Animal models of memory impairment

Memory impairment in the elderly resembles a mild temporal lobe dysfunction. Alterations in the hippocampal formation are also a probable basis for cognitive deficits in some animal models of ageing. For example, aged rats are impaired in hippocampal-dependent tests of spatial memory. Recent studies have revealed considerable structural integrity in the aged hippocampus, even in aged rats with the most impaired spatial memory. In contrast, atrophy/loss of cholinergic neurons in the basal forebrain and deficiency in cholinergic transduction in hippocampus correlate with the severity of spatial memory impairment in aged rats. This evidence supports the longstanding view that age-related loss of memory has a cholinergic basis. In this context, it is somewhat surprising that the use of a selective cholinergic immunotoxin in young rats to further test this hypothesis has revealed normal spatial memory after removing septo-hippocampal cholinergic neurons. Young rats with immunotoxic lesions, however, have other behavioural impairments in tests of attentional processing. These lines of research have implications for understanding the neurobiological basis of memory deficits in ageing and for selecting an optimal behavioural setting in which to examine therapies aimed at restoring neurobiological function.

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Muscarinic receptor-mediated GTP–Eu binding in the hippocampus and prefrontal cortex is correlated with spatial memory impairment in aged rats

Neurobiology of Aging ◽

10.1016/j.neurobiolaging.2006.02.016 ◽

2007 ◽

Vol 28 (4) ◽

pp. 619-626 ◽

Cited By ~ 20

Author(s):

Hai-Yan Zhang ◽

Mona L. Watson ◽

Michela Gallagher ◽

Michelle M. Nicolle

Keyword(s):

Prefrontal Cortex ◽

Spatial Memory ◽

Muscarinic Receptor ◽

Memory Impairment ◽

Aged Rats

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Central Role of Oxidative Stress in Age-Related Macular Degeneration: Evidence from a Review of the Molecular Mechanisms and Animal Models

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/7901270 ◽

2020 ◽

Vol 2020 ◽

pp. 1-19 ◽

Cited By ~ 9

Author(s):

Samuel Abokyi ◽

Chi-Ho To ◽

Tim T. Lam ◽

Dennis Y. Tse

Keyword(s):

Oxidative Stress ◽

Animal Models ◽

Macular Degeneration ◽

Molecular Mechanisms ◽

The Elderly ◽

Age Related Macular Degeneration ◽

Related Factor ◽

Vascular Endothelial ◽

Age Related ◽

Endothelial Growth Factor

Age-related macular degeneration (AMD) is a common cause of visual impairment in the elderly. There are very limited therapeutic options for AMD with the predominant therapies targeting vascular endothelial growth factor (VEGF) in the retina of patients afflicted with wet AMD. Hence, it is important to remind readers, especially those interested in AMD, about current studies that may help to develop novel therapies for other stages of AMD. This study, therefore, provides a comprehensive review of studies on human specimens as well as rodent models of the disease, to identify and analyze the molecular mechanisms behind AMD development and progression. The evaluation of this information highlights the central role that oxidative damage in the retina plays in contributing to major pathways, including inflammation and angiogenesis, found in the AMD phenotype. Following on the debate of oxidative stress as the earliest injury in the AMD pathogenesis, we demonstrated how the targeting of oxidative stress-associated pathways, such as autophagy and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, might be the futuristic direction to explore in the search of an effective treatment for AMD, as the dysregulation of these mechanisms is crucial to oxidative injury in the retina. In addition, animal models of AMD have been discussed in great detail, with their strengths and pitfalls included, to assist inform in the selection of suitable models for investigating any of the molecular mechanisms.

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Effect of age on cerebral venous circulation disturbances in the rat

Journal of Neurosurgery ◽

10.3171/jns.2000.93.2.0298 ◽

2000 ◽

Vol 93 (2) ◽

pp. 298-304 ◽

Cited By ~ 19

Author(s):

Hiroyuki Otsuka ◽

Hiroyuki Nakase ◽

Kiyoshi Nagata ◽

Katsuhiro Ueda ◽

Oliver Kempski ◽

...

