Epigenetic Mechanisms in Motor Habits Stability

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DESCRIPTION (provided by applicant): While motor habits are important for the development of motor skills, aberrant motor habits are implicated in drug addiction. Motor habits are uniquely different from other types of memory. They take a long time to form and are hard to be modified. We hypothesize that this unique feature makes it hard to reverse aberrant motor habits in drug addiction. What makes motor habits different from other types of memory? The answer may lie in the unique signaling pathways in striatal medium spiny neurons (MSNs). The converged inputs to the MSNs from glutamatergic neurons in the cortex and from dopamine neurons in the midbrain are implicated in corticostriatal synaptic plasticity and habit learning. Based on published studies and studies done in our lab, we hypothesize that adenylyl cyclase type V (ACS) which is selectively and highly expressed in adult striatum is a key determinant of stability of corticostriatal synapses and stability of motor habits. However, during early postnatal development, adenylyl cyclase type I (AC1) rather than ACS is highly expressed in the striatum. In contrast to ACS which promotes synaptic stability, AC1 promotes synaptic plasticity. Therefore, the silencing of AC1 expression during postnatal development and emergence of ACS as the dominant isoform may be a major event in neural development that has corresponding behavioral consequences. The AC1 promoter sequence is GC rich and contains CpG islands, making it potential targets for epigenetic regulation. The proposed studies aim to 1) examine epigenetic mechanisms in turning off AC1 expression in striatum during development; 2) test the hypothesis that reawaking AC1 expression in adult striatum will make motor habits more susceptible for modifications. These studies will point to potential epigenetic interventions in the future that may be able to treat drug addition by reversing motor habits.