Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

Berman, R. M. et al. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351–354 (2000)

Zarate, C. A. Jr et al. A randomized trial of an N-methyl-d-aspartate antagonist in treatment-resistant major depression. Arch. Gen. Psychiatry 63, 856–864 (2006)

Maeng, S. et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol. Psychiatry 63, 349–352 (2008)

Li, N. et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329, 959–964 (2010)

Autry, A. E. et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475, 91–95 (2011)

Zanos, P. et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533, 481–486 (2016)

Clements, J. A., Nimmo, W. S. & Grant, I. S. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J. Pharm. Sci. 71, 539–542 (1982)

Homayoun, H. & Moghaddam, B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J. Neurosci. 27, 11496–11500 (2007)

Matsumoto, M. & Hikosaka, O. Lateral habenula as a source of negative reward signals in dopamine neurons. Nature 447, 1111–1115 (2007)

Lammel, S. et al. Input-specific control of reward and aversion in the ventral tegmental area. Nature 491, 212–217 (2012)

Shabel, S. J., Proulx, C. D., Trias, A., Murphy, R. T. & Malinow, R. Input to the lateral habenula from the basal ganglia is excitatory, aversive, and suppressed by serotonin. Neuron 74, 475–481 (2012)

Stamatakis, A. M. & Stuber, G. D. Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nat. Neurosci. 15, 1105–1107 (2012)

Stephenson-Jones, M. et al. A basal ganglia circuit for evaluating action outcomes. Nature 539, 289–293 (2016)

Morris, J. S., Smith, K. A., Cowen, P. J., Friston, K. J. & Dolan, R. J. