This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Learning and memory involves a sequence of molecular events that leads to the modification of synaptic strength and reorganization of neuronal networks which gives rise to behavioral plasticity. Critical steps of plasticity such as synaptic transmission, calcium homeostasis, targeted delivery of newly synthesized proteins are actively regulated by mitochondria as the mobile batteries of the cell. Recent evidence showed that synaptic plasticity is accompanied with an increased delivery of mitochondria and an active remodeling of its network (Tong, 2006). The disruption of the dynamics of the mitochondrial network, manifested as functional aberration and movement disruption, could result in an energy imbalance and deficiency of synaptic plasticity which may give rise to the deterioration of cognition during aging as mitochondrial oxidative phosphorylation becomes increasingly inefficient due to elevated oxidative damage by reactive oxygen species on vital molecules essential for respiration of the cell. Drosophila has been a tremendously valuable model system for both the study of learning, memory and aging. Sophisticated genetic tools have enabled functional manipulations of sets of genes to analyze their respective roles in a variety of behaviors, neural circuitry and molecular biochemistry of brain plasticity. Parallel to the ongoing study of the mitochondrial network dynamics in the living fly brain, we have begun to address an inseparable part of the mitochondrial dynamics memory theory that is whether the mitochondrial network can be reorganized as behavioral plasticity occurs. The time scale of these events can range from minutes, as for learning and short-term memory, to days or weeks in the case of long term memory. Acute changes of mitochondrial network may reflect an active energy demand at the point of potentiation in several synapses. A more chronic change is often accompanied with protein synthesis and synaptic remodeling resulting in an overall reorganization of the circuitry. Several behavioral assays have been developed to test learning and memory formation in Drosophila. Unfortunately none of them are suitable for the test of age-related learning and memory changes. Larval learning assays only target a specific stage of fly embryonic development. Olfactory learning paradigm requires more than 500 flies, a very labor intensive process to one meaningful data point since the surviving aged flies make up less than 15% of the population. Proboscis extension test is a form of behavioral plasticity yet could not be used for associative learning and spatial learning tests. Single fly tethered flight arena setup is an elegant paradigm that monitors fly target recognition and associative learning to the scale of seconds. Yet, when the fly quits flying, so does the experiment. During aging, flies often lose their flight capability which is correlated with mitochondrial ROS production and decreased of one of critical Kreb cycle enzyme, aconitase. The same conundrum also limits the application of courtship learning in flies that are approaching the end of their lives when a drastic decline in fertility presents an insurmountable problem. An ideal method would require a minimum amount of activity on the part of the fly yet gives a clear readout of the performance index and a flexible paradigm that can be utilized to test operant manipulation, associative learning, spatial learning and even social interactive learning.
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