Reward and aversion in a heterogeneous midbrain dopamine system

Abstract

The ventral tegmental area (VTA) is a heterogeneous brain structure that serves a central role in motivation and reward processing. Abnormalities in the function of VTA dopamine (DA) neurons and the targets they influence are implicated in several prominent neuropsychiatric disorders including addiction and depression. Recent studies suggest that the midbrain DA system is composed of anatomically and functionally heterogeneous DA subpopulations with different axonal projections. These findings may explain a number of previously confusing observations that suggested a role for DA in processing both rewarding as well as aversive events. Here we will focus on recent advances in understanding the neural circuits mediating reward and aversion in the VTA and how stress as well as drugs of abuse, in particular cocaine, alter circuit function within a heterogeneous midbrain DA system. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.

Keywords: AADC; AMPAR; ATP sensitive potassium channel; Aversion; BLA; CLi; CM; ChR2; D2R; DA; DAT; Dopamine; GAD; IF; IPN; KATP; LDT; LHb; MSN; MT; Mesocortical; Mesolimbic; N-methyl-d-aspartate; NAc; NMDAR; PBP; PFC; PN; RLi; RMTg; RRF; Reward; SN; SNc; SNr; TH; VGluT2; VMAT2; VTA; Ventral tegmental area; amino acid decarboxylase; basolateral amygdala; caudal linear nucleus; channelrhodopsin 2; dopamine; dopamine D2 receptor; dopamine transporter; fasciculus retroflexus; fr; glutamic acid decarboxylase; interfascicular nucleus; interpeduncular nucleus; lVTA; lateral VTA; lateral habenula; laterodorsal tegmentum; mVTA; mammillary body; medial VTA; medial lemniscus; medial terminal nucleus of the accessory optical tract; medium spiny neuron; ml; nucleus accumbens; parabrachial pigmented nucleus; paranigral nucleus; prefrontal cortex; retrorubral field; rostral linear nucleus of the raphe; rostromedial tegmental nucleus; substantia nigra; substantia nigra pars reticulata; substantia nirgra pars compacta; tyrosine hydroxylase; ventral tegmental area; vesicular glutamate transporter 2; vesicular monoamine transporter 2; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor.

Figure 1. Dopamine neurons with unconventional electrophysiological properties are mainly located in the medial VTA of the caudal midbrain

(A) Schematic drawing showing that dopamine (DA) neurons projecting to medial prefrontal cortex (mPFC), basolateral amygdala (BLA), nucleus accumbens (NAc) core, and NAc medial shell are predominantly located in the medial VTA (IF, medial PN and medial PBP nuclei) of the caudal midbrain. These VTA subregion and projections are highlighted in green. DA neurons projecting to NAc lateral shell can be found in the lateral VTA (lateral PBP nucleus) of the caudal midbrain (highlighted in yellow). (SNr, substantia nigra pars reticulatae; SNc, substantia nigra pars compacta; ml, medial lemniscus; PBP, parabrachial pigmented nucleus; PN, paranigral nucleus; IF, interfascicular nucleus.) (B) Fluorescence microscope image (TH-immunocytochemistry in red) showing the location of DA neurons in lateral (lVTA) and medial (mVTA) VTA of the caudal midbrain. (C, D, E, F) DA neurons located in the mVTA projecting to mPFC, NAc medial shell, NAc core and BLA have unconventional electrophysiological properties including: (C) lack of a prominent Ih current, (D) high maximal firing frequencies (~20–30 Hz), (E) broad action potentials and small afterhyperpolarization and (F) a high AMPAR/NMDAR ratio under basal conditions (~0.6).

Figure 2. Many dopamine neurons with classical electrophysiological properties are located in the lateral VTA of the rostral midbrain

(A) Schematic drawing showing that dopamine (DA) neurons projecting to nucleus accumbens (NAc) lateral shell are located in the lateral VTA of the rostral midbrain. The VTA subregion and projection is highlighted in yellow. Note, that DA neurons projecting to NAc lateral shell can also be found in the caudal midbrain (see figure 1). (Abbreviations are the same as in Figure 1. fr, fasciculus retroflexus; CM, mammillary body.) (B) Fluorescence microscope image (TH-immunocytochemistry in red) showing that in the rostral midbrain the lateral VTA contains many more TH-immunopositive cells than the medial VTA (compare to figure 1B; see Lammel et al., 2008 for a detailed anatomic analysis of DA projection neurons). (C, D, E, F) DA neurons located in the lVTA projecting to NAc lateral shell have classical electrophysiological properties including: (C) a prominent Ih current, (D) firing frequencies up to 10 Hz, (E) short action potentials with prominent afterhyperpolarizations and (F) a low AMPAR/NMDAR ratio under basal conditions (~0.4).