Multiplexed neurochemical signaling by neurons of the ventral tegmental area

Abstract

The ventral tegmental area (VTA) is an evolutionarily conserved structure that has roles in reward-seeking, safety-seeking, learning, motivation, and neuropsychiatric disorders such as addiction and depression. The involvement of the VTA in these various behaviors and disorders is paralleled by its diverse signaling mechanisms. Here we review recent advances in our understanding of neuronal diversity in the VTA with a focus on cell phenotypes that participate in 'multiplexed' neurotransmission involving distinct signaling mechanisms. First, we describe the cellular diversity within the VTA, including neurons capable of transmitting dopamine, glutamate or GABA as well as neurons capable of multiplexing combinations of these neurotransmitters. Next, we describe the complex synaptic architecture used by VTA neurons in order to accommodate the transmission of multiple transmitters. We specifically cover recent findings showing that VTA multiplexed neurotransmission may be mediated by either the segregation of dopamine and glutamate into distinct microdomains within a single axon or by the integration of glutamate and GABA into a single axon terminal. In addition, we discuss our current understanding of the functional role that these multiplexed signaling pathways have in the lateral habenula and the nucleus accumbens. Finally, we consider the putative roles of VTA multiplexed neurotransmission in synaptic plasticity and discuss how changes in VTA multiplexed neurons may relate to various psychopathologies including drug addiction and depression.

Keywords: Addiction; Aversion; Co-transmission; Depression; Dopamine; GABA; Glutamate; Reward.

Figure 1. Neurons in the ventral tegmental area (VTA) are capable of multiplexed neurotransmission

Detection of tyrosine hydroxylase (TH) immunoreactivity within the VTA, (low magnification, left panel). VTA combined immunohistochemistry and in situ hybridization showing at high magnification (right panel) neurons expressing TH (green cells), glutamic acid decarboxylase mRNA (GAD 65/67; purple cells), vesicular glutamate transporter 2 mRNA (VGluT2; green or white grain aggregates) or combinations of these cell markers. Abbreviations. Left: RLi- Rostral Linear Nucleus, IF- Interfasicular Nucleus, PBP- Parabrachial Pigmented Nucleus, PN- Paranigral Nucleus, SNc- Substantia Nigra Pars Compacta, fr- fasciculus retroflexus, mp- Mammillary Peduncle, Right: TH- tyrosine hydroxylase, GAD- glutamic acid decarboxylase, VGluT2- vesicular glutamate transporter 2.

Figure 2. Ultrastructural immunolabeling reveals unpredicted mechanisms of neurotransmission within the mesohabenular and mesoaccumbal pathways

(a) Lateral habenula micrograph (left panel) showing a single mesohabenular axon terminal containing VGluT2 (scattered dark material detected by immunoperoxidase labeling) and VGaT (gold particles detected by immunogold; blue arrowheads). This single axon terminal forms both an asymmetric synapse (green arrow) and a symmetric synapse (blue arrow) with a common postsynaptic dendrite (De). Postsynaptic to a single axon terminal (middle panel), GluR1 receptors (green arrowhead) are found adjacent to asymmetric synapses (green arrows), while GABA_A receptors (blue arrowhead) are found adjacent to symmetric synapses (blue arrow). (b) Nucleus Accumbens micrograph showing a messoaccumbal axon containing both VMAT2 (scattered dark material) and VGluT2 (gold particles). VMAT2 and VGluT2 are segregated within the same axon. Note that the VGluT2 microdomain corresponds to an axon terminal establishing an asymmetric synapse (arrow) with a postsynaptic dendritic spine (sp). All scale bars represent 200 nm.