Investigating Ensemble Activity Dynamics of a Thalamo-Striatal Circuit Regulating Alcohol Seeking

PROJECT SUMMARY Alcohol use disorder (AUD) is a devastating condition that affects 29.5 million people aged 12 and older. AUD is classically characterized by a loss of behavioral control, particularly in the face of negative consequences, resulting in a loss of inhibitory control, or disinhibition, that may normally suppress alcohol seeking. Considering

this, it is critical to investigate mechanisms associated with disinhibition. One major barrier to investigating AUD progression is understanding specific cell populations that may normally serve to suppress alcohol seeking but become disinhibited following dependence. While our knowledge of neuronal ensembles in alcohol dependence

remains limited, studies on the paraventricular thalamus (PVT) projection to the nucleus accumbens (NAc) in regulating sucrose seeking have revealed distinct neuronal ensembles that emerge across the course of learning. These studies indicate that PVTàNAc encodes ensembles of inhibited neurons that function as a

“brake” on reward-seeking. Extending these findings to examine how alcohol influences thalamo-striatal neuronal ensembles is imperative for targeting inhibitory ensembles that may attenuate alcohol-seeking behaviors. My preliminary data suggest that broad optogenetic activation of PVTàNAc neurons reduces alcohol-seeking,

evidenced by decreased active lever presses and alcohol deliveries during an operant head-fixed task in nondependent mice. Conversely, optogenetic inhibition of PVTàNAc neurons releases this “brake” and promotes active lever pressing, even in the face of behavioral suppressors. Importantly, after inducing alcohol

dependence via chronic intermittent ethanol (CIE) exposure, presentation of behavioral suppressors, including direct activation of PVTàNAc neurons, no longer reduces alcohol seeking, indicative of a functional uncoupling of this circuit leading to behavioral disinhibition. These current data suggest that PVTàNAc neurons may serve

as an exciting new target for studying how chronic alcohol induces disinhibition at the level of neuronal ensemble activity. To date, no work has explored single-cell manipulation or two-photon calcium imaging of PVTàNAc neuronal ensembles in regulating alcohol seeking before and after alcohol dependence. The focus of this

proposal therefore, is to identify and manipulate specific PVTàNAc neuronal ensembles that may be altered after dependence. My overarching hypothesis is that inhibitory neuronal ensemble activity in PVTàNAc will best decode alcohol-seeking behaviors and become persistently inactivated following ethanol dependence reducing

feedforward inhibition onto PV-INs. Aim 1 will measure calcium dynamics of PVTàNAc neurons in vivo to identify unique neuronal ensembles that emerge during alcohol seeking. I will then manipulate specific PVTàNAc neurons that may be altered before and after alcohol dependence. Aim 2 will assess how inputs from PVT onto

parvalbumin neurons in the nucleus accumbens may be altered following dependence ex vivo. Collectively, this research will provide valuable and novel information on the role of thalamo-striatal ensembles to enhance our understanding of underlying mechanisms of disinhibition in AUD.