The choice of epoch duration is of prime importance and is highly related to the outcome of EEG analysis. One of the major inconveniences encountered in sleep studies is the time-consuming labor involved in electroencephalography (EEG) analysis. While each model is valuable within its own constraints and the experiments performed are guided by specific hypotheses, we seek to expand upon their methodology by offering guidance spanning from issues of mouse husbandry to choices of behavioral tests and routes of drug administration that might increase the external validity of studies and consequently optimize the translational aspect of preclinical research. Rather, the focus should be directed to the question of how the mouse genome can cope with the over-expression of the protein coded by transgene(s). We attempt to provide general guidelines and establish criteria for modeling dementia in a mouse however, interpretations of obtained results should avoid a reductionist “one gene, one disease” explanation of model characteristics. The selection of tests performed to evaluate the phenotype of a model should be guided by the key behavioral hallmarks that characterize human disorder and their homology to mouse cognitive systems. In this chapter, we describe major behavioral hallmarks of tauopathies, briefly outline the genetics underlying familial cases, and discuss the arising implications for modeling the disease in transgenic mouse systems.
At present, familial cases of dementia provide the most promising foundation for modeling neurodegenerative tauopathies, a group of heterogeneous disorders characterized by prominent intracellular accumulation of hyperphosphorylated tau protein. Its clinical diagnosis is preceded by a long prodromal period of brain pathology that encompasses both formation of extracellular amyloid and intraneuronal tau deposits in the brain and widespread neuronal death. The major symptom of Alzheimer’s disease is dementia progressing with age. Thus, implantable, peristaltic pumps provide a number of benefits compared to externalized chronic catheters and confer specific delivery to target organs. However, this was confined to the medulla, as the histone H3-acetylation was similar in the cortex of vehicle and MS275 infused rats, suggesting targeted drug delivery without systemic spillover. HDAC inhibition resulted in a significant increase in histone H3-acetylation, the hallmark for histone deacetylase inhibition. Second, in a separate group of rats, the histone deacetylase (HDAC) inhibitor, MS275, was delivered to the renal medulla. First, the vasopressin receptor-2 agonist, dDAVP, was delivered to the renal medulla resulting in a significant increase in water retention, urine osmolality and aquaporin-2 expression and phosphorylation. In this study, two protocols were used to demonstrate accurate drug delivery to the renal medulla. The current study describes a method using programmable, implantable peristaltic pumps to chronically deliver drugs in vivo, while allowing animals to remain undisturbed for accurate physiological measurements. The results suggest that animal stress and mortality related to oral gavage can be minimized when the procedure is carried out by an experienced technician.Ĭlassic methods for delivery of agents to specific organs are technically challenging and causes superfluous stress. Histopathology showed acute esophagitis and pleurisy, indicative of perforation of the esophagus, in the two mice that died but no abnormalities in the other mice. Serum cortisol levels at the time of euthanasia in mice in both groups were within the normal range. Mice subjected to gavage did not undergo changes in food or water consumption during the study, and their mean body weights and relative organ weights were similar to those of mice in the control group. The mortality rate of mice in this study was 15%. Gavage was carried out once per d for 5 d per week over 6 consecutive weeks. The authors evaluated whether oral gavage causes behavioral indicators of stress, increased mortality rate, alterations in food and water consumption and body weight or histological lesions in CD-1 mice. Oral gavage is a widely used method for administering substances to animals in pharmacological and toxicological studies.
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