Using the model system of eyeblink classical conditioning and other forms of learning and memory (hippocampus-dependent contextual fear conditioning, cerebellum-dependent rotorod), we propose to investigate structural and functional changes and associated mechanisms in the cerebellum and hippocampus over the life span in the mouse. Normal aging affects eyeblink classical conditioning similarly in all species in which older organisms have been tested, including humans. Mice - with their short life span, mapped genome, and capacity to perform a number of cognitive and behavioral tasks - are an invaluable resource to use for understanding causes of age-related impairment in learning and memory. Various brain structures and associated cognitive capacities are differentially affected in normal aging. In hippocampus- dependent learning and memory, aging is associated with reduced functional capacity of CA1 pyramidal cells, but neuron number is stable. Cerebellum-dependent learning and memory is associated with Purkinje cell loss and age-related impairment in morphology as well as function. Traditionally, cerebellar and hippocampal substrates of learning, memory, and aging have been studied independently. The major aim of this proposal is to use mouse models to test hypotheses about cerebellar-dependent and hippocampus- dependent mechanisms responsible for age-related deficits in learning and memory.
Aims 1 address associations between neuron and glia numbers in cerebellar cortex and deep nuclei and hippocampal CA1 fields and several forms of learning and memory in C57BL/6 mice.
Aim 2 explores neuron and glia number and learning in young homozygous and aging heterozygous Purkinje cell degeneration (pcd) mutant mice.
Aims 3 and 4 examine functional aging of neurons in hippocampal and cerebellar slices, respectively.
Aim 5 initiates pilot testing of the potential of GABA infusions to ameliorate impaired learning. Relevance: Research over the life span of mice using measures with parallels to human aging has the potential to extend knowledge about individual variation and differential aging in brain regions that are the substrates of learning and memory. The extended life expectancy of people in the United States and the world adds urgency to the need to identify causes and treatments for age-related cognitive deficits. This proposal has the potential to expand perspectives and devise treatments to facilitate learning and memory in older adults.
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