗

N-methyl-D-aspartate receptor binding in brains of rats at different ages.

Potential age differences in N-methyl-D-aspartate (NMDA) receptor binding were evaluated in rat brain using [3H]dizocilpine and [3H]D,L-(E)-2-amino-4-propyl-5-phosphono-3-pentanoic acid (CGP 39653) as the radioligands. Neither [3H]dizocilpine nor [3H]CGP 39653 binding in hippocampus revealed any age difference (7 vs. 23-25 months) in Bmax or Kd. High-affinity [3H]dizocilpine binding showed a developmental increase (8 vs. 2 months) in hippocampus but not in frontal cortex. No senescence-related change (25 vs. 8 months) was observed in either region. The lack of senescence-related differences in these biochemical markers does not preclude the possibility of functional changes in the NMDA receptor with aging.

2-Amino-5-phosphonovalerate↗

Stereological analysis of astrocyte and microglia in aging mouse hippocampus.

Recent evidence suggests neuroglia-mediated inflammatory mechanisms may stimulate neurodegenerative processes in mammalian brain during aging. To test the hypothesis that the number of microglia and astrocytes increase in the hippocampus during normal aging, unbiased stereological techniques were used to estimate total cell number in hippocampal subregions (CA1, dentate gyrus and hilus) of male C57BL/6J mice of different ages: 4-5 months, 13-14 months and 27-28 months. Immunocytochemical visualization for microglia and astrocytes were via Mac-1 and GFAP antibody, respectively. Estimates of total microglia and astrocyte number were assessed using the optical fractionator. No statistically significant age differences were found in the numbers of microglia or astrocytes in the hippocampal regions sampled. These findings suggest that age-related increases in the total numbers of hippocampal microglia and astrocytes is not causal for observed age-related increases in cytokine response.

Aging↗

Hippocampal neuron and synaptophysin-positive bouton number in aging C57BL/6 mice.

A loss of hippocampal neurons and synapses had been considered a hallmark of normal aging and, furthermore, to be a substrate of age-related learning and memory deficits. Recent stereological studies in humans have shown that only a relatively minor neuron loss occurs with aging and that this loss is restricted to specific brain regions, including hippocampal subregions. Here, we investigate these age-related changes in C57BL/6J mice, one of the most commonly used laboratory mouse strains. Twenty-five mice (groups at 2, 14, and 28-31 months of age) were assessed for Morris water-maze performance, and modern stereological techniques were used to estimate total neuron and synaptophysin-positive bouton number in hippocampal subregions at the light microscopic level. Results revealed that performance in the water maze was largely maintained with aging. No age-related decline was observed in number of dentate gyrus granule cells or CA1 pyramidal cells. In addition, no age-related change in number of synaptophysin-positive boutons was observed in the molecular layer of the dentate gyrus or CA1 region of hippocampus. We observed a significant correlation between dentate gyrus synaptophysin-positive bouton number and water-maze performance. These results demonstrate that C57BL/6J mice do not exhibit major age-related deficits in spatial learning or hippocampal structure, providing a baseline for further study of mouse brain aging.

Aging↗

Age-related psychomotor and spatial learning deficits in 129/SvJ mice.

The 129 mouse strain has been widely used to construct mutations that model behavioral aging in humans. The current study found significant age-related declines in both psychomotor and swim maze performance of 5-, 17-, and 27-month-old 129/SvJ mice. However, the age differences in swim maze acquisition were inconsistent with poor performance in the probe trial which assesses spatial memory. This inconsistency may result from the high degree of genetic polymorphisms and age-related visual pathology which afflicts this mouse strain. Therefore, we concluded that 129/SvJ mice present a problematic model of mammalian cognitive aging and involve a risk for behavioral contamination in studies involving mutant mice derived from this strain.

Aging↗

Developing mouse models of aging: a consideration of strain differences in age-related behavioral and neural parameters.

Increased interest is emerging for using mouse models to assess the genetics of brain aging and age-related neurodegenerative diseases. Despite this demand, relatively little information is available on aging in behavioral or neuromorphological parameters in various mouse strains that are being used to create transgenic and null mutant mice. We review several issues regarding selection of appropriate strains as follows: (1) Does the behavioral parameter exhibit a significant age by strain interaction? (2) Do the strains differ in lifespan? (3) Are there potential intervening variables, such as strain-specific performance strategies or disease, in the behavioral task being investigated that would confound the desired conclusions? (4) Does the behavioral difference have an underlying neural correlate? In this context we present a conceptual model pertaining to the selection of mouse strains and behavioral parameters for genetic analyses. We also review the importance of applying stereological techniques for determining age-related structural changes in the mouse brain as well as the potential value of a database that would catalog this information. Thus, our intention is to underscore the growing importance of mouse models of brain aging and the concomitant need for additional information about mouse aging in general.

