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.

Combined immunohistochemical and retrograde tracing reveals little evidence of innervation of the rat dentate gyrus by midbrain dopamine neurons

“…Co-labeling with markers for other neurotransmitter phenotypes showed at least some of the midbrain hippocampal projections to be GABA-containing neurons. Although it is known that the VTA consists of up to 30% GABA neurons, including interneurons, as well as projections to areas such as cortex and nucleus accumbens ( (Carr and Sesack, 2000); for review see (Creed et al, 2014)), projections to the hippocampus have not been well characterized. To obtain additional detailed information on the identity of the FG+ cells, including the quantity and topographical distribution of specific phenotypes, further investigation is certainly warranted.…”

The antero-posterior heterogeneity of the ventral tegmental area

“…The ventral tegmental area (VTA) is studied for its implication in a wide range of functions including the processing of salient sensory and emotional information, the control of motivated behavior, natural or drug-related reward, reward-related learning, mood, and their associated psychopathologies (Nestler and Carlezon, 2006;Fields et al, 2007;Grace et al, 2007;BrombergMartin et al, 2010;Hong, 2013;Creed et al, 2014;Gillies et al, 2014;Ikemoto and Bonci, 2014 Barrot).…”

Activation of D2 autoreceptors alters cocaine-induced locomotion and slows down local field oscillations in the rat ventral tegmental area

“…DAergic and GABAergic neurons composing the VTA network (Creed et al, 2014;Nair-Roberts et al, 2008;Oades and Halliday, 1987) are arranged in "subnetworks" with specific inputs and outputs (Beier et al, 2015;Lammel et al, 2008;Lammel et al, 2011;WatabeUchida et al, 2012). How these interconnected subnetworks operate over time in natural conditions is not clear, but the VTA in general is concerned with motor activity, motivation, reward and salience (Bromberg-Martin et al, 2010;Schultz, 2007) -components of the goal-directed behavior.…”