DESCRIPTION (provided by applicant): The goal of this project is to further our understanding of molecular and cellularmechanisms underlying alcohol's effects on synaptic plasticity in nucleus accumbens (NAcc) medium spiny neurons. We believe that, despite past efforts, such understanding remains elusive because the classical Bliss and Lomo model of long-term potentiation (LTP) typically used to study neuronal plasticity, presents one major limitation with regard to the NAcc. Specifically, this model is based on high-frequency stimulation (HFS; 100 Hz) paradigm that doesn't reflect NAcc in vivo physiological conditions. Indeed, NAcc medium spiny neurons (MSNs) fire between 1 and 10 Hz in freely moving animals. Moreover, MSNs receive inputs from amygdala and cortical pyramidal neurons that fire at similar low frequencies. A better approach would be to use a more physiologically relevant stimulation paradigm. Therefore, we propose to reexamine alcohol regulation of accumbens synaptic plasticity by using a new model of plasticity called Spike-Timing-Dependent Plasticity (STDP) that relies on pairing of action potentials (APs) and excitatory postsynaptic potentials (EPSP) at in vivo-like frequencies (~ 1Hz).Our preliminary data indicate that the Nucleus Accumbens undergoes both long term potentiation (tLTP) and depression (tLTD) in similar experimental conditions. These two forms of synaptic plasticity rely on separate pathways: tLTP is dependent on NMDA receptors, while tLTD requires Action Potentials. Our data also support the idea that NMDA receptors and action potentials recruit distinct intracellular calcium signaling pathways. Strikingly, we found that Ethanol dramatically inhibits tLTP, but only weakly potentiates tLTD. Our overarching hypothesis is therefore that the specific effects of Ethanol on Nucleus accumbens plasticity is caused by the differential sensitivity of calcium signaling pathways underlying tLTP and tLTD to this drug. This project should reveal new cellular and molecular mechanisms underlying synaptic plasticity in Accumbens and how they respond to ethanol exposure in conditions approaching those found in vivo.

Our ambition is to provide a cohesive vision of how alcohol regulates synaptic plasticity by integrating cardinal factors shaping neuronal electrical activity, i.e., EPSPs, APs, ion channels, factors whose regulation by alcohol is usually studied independently. The novelty of our project lies in part in our ability to evoke synaptic plasticity t very low stimulation frequency, mimicking conditions found in freely moving animals. This global approach represents a novel step towards establishing connections between alcohol long-term effects on synaptic plasticity and behavior.