Keyword(s):

Venous Occlusion ◽

Aged Rats ◽

Venous Flow ◽

Content Type ◽

Young Rats ◽

Venous Circulation ◽

Age Related ◽

Venous Infarct ◽

Group A ◽

Fine Print

Object. Mild cerebral venous circulation disturbances (CVCDs) in aged patients are frequently known to cause unexpectedly severe postoperative complications in neurosurgical practice. The object of the present study was to determine whether there are age-related differences involved in vulnerability to CVCDs.Methods. Thirty-eight male Wistar rats were used. A single cortical vein with a 100-µm diameter was occluded photochemically by using rose bengal dye and fiberoptic illumination in young (Group Y, 19 animals aged 10–14 weeks) and aged (Group A, seven animals aged 80–100 weeks) rats. Five young and seven aged animals served as sham-operated controls. Regional cerebral blood flow (rCBF) was determined from local CBF, which was measured at 25 (5 × 5) identical locations, with the occluded vein located central to the scanning field, by using a laser Doppler scanning technique every 15 minutes for 90 minutes after venous occlusion. The cerebral venous flow pattern was examined using fluorescence angiography until 90 minutes after occlusion. Histological specimens were examined 24 hours after occlusion. In Group Y, rCBF did not change significantly after venous occlusion. However, in Group A, rCBF decreased rapidly beginning 15 minutes after occlusion. Significant intergroup differences were observed 30, 60, and 90 minutes after occlusion. Venous flow arrest, which resulted in venous infarct, was observed on angiography 90 minutes after occlusion in two (10.5%) of 19 young and six (85.7%) of seven aged rats. The venous thrombus in Group A rats was significantly larger than that in Group Y rats 90 minutes after occlusion. Venous infarction was seen in all aged rats (100%) and in six young rats (31.6%); the infarct size, expressed as a percentage of the size of the ipsilateral hemisphere, was significantly larger in aged rats than in young rats.Conclusions. This study demonstrated an age-related increase in the rate and size of venous infarct following vein occlusion, suggesting that the greater vulnerability to CVCDs in the aged brain might be attributed to early and extensive hypoperfusion of circumscribed brain areas drained by the occluded vein. The larger thrombus formation in aged animals indicates that a shift in the thrombogenetic/thrombolytic equilibrium is responsible for the observed effect.

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Effects of β-adrenergic receptor agonists on drinking and arterial blood pressure in young and old rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00737.2010 ◽

2011 ◽

Vol 300 (4) ◽

pp. R1001-R1008 ◽

Cited By ~ 6

Author(s):

Robert L. Thunhorst ◽

Connie L. Grobe ◽

Terry G. Beltz ◽

Alan Kim Johnson

Keyword(s):

Blood Pressure ◽

Arterial Blood Pressure ◽

Adrenergic Receptors ◽

Adrenergic Receptor ◽

Aged Rats ◽

Middle Aged ◽

Young Rats ◽

Arterial Blood ◽

Age Related ◽

Old Rats

These experiments examined water-drinking and arterial blood pressure responses to β-adrenergic receptor activation in young (4 mo), “middle-aged” adult (12 mo), and old (29 mo) male rats of the Brown-Norway strain. We used isoproterenol to simultaneously activate β1- and β2-adrenergic receptors, salbutamol to selectively activate β2-adrenergic receptors, and the combination of isoproterenol and the β2-adrenergic receptor antagonist ICI 118,551 to stimulate only β1-adrenergic receptors. Animals received one of the drug treatments, and water drinking was measured for 90 min. About 1 wk later, animals received the same drug treatment for measurement of arterial blood pressure responses for 90 min. In some rats, levels of renin and aldosterone secretion in response to isoproterenol or salbutamol were measured in additional tests. Old and middle-aged rats drank significantly less after isoproterenol than did young rats and also had greater reductions in arterial blood pressure. Old and middle-aged rats drank significantly less after salbutamol than did young rats, although reductions in arterial blood pressure were equivalent across the ages. The β2-adrenergic antagonist ICI 118,551 abolished drinking after isoproterenol and prevented most of the observed hypotension. Renin secretion after isoproterenol and salbutamol was greater in young rats than in middle-aged rats, and wholly absent in old rats. Aldosterone secretion was reduced in old rats compared with young and middle-aged rats after treatment with isoproterenol, but not after treatment with salbutamol. In conclusion, there are age-related differences in β-adrenergic receptor-mediated drinking that can be explained only in part by age-related differences in renin secretion after β-adrenergic receptor stimulation.

