This research program is designed (a) to determine which slow outward potassium currents are reduced to increase neuronal excitability during learning in young animals, and (b) to examine how alterations in these currents may contribute to impaired learning ability in old animals. We have established a battery of hippocampally- dependent learning tasks in the Fl F344 X BN hybrid rat - trace eyeblink conditioning, trace fear conditioning and Morris water maze learning - to evaluate the temporal and spatial learning capacity of individual animals. These tasks will be used to relate overall learning abilities in young, middle aged, and old animals to biophysical and morphological characteristics of principal neurons in the hippocampus. We have previously reported that enhanced post-burst afterhyperpolarizations (AHPs) and more accommodation in CA1 neurons from aging animals reduce neuronal excitability and have suggested that these changes contribute importantly to age-dependent learning deficits. We will use whole-cell patch clamp recording techniques for studying CA1 pyramidal cells and dentate granule neurons in hippocampal slices to isolate and fully characterize changes in the slow outward potassium currents that occur during learning and aging. The currents to be studied are IAHP, Ic, and IM which generate the medium and slow afterhyperpolarization and thus are important for defining neuronal excitability in hippocampal neurons. How neurons change biophysically during the learning of three hippocampally-dependent tasks and whether training in more than one of these tasks simultaneously causes larger postsynaptic changes and/or changes in a larger percentage of hippocampal neurons will be determined. The relation of learning to hippocampal neuron excitability during aging will be extended to determine when neuronal excitability begins changing during the life span, which currents are changing to cause decreased neuronal excitability, and how these postsynaptic cellular changes are related to behavioral acquisition of learned responses.. The final question to be addressed is whether some old rats have hippocampal neurons with characteristicswhich help them to learn (learning-intact) as compared to learning-impaired animals. We will explore whether baseline neuron excitability determines whether old rats are learning-intact or learning-impaired as compared to young and middle aged animals. Our working hypothesis posits that baseline levels ofhippocampal neuronal excitabilitycontrolled by slow potassium currents as well as the system's capacity to modulate these currents are a major determinant of learning ability and defines how this capacity changes with aging. In combination with our linked proposal, we will determine if postsynaptic currents and the complement of synapses change similarly during aging in hippocampal neurons and may be a common determinant of whether age-related learning abilities remain intact or show decline during aging.
|Effective start/end date||7/1/04 → 3/31/10|
- National Institute on Aging (R37 AG008796)