A Mouse Model of Learning and Memory in Aging and AD

Albert Einstein Healthcare Network, Philadelphia PA

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Abstract

The focus of the proposal is Research Objective 18-Animal Models of Aging: Development of new informative mammalian models for aging research, including genetically defined and/or genetically altered animals. We aim to develop a mouse model for aging using the neurobiologically and behaviorally well-characterized eyeblink classical conditioning paradigm. The proposal represents entry into a new targeted, high priority area to develop a behavioral aging model in a short-lived species in which transgenic strains are available. The PI received NIA support to investigate eyeblink conditioning in aging rabbits and humans. Technical difficulties prevented the use of rat models of eyeblink conditioning until the late 1980s, and mouse models until the mid-1990s. With the rise of the mouse as biomedicine's model mammal, there are compelling reasons to implement a mouse model of aging and eyeblink conditioning. Five hypothesis-driven steps are proposed to establish a data base for inbred mice of the C57BL/6J strain aged 3-30 months. Hypotheses are based on previous research on eyeblink conditioning in other mammals, including humans. Mice will be tested in the delay and trace eyeblink conditioning procedures with several intervals between the CS and US balanced to assess the effects of CS-US interval and trace interval. It has been established that the essential role of the cerebellum in eyeblink conditioning is comparable in all mammals, including mice. We will evaluate the role of the hippocampus in the delay and trace procedures (documented in rabbits and humans but unknown in mice) in mice so that age-related effects can be better interpreted. Acoustic startle, Prepulse inhibition, Rotorod, and Morris swim task will be tested in all mice to assess for sensory and motor function and to integrate eyeblink conditioning data into the existing literature on behavior and aging in mice. Because of the striking parallels in behavior and raging in rabbits and humans, the rabbit eyeblink conditioning model has been used extensively as a preclinical test of cognition-enhancing drugs. Transgenic mice with AD-neuropathology tested on eyeblink conditioning will be an improved preclinical animal model. Eyeblink conditioning is impaired in normal human aging as early as the age-decade of 40s, and the 400 ms delay conditioning paradigm has a 95% sensitivity for Alzheimer's disease (AD). A mouse model of eyeblink conditioning and aging provides a means to assess a form of learning and memory in normal and transgenic mice that translates directly on a neurobiological and behavioral level to a test applicable in the assessment of human aging and the clinical assessment of AD.