A Novel Habenulo-Mesencephalic Circuit in Aversive Signaling

Abstract

Midbrain dopamine (DA) neurons are central to reward processes. In general, rewarding stimuli increase, and aversive stimuli decrease, both DA spike firing and terminal release. Stimulation of the lateral habenula (LHb), an area activated by aversive stimuli, or its efferent pathway the fasciculus retroflexus (fr), results in GABAergic inhibition of midbrain DA neurons, suggesting that the LHb encodes negative valence. The source of GABAergic inhibition is uncertain, but a recently described brain area, the mesopontine rostromedial tegmental nucleus (RMTg), is a strong candidate. A series of experiments was designed to elucidate the role of the LHb-RMTg-midbrain DA circuit in the encoding of aversive events. Both low and high intensity foot shocks elevated RMTg cFos, an immediate early gene that reflects cellular activation. Lesions of the fr blocked low intensity foot shock induced cFos elevation, demonstrating that the LHb is necessary for RMTg activation following mild aversive stimuli. To test whether LHb-stimulation induced inhibition of DA neurons occurs via RMTg GABA neurons, two electrophysiological experiments were conducted. In patch clamp recordings in rat parasagittal slices fr stimulation induced excitation in about half of all DA and non-DA neurons. Few neurons showed inhibition and excision of the RMTg had no effect on the DA population response to fr stimulation. In the whole animal, however, RMTg lesions decreased the prevalence of LHb-stimulation induced DA inhibition, giving physiological support for an LHb-RMTg-midbrain DA inhibitory circuit. To test whether changes in activation of the LHb-RMTg circuit alter behavioral sequelae associated with the presentation of aversive stimuli, we monitored the development of learned helplessness following manipulations of this circuit. LHb stimulation concurrent with foot shock during induction increased the prevalence of learned helplessness in rats. Conversely, lesions of the RMTg impeded the development of a helpless phenotype. We found that the LHb-RMTg circuit is activated by aversive events, mediates transient inhibition of DA neurons, and affects the development of depressive phenotypes. These data, which elucidate the role played by the LHb and RMTg in the encoding of aversive stimuli, have implications for future research in the areas of mood disorders and drug abuse.