Rodent Models Of Aging Research Articles

Age‐Related Sympathetic Ganglionic Neuropathology: Human Pathology And Animal Models

Systematic studies of the autonomic nervous system of human subjects and development of well‐defined animal models have begun to substantially improve our understanding of the pathogenesis of autonomic dysfunction in aging and may eventually provide strategies for intervention. Neuropathological studies of the sympathetic ganglia of aged human subjects and rodent models have demonstrated that neuroaxonal dystrophy involving intraganglionic terminal axons and synapses is a robust, unequivocal and consistent neuropathological finding in the aged sympathetic nervous system of man and animals. Quantitative studies have demonstrated that markedly swollen argyrophilic dystrophic axon terminals develop in the prevertebral superior mesenteric (SMG) and coeliac, but to a much lesser degree in the superior cervical ganglia (SCG) as a function of age, sex (males more than females) and diabetes. Dystrophic axons were immunoreactive for neuropeptide Y, tyrosine hydroxylase, dopamine‐beta‐hydroxylase, trkA and p75(NTR), an immunophenotype consistent with their origin from postganglionic sympathetic neurons, and contained large numbers of highly phosphorylated neurofilaments or tubulovesicular elements. The sympathetic ganglia of aged rodents also showed the hallmark changes of neuroaxonal dystrophy as a function of age and location (many more in the SMG than in the SCG). Plasticity‐related synaptic remodeling could represent a highly vulnerable target of the aging process. The fidelity of animal models to the neuropathology of aged humans suggests that similar pathogenetic mechanisms may be involved in both and that therapeutic advances in animal studies may have human application.

Age-related decline in striatal dopamine release and motoric function in Brown Norway/Fischer 344 hybrid rats

The Brown Norway/Fischer 344 F1 hybrid rats (F344BNF 1) is a newer rat model and is emerging as an important rodent model of aging. In the present study we used motoric performance tests, intracerebral microdialysis, and neurochemical measures of postmortem brain tissue to investigate the effects of aging in young (4–5 months), middle-aged (18–19), and old (24–25 months) F344BNF 1 hybrid rats. We observed that old F344BNF 1 rats exhibited decreased motoric performance, and lower levels of spontaneous and d-amphetamine-induced locomotor activity than those observed in young F344BNF 1 rats. Microdialysis measures of extracellular basal levels of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and 4-hydroxy-3-methoxyphenylacetic acid (HVA) were significantly diminished in the striata of the middle-aged and old rats as compared to levels in young animals. In addition, d-amphetamine-evoked overflow of DA was significantly decreased in the middle-aged and aged rat striatum as compared to DA overflow in young F344BNF 1 rats. Studies of postmortem brain tissue showed that the changes in overflow of DA correlated with significantly lower DA tissue content in ventral striatum and midbrain. Moreover, both dopamine turnover ratios (DOPAC/DA, HVA/DA) and the serotonin turnover ratio (5-HIAA/5-HT) were significantly elevated in the ventral striatum and nucleus accumbens. The results of this study demonstrate a correlation between reductions in striatal DA neurochemistry and diminished motor function in aged F344BNF 1 rats.

Brain-behavior linkages in aged rodent models: strategies for examining individual differences

Brain-behavior linkages in aged rodent models: strategies for examining individual differences

The effects of taurine in a rodent model of aging.

A number of excellent review articles have examined the various physiological roles of taurine in adult and developing organisms19, 20, 39. A conclusion that can be drawn from these various reviews is that there is a dearth of information on the role of taurine in aging and senescence. A few studies have examined the tissue content of taurine in aging animal models. In general taurine content seems to decline modestly with advanced age. What is unclear is whether the aging process may increase the demand for the protective and regulatory actions of taurine in cellular homeostasis. This article will briefly review what is known about changes in taurine content and function during senescence and describe our recent studies of taurine supplementation using a common rodent model of aging. We will also discuss the potential consequences of a diminished cytoprotective role of taurine in advanced aging due to a age-related decrement in taurine homeostasis.

