Input-specific control of reward and aversion in the ventral tegmental area

1] Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA [2].
Nature (Impact Factor: 41.46). 10/2012; 491(7423). DOI: 10.1038/nature11527
Source: PubMed


Ventral tegmental area (VTA) dopamine neurons have important roles in adaptive and pathological brain functions related to reward and motivation. However, it is unknown whether subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures, and whether inputs to the VTA differentially modulate such circuits. Here we show that, because of differences in synaptic connectivity, activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to the nucleus accumbens lateral shell, whereas lateral habenula neurons synapse primarily on dopamine neurons projecting to the medial prefrontal cortex as well as on GABAergic (γ-aminobutyric-acid-containing) neurons in the rostromedial tegmental nucleus. These results establish that distinct VTA circuits generate reward and aversion, and thereby provide a new framework for understanding the circuit basis of adaptive and pathological motivated behaviours.

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    • "Recent optogenetic experiments confirmed that the LDT-VTA pathway stimulation can elicit psychostimulant-like behavior in the absence of drug administration (Lammel et al., 2012). The noradrenergic input from the LC to the PPN is inhibitory, presumably via α-2 adrenergic receptors (Williams and Reiner, 1993). "
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    ABSTRACT: Interactions between the pedunculopontine (PPN) and ventral tegmental area (VTA) have been described as key brain circuitry that mediates psychostimulant-mediated reward. Intranuclear PPN/laterodorsal tegmental injections of cholinergic receptor agonists or antagonists have helped clarify the role of these nuclei on psychostimulant-induced locomotion. Also, nicotine has been shown to have an inhibitory effect on the PPN, at least initially reducing arousal. PPN activation has been involved in the animal's voluntary search for psychostimulants. On the other hand, CNS depressants like ethanol might reduce arousal by a mechanism involving the direct inhibition of the PPN. In conclusion, neural activity in the PPN is key not only to maintaining arousal but also to affecting the level of psychostimulant and depressant administration.
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    • "Axonal projections of midbrain DA neurons are split into the mesostriatal and the mesocorticolimbic pathways [1]. The complex projections, functions and interactions of distinct types of midbrain DA neurons have recently been further dissected [3] [4] [5] [6] [7] [8] [9] [10]. To briefly summarize, the mesostriatal pathway connects the SN and some VTA DA neurons with the dorsal striatum and is important for the control of voluntary movement. "
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    ABSTRACT: Glial cell line-derived neurotrophic factor (GDNF) and its canonical receptor Ret can signal together or independently to fulfill many important functions in the midbrain dopaminergic (DA) system. While Ret signaling clearly impacts on the development, maintenance and regeneration of the mesostriatal DA system, the physiological functions of GDNF for the DA system are still unclear. Nevertheless, GDNF is still considered to be an excellent candidate to protect and/or regenerate the mesostriatal DA system in Parkinson disease (PD). Clinical trials with GDNF on PD patients are, however, so far inconclusive. Here, we review the current knowledge of GDNF and Ret signaling and function in the midbrain DA system, and their crosstalk with proteins and signaling pathways associated with PD.
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    • "For example, it has recently been suggested that some DA neurons code for aversive stimuli (Lammel et al., 2012;Gunaydin et al., 2014). These cells project to mPFC, while VTA DA neurons projecting to lateral NAc shell mediate positive reinforcement (Lammel et al., 2012). It would be interesting to assess self-stimulation and progression with selective targeting (Gunaydin et al., 2014). "
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    ABSTRACT: The factors causing the transition from recreational drug consumption to addiction remain largely unknown. It has not been tested whether dopamine (DA) is sufficient to trigger this process. Here we use optogenetic self-stimulation of DA neurons of the ventral tegmental area (VTA) to selectively mimic the defining commonality of addictive drugs. All mice readily acquired self-stimulation. After weeks of abstinence, cue-induced relapse was observed in parallel with a potentiation of excitatory afferents onto D1 receptor-expressing neurons of the nucleus accumbens (NAc). When the mice had to endure a mild electric foot shock to obtain a stimulation, some stopped while others persevered. The resistance to punishment was associated with enhanced neural activity in the orbitofrontal cortex (OFC) while chemogenetic inhibition of the OFC reduced compulsivity. Together, these results show that stimulating VTA DA neurons induces behavioral and cellular hallmarks of addiction, indicating sufficiency for the induction and progression of the disease.
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