Midbrain circuit regulation of individual alcohol drinking behaviors in mice

Barbara Juarez,Jessica J Walsh,Sarah Montgomery,Scott Edwards,Hongxing Zhang,H Grégoire ,Amanda J Roberts ,Carole Morel,Yutong Liu,Yongke Lu,Dipesh Chaudhury,Allyson K Friedman,Efrain Ribeiro,Song Zhang,Ciorana Roman-Ortiz,Erin S Calipari,Leandro F Vendruscolo,Kelcy Jackson,Denise E Croote,Stacy M Ku,Georgia E Hodes,Yingbo Zhu,Marshall Crumiller,Ming‐Hu Han

doi:10.1038/s41467-017-02365-8

Abstract

Alcohol-use disorder (AUD) is the most prevalent substance-use disorder worldwide. There is substantial individual variability in alcohol drinking behaviors in the population, the neural circuit mechanisms of which remain elusive. Utilizing in vivo electrophysiological techniques, we find that low alcohol drinking (LAD) mice have dramatically higher ventral tegmental area (VTA) dopamine neuron firing and burst activity. Unexpectedly, VTA dopamine neuron activity in high alcohol drinking (HAD) mice does not differ from alcohol naive mice. Optogenetically enhancing VTA dopamine neuron burst activity in HAD mice decreases alcohol drinking behaviors. Circuit-specific recordings reveal that spontaneous activity of nucleus accumbens-projecting VTA (VTA-NAc) neurons is selectively higher in LAD mice. Specifically activating this projection is sufficient to reduce alcohol consumption in HAD mice. Furthermore, we uncover ionic and cellular mechanisms that suggest unique neuroadaptations between the alcohol drinking groups. Together, these data identify a neural circuit responsible for individual alcohol drinking behaviors.

Highlights

Alcohol-use disorder (AUD) is a debilitating addiction syndrome of ranging severity that causes tremendous personal and socioeconomic burdens[1,2]
The mesocorticolimbic dopamine system consists of ventral tegmental area (VTA) dopamine neurons projecting to neural substrates involved in reward processing, including the nucleus accumbens (NAc) and medial prefrontal cortex[5,6]
We performed in vivo recordings of putative VTA dopamine neurons between EtOH naive, low, and high alcohol drinking mice and discovered unique increases in in vivo dopaminergic firing in the low alcohol drinking population

Summary

Introduction

Alcohol-use disorder (AUD) is a debilitating addiction syndrome of ranging severity that causes tremendous personal and socioeconomic burdens[1,2]. VTA dopamine neurons display tonic, single spike activity or high frequency, burst/phasic activity, a firing pattern important in encoding behaviors associated with natural reward by increasing dopamine concentrations downstream[7,8] These neurons show functional differences based on their downstream projection target[9,10]. To parse out individual differences in alcohol drinking behaviors and to probe the VTA dopaminergic reward circuit, we used a continuous access, two-bottle choice alcohol drinking paradigm that results in low and high alcohol drinking behaviors in isogenic C57BL/6J male mice This paradigm involves the voluntary intake of alcohol, an individual behavior thought to be mediated by forebrain reward circuits, which are modulated by the mesocorticolimbic dopamine system[2,3]. We uncovered unique neurophysiological properties in the VTA-NAc circuit between low and high alcohol drinking mice that could underlie variable alcohol consumption behaviors

Methods

Results

Conclusion