Lateral habenula projections to dopamine and GABA neurons in the rat ventral tegmental area

Abstract

Ventral tegmental area (VTA) dopamine (DA) neurons and their forebrain projections are critically involved in reward processing and cognitive functions. Descending projections from the lateral habenula (LHb) play a central role in inhibiting DA cell activity in response to the absence of expected rewards. As LHb efferents are reportedly glutamatergic, their ability to inhibit DA cells would theoretically require a disynaptic connection involving VTA GABA neurons and their local collateral inputs to DA cells. To test this hypothesis, anterograde tract-tracing from the LHb was used to investigate the relative selectivity of LHb synapses onto GABA versus DA VTA neurons. LHb axons were visualized using immunoperoxidase, and DA and GABA cells were marked by immunogold-silver labeling for tyrosine hydroxylase (TH) or GABA, respectively. By ultrastructural analysis, 16% of LHb axons were observed to form synaptic contacts in the VTA, and most of these were of an intermediate morphological type that did not exhibit definitive asymmetric or symmetric character. LHb axons targeted TH- and GABA-labeled dendrites to a comparable extent (45% and 52% observed incidence, respectively). Preembedding immunogold labeling for the vesicular glutamate transporter type 2 and postembedding immunogold staining for GABA confirmed that approximately 85% of LHb terminals were glutamatergic and not GABAergic. These results suggest that the robust inhibition of DA cells evoked by the LHb is unlikely to arise from a selective innervation of VTA GABA neurons. Moreover, the LHb may mediate a direct excitation of DA cells that is over-ridden by indirect inhibition originating from an extrinsic source.

Dopamine D4Receptor Excitation of Lateral Habenula Neurons via Multiple Cellular Mechanisms

“…This is supported by anatomical data indicating that the LHb receives input from forebrain nuclei, whereas its efferents terminate in midbrain dopamine (DA) areas, such as the ventral tegmental area (VTA) and substantia nigra, as well as serotonergic brain regions (Herkenham and Nauta, 1979;Araki et al, 1984;Behzadi et al, 1990;Omelchenko et al, 2009). Many studies implicate these monoamine neurons in motivation, reward, and psychiatric illness, suggesting that the LHb may be involved in these behavioral phenomena .…”

“…Physiological studies also support this role as there is an inverted relationship between LHb and DA neuron activity, and activation of the LHb strongly inhibits midbrain DA neuron firing (Ji and Shepard, 2007;Matsumoto and Hikosaka, 2007). There is evidence that the LHb, which is largely composed of glutamatergic neurons (Geisler and Trimble, 2008;Omelchenko et al, 2009), sends a direct projection to DA and non-DA neurons in the ventral midbrain Omelchenko et al, 2009). However, this is inconsistent with strong inhibition of DA neurons during LHb activation (Christoph et al, 1986;Ji and Shepard, 2007;.…”

“…We also provide data to suggest that mLHb neurons that are activated by DA project to the RMTg, a region that strongly inhibits the majority of midbrain DA neurons (Jhou et al, 2009b). As the mLHb output neurons are thought to be glutamatergic (Geisler and Trimble, 2008;Omelchenko et al, 2009), this effect of DA would increase RMTg output to midbrain DA neurons, resulting in their inhibition. We therefore propose that the excitatory actions of DA on mLHb neurons constitute a negative feedback loop in which the duration of midbrain DA neuron activity is limited via RMTg activation.…”

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

“…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.…”

10.5937/mckg48-5899 = Functional and anatomical aspects of the habenular complex of epithalamus

“…Prema navedenim monoaminergičkim neuronima mezencefalona šalje glutamatergičke projekcije koje prave sinapse pretežno sa gaBaergičkim neuronima ventralnog tegmentalnog područja, substantiae nigrae i rostromedijalnog tegmentalnog jedra (6,22), koje inhibitorno deluju na dopaminergičke i serotonergičke neurone čiju aktivnost smanjuju. Međutim, opisan je i manji broj direktnih, ekscitatornih, glutamatergičkih projekcija lHb koje stižu do dopaminergičkih neurona mezencefalona (22)(23)(24).…”