Gilles E. Martin - US grants

DESCRIPTION (provided by applicant): It is now well established that acute and chronic alcohol alters the strength of synaptic transmission by modulating ion channels and receptors. A number of evidence suggest that the persistence of these changes, over days or weeks, explains, at least in part, alcohol long-lasting deleterious effects on behavior. Long-term potentiation (LTP) and depression (LTD) are the two most widely studied paradigms of such persistent synaptic alterations. To date, acute and chronic alcohol effects on LTP have been examined in structures of the limbic system (hippocampus, amygdala) and in the cortex. However, no study has been carried out in the nucleus accumbens (NAcc), a region believed to underlie the rewarding properties of all drugs of abuse, including that of alcohol. Furthermore, LTD has been largely ignored by all these studies. This leaves a number of questions regarding the cellular underpinnings of LTD regulation by alcohol. We hypothesize that LTD results from the interactions between synaptic potentials and backpropagating (b-APs), and that b-APs mediate EtOH effects on LTD. We believe that this attempt to bring together various fields of neurosciences (neuronal information processing and synaptic plasticity) will further our understanding of the cellular mechanisms employed by drugs of abuse to sustain their effects over long periods of time. The goal of this project is to examine the role of backpropagating action potentials in mediating the acute effects of alcohol on long- term potentiation depression (LTD), a well-known form of learning and memory paradigms. This study will be carried out in the nucleus accumbens, a major brain region responsible for the rewarding properties of all drugs of abuse. We believe this will represent an important step towards elucidating the cellular mechanisms underlying long-term persistent negative effects of alcohol on behavior.

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.

The ambition of this proposal is to identify the cellular underpinnings of the early transition between casual to sustain drinking using drinking-in-the-dark model. We propose to employ a variety of complementary approaches, including mouse genetics, optogenetics, behavior and biophysical approaches to test the overarching hypothesis that computing of the synaptic strength of cortical and amygdala inputs (a phenomenon also known as synaptic gating) is a mechanism enabling nucleus accumbens medium spiny neurons to integrate cognitive and emotional information, and is modulated by alcohol exposure to control consumption. We postulate that this cellular mechanism contributes to the vulnerability of adolescents to binge drinking.