title: Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat.
abstract: The lateral habenula, a phylogenetically conserved epithalamic structure, is activated by aversive stimuli and reward omission. Excitatory efferents from the lateral habenula predominately inhibit midbrain dopamine neuronal firing through a disynaptic, feedforward inhibitory mechanism involving the rostromedial tegmental nucleus. However, the lateral habenula also directly targets dopamine neurons within the ventral tegmental area, suggesting that opposing actions may result from increased lateral habenula activity. In the present study, we tested the effect of habenular efferent stimulation on dopamine and nondopamine neurons in the ventral tegmental area of Sprague-Dawley rats using a parasagittal brain slice preparation. Single pulse stimulation of the fasciculus retroflexus excited 48% of dopamine neurons and 51% of nondopamine neurons in the ventral tegmental area of rat pups. These proportions were not altered by excision of the rostromedial tegmental nucleus and were evident in both cortical- and striatal-projecting dopamine neurons. Glutamate receptor antagonists blocked this excitation, and fasciculus retroflexus stimulation elicited evoked excitatory postsynaptic potentials with a nearly constant onset latency, indicative of a monosynaptic, glutamatergic connection. Comparison of responses in rat pups and young adults showed no significant difference in the proportion of neurons excited by fasciculus retroflexus stimulation. Our data indicate that the well-known, indirect inhibitory effect of lateral habenula activation on midbrain dopamine neurons is complemented by a significant, direct excitatory effect. This pathway may contribute to the role of midbrain dopamine neurons in processing aversive stimuli and salience.
authors.affiliation: Maryland Psychiatric Research Center, Catonsville, Maryland; and Department of Psychiatry, University of Maryland-Baltimore, Baltimore, Maryland lbrown@mprc.umaryland.edu.
authors.forename: P Leon
authors.initials: PL
authors.lastname: Brown
authors.affiliation: Maryland Psychiatric Research Center, Catonsville, Maryland; and Department of Psychiatry, University of Maryland-Baltimore, Baltimore, Maryland.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Shepard
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism; D004558:Electric Stimulation; D005260:Female; D019262:Habenula / Q000033:anatomy & histology* / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D007150:Immunohistochemistry; D008297:Male; D008839:Microelectrodes; D009434:Neural Pathways / Q000033:anatomy & histology / Q000187:drug effects / Q000254:growth & development / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D046509:Tissue Culture Techniques; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000033:anatomy & histology* / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D017470:Receptors, Glutamate; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: brain slice; dopamine; lateral habenula; rostromedial tegmental nucleus; tail of the ventral tegmental area; tyrosine hydroxylase