Elsevier

Neuroscience

Volume 168, Issue 2, 30 June 2010, Pages 463-476
Neuroscience

Cognitive, Behavioral and Systems Neuroscience
Research Paper
Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain

https://doi.org/10.1016/j.neuroscience.2010.03.050Get rights and content

Abstract

The concept of cortical-subcortical loops emphasizes the importance of the basal ganglia for motor, psychomotor, and emotional cortical functions. These loops are bidirectionally controlled by the midbrain dopaminergic system, predominantly but not exclusively at the level of the striatum including the accumbens nucleus. Successful behaviors increase the activities of the mesostriatal (arising in the complex part of the substantia nigra) and mesolimbic (arising in the ventral tegmental area, VTA) neurons, thereby reinforcing the corresponding actions. In contrast, unsuccessful behaviors result in an increased activation of the lateral habenular complex (LHb), thereby decreasing the activities of mesolimbic neurons. Correspondingly, electrical stimulation of the LHb effectively blocks neuronal activity in the VTA. Whether this block is due to an inhibitory projection from the LHb to the VTA, or whether axons from excitatory LHb neurons target inhibitory neurons within the VTA, is presently not known. Here we show, using in situ hybridization and immunocytochemical double labeling at the light and electron microscopic level, that GABAergic neurons are scarce in the LHb and that glutamatergic axons from the LHb mostly target GABAergic neurons in the VTA and the mesopontine rostromedial tegmental nucleus (RMTg), also known as tail of the VTA (tVTA). These data explain the inhibitory effect of LHb activation on the VTA. In addition, however, a small number of LHb terminals in the VTA actually contacts dopaminergic neurons. The biological importance of these terminals requires further investigation.

Section snippets

Chemicals

Chemicals were obtained from Sigma-Aldrich, Taufkirchen, Germany, if not indicated otherwise. Sources of primary antibodies are depicted in Table 1. Biotin-labeled secondary antibodies and the ABC-Elite complex were from Vector (Vector Laboratories, Burlingame, CA, USA) and gold-labeled secondary antibodies from Nanoprobes (Yaphank, NY, USA).

Animals

All animal experiments were conducted in accordance with the guidelines of the European Communities Council directive 86/609/EEC and were approved by the

Results

The inhibitory control of the lateral habenular complex (LHb) over the dopaminergic (DA) neurons in the VTA is well documented (see introduction). It is not known, whether this inhibition is due to a direct inhibitory (GABAergic or glycinergic) influence or due to an excitatory (cholinergic or glutamatergic) projection via inhibitory neurons in the ventral mesencephalon. Immunocytochemical screening of the LHb for glycinergic neurons with antibodies against the glycine transporter and for

Discussion

The prominent projections from the LHb complex to the ventral mesencephalon are well known (Phillipson, 1979, Herkenham and Nauta, 1979, Oades and Halliday, 1987, Geisler et al., 2007, Geisler and Trimble, 2008, Jhou et al., 2009a, Jhou et al., 2009b, Kaufling et al., 2009). In agreement with previous reports (Araki et al., 1988), we found that midbrain terminals from the LHb primarily project to the VTA and the tVTA/RMTg and only slightly to medial aspects of the substantia nigra pars compacta

Acknowledgments

This work was supported with help from Heike Heilmann and Ina Wolter in data collection, Gregor Laube in electron microscopy, Christian Derst in providing the riboprobes, and comments of René Bernard and Torsten Weiβ on a previous version of this manuscript. This work is part of the MD thesis of Katja Brinschwitz at the Institut für Integrative Neuroanatomie, Charité - Universitätsmedizin Berlin.

References (60)

  • S. Murase et al.

    Prefrontal cortex regulates burst firing and transmitter release in rat mesolimbic dopamine neurons studied in vivo

    Neurosci Lett

    (1993)
  • T. Nishikawa et al.

    Evidence for, and nature of, the tonic inhibitory influence of habenulointerpeduncular pathways upon cerebral dopaminergic transmission in the rat

    Brain Res

    (1986)
  • R.D. Oades et al.

