Multiplexed neurochemical signaling by neurons of the ventral tegmental area
Introduction
Midbrain dopamine neurons (DA) are most often associated with reward processing of both natural rewards (e.g., food, water, etc.) and drugs of abuse (Schultz, 2002, Wise, 2004, Sulzer, 2011). Over fifty years of intense research has led to the proposal that neurons belonging to the ventral tegmental area (VTA), which includes but is not limited to DA neurons, are paramount to reward processing. Many hypotheses have been put forward regarding the specific function of VTA DA neurons in reward processing, such as decision making (Salamone and Correa, 2002a, Salamone and Correa, 2002b, Saddoris et al., 2015), flexible approach behaviors (Nicola, 2010), incentive salience (Berridge and Robinton, 1998, Berridge, 2007), and learning or the facilitation of memory formation (Adcock et al., 2006, Steinberg et al., 2013). However, several studies have also shown that VTA DA neurons are involved in the processing of aversive outcomes (Laviolette et al., 2002, Young, 2004, Pezze and Feldon, 2004, Brischoux et al., 2009, Lammel et al., 2012, Twining et al., 2014, Hennigan et al., 2015), fear (Abraham et al., 2014), aggression (Yu et al., 2014a, Yu et al., 2014b), depression (Tidey and Miczek, 1996, Tye et al., 2013), and drug withdrawal (Grieder et al., 2014). Other hypotheses have proposed that VTA DA neurons play a more general role in processes such as associative learning (Brown et al., 2012), arousal (Horvitz, 2000), or general motivational salience and cognition (Bromberg-Martin et al., 2010).
The functional diversity associated with the VTA may be mediated, in part, by different VTA subpopulations of neurons. A particular advancement that may subserve the functional diversity of the VTA is the recent discovery of neurons that are capable of signaling using one or more neurotransmitters. In the present review, we cover recent literature on the diversity of VTA neuronal phenotypes as they relate to ‘multiplexed neurotransmission’. We refer the reader to recent comprehensive reviews detailing VTA cellular composition, VTA efferent and afferents, and VTA functions (Oades and Halliday, 1987, Fields et al., 2007, Ikemoto, 2007, Nair-Roberts et al., 2008, Morales and Pickel, 2012, Trudeau et al., 2013, Morales and Root, 2014, Pignatelli and Bonci, 2015, Saunders et al., 2015b, Lüthi and Lüscher, 2014). Moreover, the present review does not cover co-transmission of neurotransmitters and neuropeptides, which has long been known and recently reviewed (Morales and Pickel, 2012). Here, we use the phrase “multiplexed neurotransmission” to describe neurons that are capable of signaling using two or more neurotransmitters. In many circuits, our understanding of the specific mechanisms by which neurons utilize multiple neurotransmitters is limited. Thus, we have chosen the term multiplexed neurotransmission to encompass known and unknown mechanisms of co-release and co-transmission (e.g., Nusbaum et al., 2001, El Mestikawy et al., 2011), while also allowing for the possibility of independent release of individual neurotransmitters either in time or space.
Section snippets
Cellular diversity in the ventral tegmental area
Following the discovery of DA as a chemical neurotransmitter in the brain (Montagu, 1957), the DAergic neurons in the “ventral tegmental area of Tsai” (Nauta, 1958) were identified by formaldehyde histofluorescence (Carlsson et al., 1962). These neurons, along with other catecholaminergic and serotonergic neurons throughout the brain were shown to comprise twelve discrete cell groups (labeled as A1–A12 groups; Dahlström and Fuxe, 1964). One feature of the A10 group, in particular, is the
Multiplexed signaling by VTA-GluT2 neurons
Following the discovery of VTA-VGluT2 neurons, further characterization of these neurons demonstrated that they are very diverse in their molecular composition, signaling properties and neuronal connectivity. Whereas many VTA-VGluT2 neurons lack both DAergic and GABAergic markers, there are subpopulations of VTA-VGluT2 neurons that co-express molecules responsible for the synthesis or vesicular transport of either DA or GABA (Li et al., 2013, Root et al., 2014a). Although the distinct targets
Functional diversity by VTA neurons
The functional diversity of VTA neurons has been constantly updated (Stamatakis et al., 2013, Root et al., 2014b, Mejias-Aponte et al., 2015, Eddine et al., 2015, Kotecki et al., 2015, Beier et al., 2015). As detailed above, the multiplexed neurotransmission of the VTA-VGluT2 neurons is an emerging factor involved in the complexity of VTA function. Based on observations that different combinations of neurotransmitters are multiplexed throughout the brain (Trudeau, 2004, Gillespie et al., 2005,
Multiplexed transmission: future directions and considerations for synaptic plasticity
Our ever-expanding knowledge of multiplexed signaling opens the door to new predictions about synaptic plasticity. For example, though activation of the mesohabenular projection results in glutamate and GABA release, firing patterns of LHb neurons indicate a predominant GABA-induced decrease in firing rate of LHb neurons in rodents (Root et al., 2014a). Drugs of abuse, depression, and stress alter LHb function to favor glutamatergic excitation and demote GABAergic inhibition (Meshul et al., 1998
Acknowledgements
The Intramural Research Program of the National Institute on Drug Abuse, US National Institutes of Health (IRP/NIDA/NIH) supported this work.
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