Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain

Brinschwitz, K.; Dittgen, Anja; Madai, Vince I.; Lommel, R.; Geisler, Stefanie; Veh, Rüdiger W.

doi:10.1016/j.neuroscience.2010.03.050

Cited by 179 publications

(168 citation statements)

References 62 publications

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“…These observations are mostly in line with those of previous studies. Thus, the position and density of anterogradely labeled fibers in the VTA proper described here are similar to those described in previous studies examining LHb inputs to the VTA (e.g., Herkenham and Nauta, 1979;Araki et al, 1988;Omelchenko et al, 2009;Brinschwitz et al, 2010). Our observation of many PHA-L-labeled LHb axons in the VTA interpreted as fibers of passage is supported by the findings of recent ultrastructural studies that estimated a much lower synaptic incidence of LHb axons in the VTA (Omelchenko et al, 2009) than in the RMTg (Balcita-Pedicino et al, 2011).…”

Section: Topographical Position Of the Rmtgsupporting

confidence: 90%

“…There is now overwhelming evidence that a direct projection from the LHb to the VTA proper is glutamatergic Brinschwitz et al, 2010) and comparatively sparse, forming only a few synapses with no overt selectivity for GABA versus DA neurons (Omelchenko et al, 2009). Altogether, these findings indicate that the LHb may only exert a modest direct influence on VTA neurons, suggesting that the mostly GABAergic RMTg might be a critical relay for LHb inputs to the VTA.…”

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confidence: 99%

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Differential projections from the lateral habenula to the rostromedial tegmental nucleus and ventral tegmental area in the rat

Gonçalves

Sego

Metzger

2012

J of Comparative Neurology

118

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The mesopontine rostromedial tegmental nucleus (RMTg) is a mostly γ-aminobutyric acid (GABA)ergic structure believed to be a node for signaling aversive events to dopamine (DA) neurons in the ventral tegmental area (VTA). The RMTg receives glutamatergic inputs from the lateral habenula (LHb) and sends substantial GABAergic projections to the VTA, which also receives direct projections from the LHb. To further specify the topography of LHb projections to the RMTg and VTA, small focal injections of the anterograde tracer Phaseolus vulgaris leucoagglutinin were aimed at different subdivisions of the LHb. The subnuclear origin of LHb inputs to the VTA and RMTg was then confirmed by injections of the retrograde tracer cholera toxin subunit b into the VTA or RMTg. Furthermore, we compared the topographic position of retrogradely labeled neurons in the RMTg resulting from VTA injections with that of anterogradely labeled axons emerging from the LHb. As revealed by anterograde and retrograde tracing, LHb projections were organized in a strikingly topographic manner, with inputs to the RMTg mostly arising from the lateral division of the LHb (LHbL), whereas inputs to the VTA mainly emerged from the medial division of the LHb (LHbM). In the RMTg, profusely branched LHb axons were found in close register with VTA projecting neurons and were frequently apposed to the latter. Overall, our findings demonstrate that LHb inputs to the RMTg and VTA arise from different divisions of the LHb and provide direct evidence for a disynaptic pathway that links the LHbL to the VTA via the RMTg.

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Section: Topographical Position Of the Rmtgsupporting

confidence: 90%

mentioning

confidence: 99%

Differential projections from the lateral habenula to the rostromedial tegmental nucleus and ventral tegmental area in the rat

Gonçalves

Sego

Metzger

2012

J of Comparative Neurology

118

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“…Noteworthy, activity of DA and LHb neurons appears to be causally correlated, as electrical stimulation of the LHb inhibits DA neurons (Christoph et al, 1986;Ji and Shepard, 2007;Matsumoto and Hikosaka, 2007). However, the sparse innervation of DA neurons by excitatory LHb afferents (Brinschwitz et al, 2010;Omelchenko et al, 2009) unlikely explains this inhibition, and the presence of an area intermediate between the LHb and the VTA was originally postulated. Elegant studies by Jhou et al (2009a, b) revealed that g-aminobutyric acid (GABA) neurons in the rostromedial tegmental nucleus (RMTg), a region also denominated as 'tail' of the VTA (Perrotti et al, 2005), integrate input from the LHb and send output projection to midbrain DA neurons.…”