    Ventral tegmental (A 10) system: neurobiology. 1Anatomy and connectivity

    Brain Res Rev

    (1987)
  • L.W. Swanson

    The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat

    Brain Res Bull

    (1982)
  • E.J. Van Bockstaele et al.

    GABA-containing neurons in the ventral tegmental area project to the nucleus accumbens in rat brain

    Brain Res

    (1995)
  • M. Wu et al.

    Subpallidal outputs to the nucleus accumbens and the ventral tegmental area: anatomical and electrophysiological studies

    Brain Res

    (1996)
  • K.H. Andres et al.

    General methods for characterization of brain regions

  • K.H. Andres et al.

    Subnuclear organization of the rat habenular complexes

    J Comp Neurol

    (1999)
  • A.I. Basbaum et al.

    WGA-apo-HRP-gold: a new retrograde tracer for light- and electron-microscopic single—and double-label studies

    J Comp Neurol

    (1987)
  • A.J. Blood et al.

    Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion

    Proc Natl Acad Sci U S A

    (2001)
  • K. Brinschwitz et al.

    Glutamatergic fibers from the lateral habenula do not terminate on dopaminergic neurons in the ventral tegmental area

    Soc Neurosci Abstr

    (2005)
  • D.B. Carr et al.

    GABA-containing neurons in the rat ventral tegmental area project to the prefrontal cortex

    Synapse

    (2000)
  • P.J. Charlety et al.

    Burst firing of mesencephalic dopamine neurons is inhibited by somatodendritic application of kynurenate

    Acta Physiol Scand

    (1991)
  • K. Chergui et al.

    Tonic activation of NMDA receptors causes spontaneous burst discharge of rat midbrain dopamine neurons in vivo

    Eur J Neurosci

    (1993)
  • G.R. Christoph et al.

    Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmentum area of the rat

    J Neurosci

    (1986)
  • A. Dittgen et al.

    Anterior and posterior parts of the rat ventral tegmental area receive topographically distinct afferents from the lateral habenular complex

    Soc Neurosci Abst Atlanta

    (2006)
  • M. Esclapez et al.

    Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms

    J Neurosci

    (1994)
  • S.B. Floresco et al.

    Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission

    Nat Neurosci

    (2003)
  • G.L. Forster et al.

    Laterodorsal tegmental stimulation elicits dopamine efflux in the rat nucleus accumbens by activation of acetylcholine and glutamate receptors in the ventral tegmental area

    Eur J Neurosci

    (2000)
  • S. Geisler et al.

    Morphologic and cytochemical criteria for the identification and delineation of individual subnuclei within the lateral habenular complex of the rat

    J Comp Neurol

    (2003)
  • Cited by (158)

    • Tonic activity in lateral habenula neurons acts as a neutral valence brake on reward-seeking behavior

      2022, Current Biology
      Citation Excerpt :

      To compare these results with other methods used for recording LHb neural activity, we used fiber photometry to record the activity of genetically targeted glutamatergic LHb neurons in Vglut2-ires-Cre mice63 during performance of the same task (Figures S1A and S1B). Most neurons in the LHb are glutamatergic and express Vglut2,64 and Vglut2-ires-Cre mice have previously been used to target the LHb.65,66 We also recorded LHb neural activity in C57BL6/J mice using multi-unit electrophysiology (Figures S1E and S1F).

    View all citing articles on Scopus
    1

    Present address: Unfallkrankenhaus Berlin, Klinik für Hals-, Nasen und Ohrenheilkunde, Warener Strasse, D-712683 Berlin, Germany.

    2

    Present address: Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Frauenheilkunde/Geburtshilfe, Bereich Gynäkologie–OP, Charitéplatz 1, D-10117 Berlin, Germany.

    3

    Present address: Department of Neurology, Washington University/Barnes Jewish Hospital, 1 BJH Plaza, St. Louis, MO 63110, USA.

    View full text