Pathway specific ecstasy-induced plasticity of excitability in the subiculum

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DESCRIPTION (provided by applicant): The subiculum (SUB) subregion of the hippocampal formation functions as an interface between the brain's memory systems, and motivation/reward systems. We have shown that the SUB is vulnerable to psychostimulant-induced plastic changes in its excitability. This form of plasticity can alter the SUB integration of synaptic input, and accordingly, its output, thus disrupting the routing of information out of the hippocampus to the SUB target structures, including the nucleus accumbens and prefrontal cortex. It is clear that repeated MDMA exposure disrupts hippocampal and reward related learning and memory, but the neurophysiological mechanisms responsible for these effects have thus far escaped detection. We have shown that SUB bursting neurons are more vulnerable to repeated d-amphetamine-induced plasticity, which decreases their Na+ channel function and alters the timing of their bursting output but it is not known whether MDMA can do the same. Although the two main target structures of the SUB are well established the functional differences between neurons that project to the two major output structures of the SUB are unknown. This is particularly relevant since we have characterized two functional classes of SUB neurons as bursting and non-bursting with potentially differing susceptibility to MDMA induced functional alterations. We plan to use an innovative combination of retrograde dye labeling and patch-clamping measurements of intrinsic excitability from SUB neurons that project specifically to either the prefrontal cortex or nucleus accumbens to functionally characterize neurons in association with their target. This work will: 1) Establish if repeated MDMA alters SUB neuronal intrinsic excitability and dendritic morphology; 2) Determine if SUB neurons classified based on their projection target (accumbens or prefrontal cortex) or their output mode (bursting or nonbursting) exhibit differential MDMA-induced plasticity; and 3) Provide the basis for a larger research plan dedicated to understanding the mechanism and significance of the pathway specific MDMA induced plasticity. A detailed understanding of the functional output that the SUB sends to its targets in the accumbens or frontal cortex and how this output may be altered by repeated exposure to MDMA will greatly improve our interpretation of information flow out of the hippocampus and the cognitive disruptive effects of MDMA. PUBLIC HEALTH RELEVANCE: The club drug ecstasy activates areas of the brain that control emotion, memory, motivation and pleasure in rats, monkeys and humans alike, but if it is taken repeatedly, just a few doses can cause widespread damage to these regions. The brain region most vulnerable to damage is called the subiculum and it plays an important role as an interface between memory systems and motivation/emotion systems. The goal of this proposal is to use a rodent model to determine what kind of information the subiculum transmits and examine how this is altered after short and long-term withdrawal from ecstasy.