Dissection and optogenetic manipulation of the Habenula-IPN cell-specific neuronal networks in the control of pain and addiction
Final Report Abstract
The medial habenula (MHb) is a small, bilateral epithalamic structure, implicated in nicotine addictive behavior. It projects to the single midline interpeduncular nucleus (IPN) in the midbrain tegmentum via the fasciculus retroflexus (FR). This project revealed four important physiological and behavioral aspects of the MHb-IPN axis: I: Neurons of the MHb showed spontaneous action potential activity, which was increased upon application of nicotine. This effect was even enhanced in mice undergoing nicotine withdrawal. Pharmacological suppression of the pacemaking activity in the MHb of nicotine naïve mice in vivo resulted in nicotine withdrawal like behavior. We hence speculated, that altered activity in cholinergic neurons of the MHb might contribute to difficulties in smoking cessation in humans. II: In vitro, Acetylcholine (ACh) is only released in the IPN upon high frequency stimulation of MHb terminals, but its specific role in nicotine addiction was not known. This project revealed, that ACh is co-released with glutamate from MHb terminals in the IPN. ACh acts synergistically to help vesicular glutamate packing. Deletion of the ACh producing enzyme Choline- Acetyltransferase (ChAT) revealed, that nicotine-dependent behaviors such as nicotine-conditioned reward and withdrawal are controlled by the release of ACh from MHb neurons. III: Molecular profiling studies done in this project revealed a high and almost exclusive expression of the orphan G-protein coupled receptor 151 (GPR 151) within the habenula-interpeduncular axis. This project revealed a highly specified physiological role of the GPR 151 in MHb to IPN synaptic transmissions, and further showed its role for nicotine addiction and response to the analgesic morphine. IV: Two novel neuronal subpopulations in the IPN were characterized molecularly and physiologically. Further studies will reveal their role in nicotine addiction and nicotine withdrawal. These results revealed important aspects of nicotine addiction and further underlined the role of the MHB-IPN axis in addiction.
Publications
- (2013). Reexposure to nicotine during withdrawal increases the pacemaking activity of cholinergic habenular neurons. Proceedings of the National Academy of Sciences of the United States of America 110, 17077-17082
Görlich, A., Antolin-Fontes, B., Ables, J.L., Frahm, S., Slimak, M.A., Dougherty, J.D., and Ibanez-Tallon, I.
(See online at https://doi.org/10.1073/pnas.1313103110) - (2015). The habenulo-interpeduncular pathway in nicotine aversion and withdrawal. Neuropharmacology 96, 213-222
Antolin-Fontes, B., Ables, J.L., Görlich, A., and Ibanez-Tallon, I.
(See online at https://doi.org/10.1016/j.neuropharm.2014.11.019) - An Essential Role of Acetylcholine- Glutamate Synergy at Habenular Synapses in Nicotine Dependence. eLife 2015;4:e11396, PDF 31 S.
Frahm, S., Antolin-Fontes, B., Görlich, A., Zander, J.F., Ahnert-Hilger, G., and Ibanez-Tallon, I.
(See online at https://doi.org/10.7554/eLife.11396)