Delayed matching-to-sample performance by rats in a new avoidance-motivated maze: Response to scopolamine and fimbria-fornix lesions

A new avoidance-motivated detour-maze in which memory for an immediately preceding sample event could be assessed was evaluated by testing seven 6-month-old male F-344 rats with a delayed matching-to-sample (DMTS) paradigm. Rats first received extensive pretraining with this paradigm over several months and after a minimum of 1,390 choice-trials demonstrated great proficiency in this maze. Studies were then conducted to establish cholinergic and hippocampal involvement in the DMTS task by using drug manipulations (scopolamine and physostigmine), and after lesions to the fimbria-fornix (FF) pathway. A high dose (1.0 mg/kg) of scopolamine but not a low dose (0.3 mg/kg) significantly interfered with choice accuracy as measured by errors and trials to criterion; physostigmine (0.01 and 0.03 mg/kg) had no significant effect; and fimbria lesions significantly disrupted both choice accuracy and runtime performance. Disruption was most pronounced on difficult problems (different paths to the goal). After lesions only, considerable within-trial perseverative errors occurred during the early postlesion weeks on four difficult problems from among the 18 tested. Results were discussed in terms of (a) specificity of this disruption, (b) indications of proactive interference effects, and (c) the movement-related excitation component of maze learning. The present results accord with earlier findings of disruption by scopolamine and FF lesions in a 14-unit T-maze, both mazes having similar performance requirements of shock avoidance and multiple 90-degree turns along the paths to the goal. The present results affirm that this new detour maze provides a viable approach for assessing cognitive performance in a within-subjects design and thereby offers new possibilities for testing various aspects of cognitive processing, particularly for aged rodent models, in a complex aversive situation.

An Analysis of Synapsin II, a Neuronal Phosphoprotein, in Postmortem Brain Tissue From Alcoholic and Neuropsychiatrically Ill Adults and Medically Ill Children and Young Adults

Synapsin II (formerly known as protein III) is a synaptic vesicle-associated neuronal phosphoprotein that may be involved in the regulation of neurotransmitter release. Synapsin II was studied in postmortem brain samples from 132 individuals with various neuropsychiatric and medical diagnoses. Molecular weight variants of synapsin II were present in 73% of samples from alcoholic individuals but in only 31% of samples from non-diseased individuals, thus confirming our two previous reports of an association between synapsin II variants and alcoholism. The presence of synapsin II variants was not correlated with age or nutritional state. Synapsin II variants were also present in 56% of samples from individuals with schizophrenia and 41% of samples from individuals with Huntington's disease. Synapsin II variants were present in samples from children and young adults, consistent with the possibility that synapsin II variants may reflect a genetically inherited trait. Synapsin II variants were not found in any of 18 rodent models of alcoholism, aging, or vitamin B deficiency, suggesting that synapsin II variants may be a uniquely human trait.

Effects of aging on insulin synthesis and secretion. Differential effects on preproinsulin messenger RNA levels, proinsulin biosynthesis, and secretion of newly made and preformed insulin in the rat.

Aging in men and rodents is associated with a marked decline in glucose stimulated insulin secretion by pancreatic beta cells (B cells). Secreted insulin is the end result of a series of steps along the biosynthetic protein-secretion pathway, including insulin gene transcription, processing of transcripts to preproinsulin mRNA, translation of mRNA, segregation and processing of newly made proinsulin in secretory vesicles, proinsulin to insulin conversion, transport of vesicles to the plasma membrane, and exocytosis. We have examined the influence of age at three stages along this pathway: preproinsulin mRNA levels, proinsulin synthesis, and secretion of newly made and preformed insulin, using Fischer rats, a widely studied rodent model of aging. Pancreatic weights and total insulin contents, islet sizes, and mean insulin content per islet were the same in young adult (4-5 mo) and senescent (21-22 mo) animals. There was no effect of age on preproinsulin mRNA levels in whole pancreata of fed animals, or in isolated islets cultured for 16 h in 5.5 mM glucose. Proinsulin biosynthesis and the secretion of newly made insulin were compared in isolated islets preincubated in 5.5 mM glucose. After a pulse label at 16.7 mM glucose, proinsulin synthesis, assayed by immunoprecipitation, was decreased 16% in 7 mo islets and 39% in 21-22 mo islets, compared with 4-5 mo islets, though total protein synthesis was not reduced. When chased at 2.8 mM glucose, 4-5 month and 21-22 mo islets showed no difference in release of preformed or newly made insulin. When chased at 16.7 mM glucose, there was a significant decrease in the secretion of newly made insulin in the old islets compared with the young islets. There was preferential release of newly made insulin over preformed insulin in both young and old islets. However, since secretion of preformed insulin was decreased much more than secretion of newly made insulin in senescent islets, these displayed a two- to threefold increase in the proportion of newly made insulin relative to total immunoreactive insulin released compared with young adult islets. The differential effects of aging on these steps in the insulin synthesis-secretion pathway may be due to varying impairments in signals transducing the glucose stimulus into the wide range of B cell responses to glucose.