Advances in the treatment and understanding of AD are hampered by the lack of appropriate animal model systems. None of the model systems studied have led to the development of any of the neuropathological hallmarks of AD, such as neuritic plaques and neurofibrillary tangles. The human neurofilament mid-sized transgenic mouse (NF-M) has been neuropathologically characterized and found to possess some of the pathological features of AD. Whether or not these animals represent a more adequate model of the cognitive deficits of AD than the models currently available remains to be determined. The goal of this project is to determine the degree to which the NF-M mouse models the cognitive and pharmacological features of AD relative to operationally defined criteria for an adequate animal model system. We will test the hypotheses that a) the NF-M transgene produces learning and memory deficits; b) these cognitive impairments follow a time course similar to the time course of development of neuropathologic lesions; c) the NF-M transgenic mice are hypersensitive to anticholinergic agents and hyposensitive to cholinomimetic agents; and d) the in vivo cognitive deficits are reflected in deficits in the hippocampal long term potentiation (LTP) model of learning and memory. Pilot studies have been conducted to determine the appropriate parameters and procedures for the proposed behavioral studies. The locomotor activity and open field behavior of non-transgenic mice have been studies and parameters for assessing short and long-term habituation have been established. Passive avoidance acquisition and retention parameters have been outlined in non-transgenic mice with and without cognitive deficits caused by lesions of the cholinergic forebrain. Animals transgenic for the human vasopressin gene have been behaviorally characterized and studied using a subset of the assessment procedures proposed for the study of NF-M mice. Finally, fifteen DBA/J2 female mice have been mated with 10 NF-M transgenic males and a mating schedule has been worked out to provide the requisite numbers of animals for the proposed studies. Longitudinal studies of learning and memory will begin within the next 4 weeks when the first of the NF-M transgenic litters are weaned.
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