| The pressures of natural selection have gradually honed the brain into an efficient learning machine. From birth to death, the brain is occupied with the forming, pruning and reforming of its neural pathways to store information about the environment it inhabits. As the brain ages into senescence, the storage of new information becomes more difficult, and in some cases, previously stored memories deteriorate and are lost. Preventing or reversing the age-related memory loss requires first a thorough understanding of the processes underlying information processing and storage. In addition to synaptic plasticity, the intrinsic properties of neurons, such as input resistance, back propagation of action potentials, and hyperpolarizing currents, play an important role in how synaptic input is received, processed, and communicated in a neural network. Alterations in these intrinsic processes dictate how a neuron will respond to synaptic input, and thus are equally important as synaptic changes to the learning capacity of the brain. In particular, the size of the post-burst afterhyperpolarization (AHP) of hippocampal neurons is known to correlate strongly with the success or failure of hippocampus-dependent learning. Additionally, the post-burst AHP of hippocampal neurons is increased in aging subjects, contributing to increased difficulty learning hippocampus-dependent tasks. It was not previously known if other hyperpolarizations were similarly linked to learning or altered by aging. This thesis project undertook to examine the BK-mediated fast AHP for learning-related and aging-related changes. The results reported here show that the fast AHP, like the post-burst AHP, is reduced in hippocampal neurons after learning trace eyeblink conditioning. However, unlike the post-burst AHP, there is no aging-related alteration in the size of the fast AHP. Further differences in the role of the fast AHP, as compared to the post-burst AHP, in learning are revealed by pharmacologically blocking the fast AHP in vivo, which impairs learning. Reducing the post-burst AHP in vivo using similar techniques leads to improved learning. Thus these two hyperpolarizations, though similar in many respects, are differentially regulated during learning, and in aging. Because the channel identity of the fast AHP is known, the mechanisms of the learning-related reduction of the fast AHP were sought. Experiments indicate that BK channels of neurons from trained subjects have a lower open probability at depolarized potentials. It is theorized that this lower open probability is due to the phosphorylation state of the channel. |
