Distinct Signaling by Ventral Tegmental Area Glutamate, GABA, and Combinatorial Glutamate-GABA Neurons in Motivated Behavior

Abstract

SUMMARY Ventral tegmental area (VTA) neurons play roles in reward and aversion. We recently discovered that the VTA has neurons that co-transmit glutamate and GABA (glutamate-GABA co-transmitting neurons), transmit glutamate without GABA (glutamate-transmitting neurons), or transmit GABA without glutamate (GABA-transmitting neurons). However, the functions of these VTA cell types in motivated behavior are unclear. To identify the functions of these VTA cell types, we combine recombinase mouse lines with INTRSECT2.0 vectors to selectively target these neurons. We find that VTA cell types have unique signaling patterns for reward, aversion, and learned cues. Whereas VTA glutamate-transmitting neurons signal cues predicting reward, VTA GABA-transmitting neurons signal cues predicting the absence of reward, and glutamate-GABA co-transmitting neurons signal rewarding and aversive outcomes without signaling learned cues related to those outcomes. Thus, we demonstrate that genetically defined subclasses of VTA glutamate and GABA neurons signal different aspects of motivated behavior.

Lateral ventral tegmental area GABAergic and glutamatergic modulation of conditioned learning

“…Our cell-type-specific calcium imaging provides important information for the understanding of the relative contribution of lVTA neurons in associative behaviors. First of all, when considering the Vgat-and Vglut2-expressing neurons as neuronal ensembles, we confirmed the recent fiber photometry observations that both ensembles are overall excited by CS+ and FS stimuli (Root et al, 2020). We further investigated the heterogeneities in these populations by examining how they behaved at the single-cell level.…”

Cerebellar Activation Bidirectionally Regulates Nucleus Accumbens Core and Medial Shell

“…Given the known heterogeneity of VTA neural populations 88,89 , DCN inputs could activate dopaminergic, GABAergic, glutamatergic, and/or dual neurotransmitter-releasing neurons. This diversity in neural types, which are known to project to NAc with some subregion-specificity 59,83,[90][91][92][93][94] , could at least partly explain the differences in responses and onset latencies we observed in our experiments. For example, the action of dopamine on G protein-coupled receptors to modulate neuronal activity could be responsible for the long latencies and/or duration in NAc Med inhibitory responses.…”

“…Here, we focused on the nucleus accumbens (NAc), a complex limbic structure that shares reward, motivation and affective functionality with the CB 51,52 . Stimulation of CB cortex or deep cerebellar nuclei (DCN) modulates levels of NAc dopamine --an important, but not exclusive, regulator of NAc functions [53][54][55][56][57][58][59] . However, how the CB connects to NAc is unknown.…”

Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction

“…These response patterns were also unique when compared to the response pattern of VTA dopamine cells. Together, these data suggest that neurocircuits other than dopamine play unique roles in responding to appetitive and aversive stimuli ( 106 ).…”