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Enhanced Calcium Buffering in F344 Rat Cholinergic Basal Forebrain Neurons Is Associated With Age-Related Cognitive Impairment

Journal of Neurophysiology ◽

10.1152/jn.00301.2009 ◽

2009 ◽

Vol 102 (4) ◽

pp. 2194-2207 ◽

Cited By ~ 18

Author(s):

David Murchison ◽

Angelika N. McDermott ◽

Candi L. LaSarge ◽

Kathryn A. Peebles ◽

Jennifer L. Bizon ◽

...

Keyword(s):

Basal Forebrain ◽

Cholinergic Neurons ◽

Cognitive Status ◽

Cognitively Impaired ◽

Aged Rats ◽

Middle Aged ◽

Cholinergic Basal Forebrain ◽

Age Related ◽

Forebrain Neurons ◽

Firing Properties

Alterations in neuronal Ca2+ homeostasis are important determinants of age-related cognitive impairment. We examined the Ca2+ influx, buffering, and electrophysiology of basal forebrain neurons in adult, middle-aged, and aged male F344 behaviorally assessed rats. Middle-aged and aged rats were characterized as cognitively impaired or unimpaired by water maze performance relative to young cohorts. Patch-clamp experiments were conducted on neurons acutely dissociated from medial septum/nucleus of the diagonal band with post hoc identification of phenotypic marker mRNA using single-cell RT-PCR. We measured whole cell calcium and barium currents and dissected these currents using pharmacological agents. We combined Ca2+ current recording with Ca2+-sensitive ratiometric microfluorimetry to measure Ca2+ buffering. Additionally, we sought changes in neuronal firing properties using current-clamp recording. There were no age- or cognition-related changes in the amplitudes or fractional compositions of the whole cell Ca2+ channel currents. However, Ca2+ buffering was significantly enhanced in cholinergic neurons from aged cognitively impaired rats. Moreover, increased Ca2+ buffering was present in middle-aged rats that were not cognitively impaired. Firing properties were largely unchanged with age or cognitive status, except for an increase in the slow afterhyperpolarization in aged cholinergic neurons, independent of cognitive status. Furthermore, acutely dissociated basal forebrain neurons in which choline acetyltransferase mRNA was detected had the electrophysiological profiles of identified cholinergic neurons. We conclude that enhanced Ca2+ buffering by cholinergic basal forebrain neurons may be important during aging.

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Hypotension- and osmotically induced thirst in old Brown Norway rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00118.2009 ◽

2009 ◽

Vol 297 (1) ◽

pp. R149-R157 ◽

Cited By ~ 11

Author(s):

Robert L. Thunhorst ◽

Terry G. Beltz ◽

Alan Kim Johnson

Keyword(s):

Arterial Pressure ◽

Brown Norway ◽

Aged Rats ◽

Middle Aged ◽

Young Rats ◽

Age Related ◽

Cellular Dehydration ◽

Old Rats ◽

Middle Aged Adult ◽

Norway Rats

Compared to young cohorts, old rats drink less water in response to several thirst-inducing stimuli. In these experiments, we characterized water drinking in response to hypotension and cellular dehydration in young (4 mo), middle-aged adult (12 mo) and old (29–30 mo) male Brown Norway rats. We injected the vasodilator, minoxidil as an intravenous bolus in a range of doses (0–20 mg/kg), so that drinking responses could be compared at equivalent reductions of arterial pressure. Old rats had greatly diminished reflex tachycardia and became significantly more hypotensive after minoxidil compared with young and middle-aged rats. When compared at equivalent reductions of arterial pressure, old rats drank one-third as much as middle-aged rats, and one-fifth as much as young rats. In addition, there were age-related deficits in drinking in response to a range of administered loads of sodium (0.15–2 M NaCl, 2 ml/100 g body wt). Urinary excretion of water and sodium in response to the loads was equivalent across ages. Both middle-aged and old rats were less able than young rats to repair their water deficits after sodium loading, attributable almost entirely to their reduced drinking responses compared with young rats. Lastly, age-related declines in drinking appeared to be more severe in response to hypotension than in response to cellular dehydration.

