The inhibitory influence of the lateral habenula on midbrain dopamine cells: ultrastructural evidence for indirect mediation via the rostromedial mesopontine tegmental nucleus.
ABSTRACT 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.
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ABSTRACT: Morphine is a highly potent analgesic with high addictive potential in specific contexts. Although dopamine neurons of the ventral tegmental area (VTA) are widely believed to play an essential role in the development of drug addiction, neuronal circuits underlying morphine action on dopamine neurons have not been fully elucidated. Here we combined in vivo electrophysiology, tract-tracing experiments, and targeted neuronal inactivation to dissect a neural circuit for acute morphine action on dopamine neurons in rats. We found that in vivo, morphine targets the GABAergic tail of the VTA, also called the rostromedial tegmental nucleus, to increase the firing of dopamine neurons through the activation of VTA μ opioid receptors expressed on tail of the VTA/rostromedial tegmental nucleus efferents. Our data also reveal that in the absence of VTA glutamatergic tone, there is no morphine-induced activation of dopamine neurons. These results define the anatomical organization and functional role of a neural circuit for acute morphine action on dopamine neurons.Proceedings of the National Academy of Sciences 09/2011; 108(39):16446-50. · 9.68 Impact Factor
Article: Electrical stimulation of the primate lateral habenula suppresses saccadic eye movement through a learning mechanism.[show abstract] [hide abstract]
ABSTRACT: The lateral habenula (LHb) is a brain structure which represents negative motivational value. Neurons in the LHb are excited by unpleasant events such as reward omission and aversive stimuli, and transmit these signals to midbrain dopamine neurons which are involved in learning and motivation. However, it remains unclear whether these phasic changes in LHb neuronal activity actually influence animal behavior. To answer this question, we artificially activated the LHb by electrical stimulation while monkeys were performing a visually guided saccade task. In one block of trials, saccades to one fixed direction (e.g., right direction) were followed by electrical stimulation of the LHb while saccades to the other direction (e.g., left direction) were not. The direction-stimulation contingency was reversed in the next block. We found that the post-saccadic stimulation of the LHb increased the latencies of saccades in subsequent trials. Notably, the increase of the latency occurred gradually as the saccade was repeatedly followed by the stimulation, suggesting that the effect of the post-saccadic stimulation was accumulated across trials. LHb stimulation starting before saccades, on the other hand, had no effect on saccade latency. Together with previous studies showing LHb activation by reward omission and aversive stimuli, the present stimulation experiment suggests that LHb activity contributes to learning to suppress actions which lead to unpleasant events.PLoS ONE 01/2011; 6(10):e26701. · 4.09 Impact Factor