Aging↗

An assessment of behavioral aging in the Mongolian gerbil.

Male Mongolian gerbils (Meriones unguiculatus) 14-54 months old (n = 77) were evaluated in a battery of psychomotor (open field, locomotor, and runwheel activity, rotorod performance) and learning (one-way active avoidance in a straight runway and in 14-unit T-maze performance) tests. Body weight and seizure activity were also monitored. According to linear regression analysis, runwheel activity decreased with age; and the number of errors in the 14-unit T-maze increased as a function of age (ps < 0.05). None of the other behavioral measures or body weight were significantly correlated with age. This gerbil strain (Tumblebrook Farms; West Brookfield, MA) tended to be very prone to seizures with 64% of the gerbils experiencing at least one seizure while being tested. Seizures tended to occur when the gerbil was exposed to a novel situation (e.g., initial weighing, placement on the rotorod). An age-related decline in some aspects of psychomotor and learning performance was observed, suggesting the gerbil as an additional mammalian model of aging. The high incidence of seizure activity presented a complicating and confounding variable to the interpretation of the results of the behavioral tests used in the present study. Interventions to control seizure activity (e.g., systematic, controlled breeding; adaptation to apparati) in this model will likely increase its viability as a mammalian model of aging.

Aging↗

Application of gene therapy to treat age-related loss of dopamine D2 receptor.

We have investigated the feasibility of using gene therapy to attenuate the age-related decline in striatal dopamine D2 receptors (D2R) associated with reduced motor control. To this end, we have constructed an adenoviral vector containing the cDNA for the rat D2R. When injected into HeLa and HS24 cells in vitro, the vector induced an abundant message for D2R, as demonstrated by Northern analysis, and produced a membrane-bound protein capable of binding a D2R ligand, [3H]spiperone. When injected into rat striatum in vivo, the vector produced a marked increase in D2R near the site of injection, as evidenced by increased [3H]spiperone binding as well as by another more specific ligand, [125I]iodosulpride. The D2R produced in the striatum were functional, as evidenced by rotational behavior induced by a subcutaneous injection of the dopamine agonist, apomorphine. However, we did not observe any significant improvement in motor performance during preliminary experiments in which aged rats received bilateral striatal injections of the vector. In young rats, vector-induced expression of D2R in striatum was increased markedly three to five days after infection, but then declined to baseline levels by day 21. Loss of expression in aged rats proceeded at a somewhat lower rate. Because of the loss of expression and lack of significant performance enhancement in aged rats following vector injection into the striatum, we are now pursuing other strategies. These include functional assessment of the current vector in D2R null mutant mice as well as construction of new vectors that may yield more long-term expression.

Aging↗

Aged mice exhibit greater mortality concomitant to increased brain and plasma TNF-alpha levels following intracerebroventricular injection of lipopolysaccharide.

BACKGROUND: Age-related defects in the development of peripheral inflammatory responses have been observed in rodents and humans. OBJECTIVE: We examined the effects of age on a centrally injected endotoxin-induced cytokine production and cellular activation in mice. METHODS: Male C57BL/6J (B6) mice, C3H/HeN mice, and C3H/HeJ mice received an intracerebroventricular injection of lipopolysaccharide (LPS) and were sacrificed at various times (2, 4, 8 h) thereafter. ELISA for IL-1beta, IL-6, IL-12, and TNF-alpha were conducted on forebrain tissue homogenates as well as plasma samples, and lectin staining to detect activated microglia was prepared for selected brain slices. RESULTS: Intracerebroventricular injection of LPS in B6 mice produced an age-associated increase in mortality which was paralleled with a significant increase in brain and plasma levels of TNF-alpha. AntiTNF-alpha- and IL-6-immunoreactive cells possessed macrophagelike morphologies and were observed along the LPS injection tract and scattered throughout the hilus of the dorsal hippocampus and cerebral cortices. This LPS-mediated response was found to be specific in that the LPS-hyporesponsive mouse strain (C3H/HeJ) failed to demonstrate significant brain or plasma levels of TNF-alpha after LPS administration compared to C3H/HeN mice. CONCLUSION: These results suggest that the age-related increases in TNF-alpha production and mortality following the intracerebroventricular administration of LPS may be due to an increased endotoxin hypersensitivity of brain microglia/macrophages within aged animals.

Aging↗