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.

Multi-transmitter neurons in the mammalian central nervous system

“…It is possible that DAN-mediated glutamate release in both NAC and striatum originates from VTA axons, since these also enter the dorsal striatum but reflect different aspects of behavior than do SNC DA axons[40]. The presynaptic regulation of glutamate release from DANs is different than that of GABA/DA, suggesting that the release sites are likely distinct, consistent with ultrastructural analyses (Figure 1C, [25,41,42]). The function of glutamate releasing DA neurons is unknown and whether glutamate/DA neurons also release GABA has not been determined electrophysiologically.…”

Neuronal Depolarization Drives Increased Dopamine Synaptic Vesicle Loading via VGLUT

“…Neuroanatomical evidence from rodent VTA DA neurons shows that subpopulations of their projections can release both DA and glutamate (Barker et al, 2016; Chuhma et al, 2009). Moreover, VGLUT2 and VMAT2 are co-expressed in these same neurons (Hnasko et al, 2010; Morales and Root, 2014).…”

“…Currently, however, there is no ultrastructural evidence demonstrating co-localization of these transporters to the same vesicles. VGLUT2 and VMAT2 have been shown to segregate in discrete subpopulations of vesicles within the same axons of mesoaccumbens fibers (Barker et al, 2016; Zhang et al, 2015). Though these ultrastructural immunolabeling studies examined fields in great detail, the areas sampled to determine transporter localization in these earlier studies are limited.…”

Preservation of Essential Odor-Guided Behaviors and Odor-Based Reversal Learning after Targeting Adult Brain Serotonin Synthesis

“…Instead, we may benefit from recognizing a far more limited role of 5-HT in olfactory system function and perception. Further, this work provides a foundation to probe for compensatory synaptic mechanisms whereby our olfactory system may engage in informing behaviors, including those involving transmitter corelease (Trudeau, 2004; Zhou et al, 2005; Barker et al, 2016). …”