Section: Introductionmentioning

confidence: 99%

Effects of Drugs of Abuse on Putative Rostromedial Tegmental Neurons, Inhibitory Afferents to Midbrain Dopamine Cells

Lecca

Melis

Luchicchi

et al. 2010

Neuropsychopharmacol

139

163

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Recent findings have underlined the rostromedial tegmental nucleus (RMTg), a structure located caudally to the ventral tegmental area, as an important site involved in the mechanisms of aversion. RMTg contains g-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding midbrain dopamine (DA) neurons. One of the key features of drug addiction is the perseverance of drug seeking in spite of negative and unpleasant consequences, likely mediated by response suppression within neural pathways mediating aversion. To investigate whether the RMTg has a function in the mechanisms of addicting drugs, we studied acute effects of morphine, cocaine, the cannabinoid agonist WIN55212-2 (WIN), and nicotine on putative RMTg neurons. We utilized single unit extracellular recordings in anesthetized rats and whole-cell patch-clamp recordings in brain slices to identify and characterize putative RMTg neurons and their responses to drugs of abuse. Morphine and WIN inhibited both firing rate in vivo and excitatory postsynaptic currents (EPSCs) evoked by stimulation of rostral afferents in vitro, whereas cocaine inhibited discharge activity without affecting EPSC amplitude. Conversely, nicotine robustly excited putative RMTg neurons and enhanced EPSCs, an effect mediated by a7-containing nicotinic acetylcholine receptors. Our results suggest that activity of RMTg neurons is profoundly influenced by drugs of abuse and, as important inhibitory afferents to midbrain DA neurons, they might take place in the complex interplay between the neural circuits mediating aversion and reward.

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“…Thirdly, stimulating LHb neurons will inhibit DA neurons [21]. The inhibition of LHb on DA neurons may arise from the direct projection from LHb neuron to inhibitory interneurons in the VTA/SNc [23] or indirectly through some inhibitory nucleus. In fact, experiments have revealed a path from the LHb to DA neurons through RMTg and neurons in the RMTg seem to encode aversive stimuli [19,20].…”

Section: Lhb Inhibits Snc/vta Via Rmtgmentioning

confidence: 99%

Parallel Excitatory and Inhibitory Neural Circuit Pathways Underlie Reward‐Based Phasic Neural Responses

2018

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Phasic activity of dopaminergic (DA) neurons in the ventral tegmental area or substantia nigra compacta (VTA/SNc) has been suggested to encode reward-prediction error signal for reinforcement learning. Recent studies have shown that the lateral habenula (LHb) neurons exhibit a similar response, but for nonrewarding or punishment signals. Hence, the transient signaling role of LHb neurons is opposite that of DA neurons and also that of several other brain nuclei such as the border region of the globus pallidus internal segment (GPb) and the rostral medial tegmentum (RMTg). Previous theoretical models have investigated the neural circuit mechanism underlying reward-based phasic activity of DA neurons, but the feasibility of a larger neural circuit model to account for the observed reward-based phasic activity in other brain nuclei such as the LHb has yet to be shown. Here, we propose a largescale neural circuit model and show that parallel excitatory and inhibitory pathways underlie the learned neural responses across multiple brain regions. Specifically, the model can account for the phasic neural activity observed in the GPb, LHb, RMTg, and VTA/SNc. Based on sensitivity analysis, the model is found to be robust against changes in the overall neural connectivity strength. The model also predicts that striosomes play a key role in the phasic activity of VTA/SNc and LHb neurons by encoding previous and expected rewards. Taken together, our model identifies the important role of parallel neural circuit pathways in accounting for phasic activity across multiple brain areas during reward and punishment processing.

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Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain

Cited by 179 publications

References 62 publications

Differential projections from the lateral habenula to the rostromedial tegmental nucleus and ventral tegmental area in the rat

Differential projections from the lateral habenula to the rostromedial tegmental nucleus and ventral tegmental area in the rat

Effects of Drugs of Abuse on Putative Rostromedial Tegmental Neurons, Inhibitory Afferents to Midbrain Dopamine Cells

Parallel Excitatory and Inhibitory Neural Circuit Pathways Underlie Reward‐Based Phasic Neural Responses

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