Balcita-Pedicino JJ, Omelchenko N, Bell R, Sesack SR. The inhibitory influence of the lateral habenula on midbrain dopamine cells: ultrastructural evidence for indirect mediation via the rostromedial tegmental nucleus. J Comp Neurol 519: 1143-1164
The lateral habenula (LHb) provides an important source of negative reinforcement signals to midbrain dopamine (DA) cells in the substantia nigra and ventral tegmental area (VTA). This profound and consistent inhibitory influence involves a disynaptic connection from glutamate neurons in the LHb to some population of γ-aminobutyric acid (GABA) cells that, in turn, innervates DA neurons. Previous studies demonstrated that the GABA cells intrinsic to the VTA receive insufficient synaptic input from the LHb to serve as the primary source of this intermediate connection. In this investigation, we sought ultrastructural evidence supporting the hypothesis that a newly identified region of the brainstem, the rostromedial mesopontine tegmental nucleus (RMTg), is a more likely candidate for inhibiting midbrain DA cells in response to LHb activation. Electron microscopic examination of rat brain sections containing dual immunoreactivity for an anterograde tracing agent and a phenotypic marker revealed that: 1) more than 55% of the synapses formed by LHb axons in the RMTg were onto GABA-labeled dendrites; 2) more than 80% of the synapses formed by RMTg axons in the VTA contacted dendrites immunoreactive for the DA synthetic enzyme tyrosine hydroxylase; and 3) nearly all RMTg axons formed symmetric synapses and contained postembedding immunoreactivity for GABA. These findings indicate that the newly identified RMTg region is an intermediate structure in a disynaptic pathway that connects the LHb to VTA DA neurons. The results have important implications for understanding mental disorders characterized by a dysregulation of reward circuitry involving LHb and DA cell populations.
"Then, the sections were processed for TH immunogold-silver staining, using gold-conjugated secondary antibody goat antirabbit (Aurion, Electron Microscopy Science, 1/50) and IntenSE M silver kit reagent (GE Healthcare) for the silver intensification of gold label. The semiquantitative ultrastructural analysis was done as previously described (Omelchenko et al, 2006; Balcita-Pedicino et al, 2011). "
[Show abstract][Hide abstract] ABSTRACT: Midbrain dopamine neurons are implicated in various psychiatric and neurological disorders. The GABAergic tail of the ventral tegmental area (tVTA), also named the rostromedial tegmental nucleus (RMTg), displays dense projections to the midbrain and exerts electrophysiological control over dopamine cells of the VTA. However, the influence of the tVTA on the nigrostriatal pathway, from the substantia nigra pars compacta (SNc) to the dorsal striatum, and on related functions remains to be addressed. The present study highlights the role played by the tVTA as a GABA brake for the nigrostriatal system, demonstrating a critical influence over motor functions. Using neuroanatomical approaches with tract-tracing and electron microscopy, we reveal the presence of a tVTA-SNc-dorsal striatum pathway. Using in vivo electrophysiology, we prove that the tVTA is a major inhibitory control center for SNc dopamine cells. Using behavioral approaches, we demonstrate that the tVTA controls rotation behavior, motor coordination and motor skill learning. The motor enhancements observed after ablation of the tVTA are in this regard comparable to the performance enhancing properties of amphetamine, a drug used in doping. These findings demonstrate that the tVTA is a major GABA brake for nigral dopamine systems and nigrostriatal functions, and they raise important questions about how the tVTA is integrated within basal ganglia circuitry. They also warrant further research on the tVTA's role in motor and dopamine-related pathological contexts such as Parkinson's disease.Neuropsychopharmacology accepted article preview online, 4 June 2014; doi:10.1038/npp.2014.129.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2014; 39(12). DOI:10.1038/npp.2014.129 · 7.05 Impact Factor
"There is now overwhelming evidence that the RMTg is an intermediate structure in a pathway that connects the LHb to midbrain DA neurons (Jhou et al., 2009b; Balcita-Pedicino et al., 2011; Gonçalves et al., 2012) and that both the LHb and RMTg are central structures of an anti-reward circuit that encode disappointments and expectation of negative conditions. Thus, neurons in the LHb (Matsumoto and Hikosaka, 2007, 2009) and RMTg (Jhou et al., 2009a; Lecca et al., 2011; Hong et al., 2011) respond to the negative value of a stimulus and are primarily excited by reward omission and aversive stimuli and outcomes. "
[Show abstract][Hide abstract] ABSTRACT: Neural activity in dopaminergic areas such as the ventral tegmental area is influenced by timing processes, in particular by the temporal expectation of rewards during Pavlovian conditioning. Receipt of a reward at the expected time allows to compute reward-prediction errors which can drive learning in motor or cognitive structures. Reciprocally, dopamine plays an important role in the timing of external events. Several models of the dopaminergic system exist, but the substrate of temporal learning is rather unclear. In this article, we propose a neuro-computational model of the afferent network to the ventral tegmental area, including the lateral hypothalamus, the pedunculopontine nucleus, the amygdala, the ventromedial prefrontal cortex, the ventral basal ganglia (including the nucleus accumbens and the ventral pallidum), as well as the lateral habenula and the rostromedial tegmental nucleus. Based on a plausible connectivity and realistic learning rules, this neuro-computational model reproduces several experimental observations, such as the progressive cancelation of dopaminergic bursts at reward delivery, the appearance of bursts at the onset of reward-predicting cues or the influence of reward magnitude on activity in the amygdala and ventral tegmental area. While associative learning occurs primarily in the amygdala, learning of the temporal relationship between the cue and the associated reward is implemented as a dopamine-modulated coincidence detection mechanism in the nucleus accumbens.
Frontiers in Neurorobotics 01/2014; 8:4. DOI:10.3389/fnbot.2014.00004
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