VTA GABA neurons modulate specific learning behaviors through the control of dopamine and cholinergic systems

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.

Keywords: NAc; VTA; acetylcholine; benzodiazepine; dopamine; interneuron; optogenetics; pharmacogenetics.

Figure 1

Inhibitory and modulatory connections between the VTA and the NAc. The VTA is composed of two major cell types: GABAergic neurons (green) and DA neurons (grey). Glutamate neurons are not schematized for clarity. GABA interneurons control the activity of DA cells that release DA in the NAc through their long-range projections. In turn, MSNs send projections back to the VTA, preferentially inhibiting GABA cells and thus disinhibiting DA neurons. Some GABA neurons also send long-range projections to the NAc, where they selectively inhibit CINs. Abbreviations: VTA: ventral tegmental area; NAc: nucleus accumbens; GABA: γ-aminobutyric acid; DA: dopamine; CIN: cholinergic interneuron; MSN: medium sized-spiny neuron.

Figure 2

VTA GABA neurons drive specific behaviors through the control of the DA and cholinergic systems. (A) Left, VTA GABA neurons are selectively infected to express ChR2-eYFP (green, AAV-ChR2-eYFP-flox in the VTA of GADcre+ mice). Middle, in vivo example trace of single unit recording of a GABA and a DA cell showing that blue-light stimulation induces a time locked increase of firing rate in infected GABA neurons and as a consequence a shut down in the activity of DA cells. Right, dynamic conditioned place aversion (CPA): GADcre+ mice developed an aversion for the blue-light paired chamber compared to GADcre− mice. This is shown on the example tracking trace of a GADcre+ mouse and on the aversive learning curve plotting the relative time spent in the conditioned chamber for both groups of mice. (B) Left, the ventral tegmental area (VTA) contains DA neurons expressing α3-containing GABA_A receptors and GABA cells that express α1-containing GABA_A receptors. Middle, in vivo example trace of single unit recording of GABA and DA cells before and after midazolam (MDZ) tail vein injection. GABA neurons decrease their basal firing rate, leading to the disinhibiton of DA cells, which increase their firing rate. These effects are abolished in α1-knock-in mice in which GABA_A receptors containing the α1 subunit isoform are insensitive to BDZs. Right, oral-self administration of MDZ paradigm: WT mice preferred to consume from the MDZ containing solution whereas this preference is not developed in α1-knock-in mice. (C) Left, same preparation as in B, VTA GABA projection neurons selectively inhibit CIN of the NAc. Middle, in vivo example trace of single unit recording of GABA and CIN cells showing that in response to blue-light stimulation CIN are completely inhibited due to the excitation of VTA GABA cells. Right, activation of these fibers during the association of a conditioned stimulus (CS+, white noise) to an aversive outcome (brief mild footshock) enhances the ability to subsequently discriminate between the conditioned stimulus and the unconditioned stimulus (CS, pure tone) that was not paired with an aversive outcome, as shown on the graph for the percentage of freezing measured on the test day in response to CS+ and CS− for both groups of mice. Abbreviations: VTA: ventral tegmental area; NAc: nucleus accumbens; WT: wild type mouse; α1KI: α1 subunit point mutant knock-in mouse; BDZ: benzodiazepine; GABA: γ-aminobutyric acid; DA: dopamine; CIN: cholinergic interneuron; MSN: medium sized-spiny neuron. Adapted from Tan et al. (2010, 2012) and Brown et al. (2012).