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Aging and cardioprotection

Journal of Applied Physiology ◽

10.1152/japplphysiol.00647.2007 ◽

2007 ◽

Vol 103 (6) ◽

pp. 2120-2128 ◽

Cited By ~ 61

Author(s):

Arshad Jahangir ◽

Sandeep Sagar ◽

Andre Terzic

Keyword(s):

Animal Models ◽

Healthy Aging ◽

Myocardial Dysfunction ◽

Experimental Studies ◽

Structural Heart Disease ◽

The Elderly ◽

Therapeutic Interventions ◽

Limited Information ◽

Aging Heart ◽

Age Related

Advanced age is a strong independent predictor for death, disability, and morbidity in patients with structural heart disease. With the projected increase in the elderly population and the prevalence of age-related cardiovascular disabilities worldwide, the need to understand the biology of the aging heart, the mechanisms for age-mediated cardiac vulnerability, and the development of strategies to limit myocardial dysfunction in the elderly have never been more urgent. Experimental evidence in animal models indicate attenuation in cardioprotective pathways with aging, yet limited information is available regarding age-related changes in the human heart. Human cardiac aging generates a complex phenotype, only partially replicated in animal models. Here, we summarize current understanding of the aging heart stemming from clinical and experimental studies, and we highlight targets for protection of the vulnerable senescent myocardium. Further progress mandates assessment of human tissue to dissect specific aging-associated genomic and proteomic dynamics, and their functional consequences leading to increased susceptibility of the heart to injury, a critical step toward designing novel therapeutic interventions to limit age-related myocardial dysfunction and promote healthy aging.

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Experimental Models of Glaucoma: A Powerful Translational Tool for the Future Development of New Therapies for Glaucoma in Humans—A Review of the Literature

Medicina ◽

10.3390/medicina55060280 ◽

2019 ◽

Vol 55 (6) ◽

pp. 280 ◽

Cited By ~ 4

Author(s):

Karine Evangelho ◽

Claudio A. Mastronardi ◽

Alejandra de-la-Torre

Keyword(s):

Animal Models ◽

Clinical Application ◽

Complex Disease ◽

Ganglion Cells ◽

Experimental Period ◽

The Elderly ◽

Clinical Results ◽

Experimental Models ◽

Common Complex Disease ◽

Age Related

Glaucoma is a common complex disease that leads to irreversible blindness worldwide. Even though preclinical studies showed that lowering intraocular pressure (IOP) could prevent retinal ganglion cells loss, clinical evidence suggests that lessening IOP does not prevent glaucoma progression in all patients. Glaucoma is also becoming more prevalent in the elderly population, showing that age is a recognized major risk factor. Indeed, recent findings suggest that age-related tissue alterations contribute to the development of glaucoma and have encouraged exploration for new treatment approaches. In this review, we provide information on the most frequently used experimental models of glaucoma and describe their advantages and limitations. Additionally, we describe diverse animal models of glaucoma that can be potentially used in translational medicine and aid an efficient shift to the clinic. Experimental animal models have helped to understand the mechanisms of formation and evacuation of aqueous humor, and the maintenance of homeostasis of intra-ocular pressure. However, the transfer of pre-clinical results obtained from animal studies into clinical trials may be difficult since the type of study does not only depend on the type of therapy to be performed, but also on a series of factors observed both in the experimental period and the period of transfer to clinical application. Conclusions: Knowing the exact characteristics of each glaucoma experimental model could help to diminish inconveniences related to the process of the translation of results into clinical application in humans.

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