Loss of Inhibitory Control in Alcohol Seeking and Dependence: Role of Thalamostriatal Circuitry

点击翻译按钮获取中文摘要

PROJECT SUMMARY Maladaptive alcohol seeking, a hallmark of alcohol use disorder (AUD), is thought to be driven not only by increased function of neural circuitry that drives natural reward seeking, but also by loss of control of circuitry that serves to suppress behaviors incompatible with safety and survival. The posterior paraventricular thalamus, (pPVT), and its projections to the nucleus accumbens (NAc), provide feedforward inhibition onto dopamine receptor-expressing medium spiny neurons (MSNs) which are largely responsible for promoting reward- motivated behaviors. Stimuli and situations that naturally serve to limit maladaptive behaviors, such as behavioral threats, have been shown to activate these pPVT®NAc projection neurons and suppress behavior through the activation of downstream parvalbumin inhibitory interneurons (PV-INs). Our labs have shown that an acute stressor (TMT predator odor), quinine-adulteration of alcohol and optogenetic activation of pPVT®NAc circuitry reduces reward- and, of particular importance to this proposal, alcohol-seeking in non-dependent mice. Furthermore, we show that the ability of this circuit to provoke behavioral inhibition is lost after the induction of alcohol dependence. These behavioral adaptations parallel reduced synaptic efficacy at pPVT®NAc glutamatergic synapses onto downstream PV-INs in alcohol-dependent mice. Our data therefore suggest, for the first time, that pPVT®NAc projection neurons are responsible for the suppression of alcohol-seeking behavior but are dysregulated by chronic alcohol exposure. We formally test independent components of this hypothesis in three independent Aims. In Aim 1, using two-photon calcium imaging we will measure and longitudinally track neuronal ensemble dynamics in both pPVT®NAc projections and NAc PV-INs during alcohol self-administration, consumption, and tests of behavioral inhibition in non-dependent and dependent mice. Aim 2 will explore the effects of chronic alcohol exposure on intrinsic and synaptic adaptations in pPVT synaptic inputs to both PV-INs and MSNs in the NAc using slice electrophysiology. Lastly, in Aim 3 we will determine whether activation of pPVT®NAc inputs and/or activation of PV-INs in the NAc are sufficient to restore feedforward inhibition and control alcohol-seeking in non-dependent vs. dependent mice. This project will identify how activity in a principal – but understudied – reward circuit changes from the onset of alcohol use to dependence and will further determine how this activity influences the expression and suppression of alcohol seeking.