Abstract
The mesolimbic reward system is primarily comprised of the ventral tegmental area (VTA) and the nucleus accumbens (NAc) as well as their afferent and efferent connections. This circuitry is essential for learning about stimuli associated with motivationally-relevant outcomes. Moreover, addictive drugs affect and remodel this system, which may underlie their addictive properties. In addition to dopamine (DA) neurons, the VTA also contains approximately 30% γ-aminobutyric acid (GABA) neurons. The task of signaling both rewarding and aversive events from the VTA to the NAc has mostly been ascribed to DA neurons and the role of GABA neurons has been largely neglected until recently. GABA neurons provide local inhibition of DA neurons and also long-range inhibition of projection regions, including the NAc. Here we review studies using a combination of in vivo and ex vivo electrophysiology, pharmacogenetic and optogenetic manipulations that have characterized the functional neuroanatomy of inhibitory circuits in the mesolimbic system, and describe how GABA neurons of the VTA regulate reward and aversion-related learning. We also discuss pharmacogenetic manipulation of this system with benzodiazepines (BDZs), a class of addictive drugs, which act directly on GABAA receptors located on GABA neurons of the VTA. The results gathered with each of these approaches suggest that VTA GABA neurons bi-directionally modulate activity of local DA neurons, underlying reward or aversion at the behavioral level. Conversely, long-range GABA projections from the VTA to the NAc selectively target cholinergic interneurons (CINs) to pause their firing and temporarily reduce cholinergic tone in the NAc, which modulates associative learning. Further characterization of inhibitory circuit function within and beyond the VTA is needed in order to fully understand the function of the mesolimbic system under normal and pathological conditions.
Highlights
Learning about motivationally relevant stimuli in the environment is critical for all aspects of survival, from feeding and reproduction to avoiding dangerous or aversive situations
Using in vivo extracellular recording in ventral tegmental area (VTA) ChR2 injected and anesthetized GAD-cre mice to monitor DA neuron activity, we have shown that driving activity of VTA GABA neurons strongly inhibits DA neuron spontaneous firing rate (Tan et al, 2012; Figure 2A)
Using ex vivo whole cell recording methods in GAD-cre mice expressing ChR2 in VTA GABA cells, we showed that the connection between VTA GABAergic projection neurons (GPNs) and cholinergic interneurons (CINs) in the nucleus accumbens (NAc) is monosynaptic
Summary
Learning about motivationally relevant stimuli in the environment is critical for all aspects of survival, from feeding and reproduction to avoiding dangerous or aversive situations. Long-range GABA projections from the VTA to the NAc selectively target cholinergic interneurons (CINs; Figure 1), regulating local ACh release and modulating associative learning.
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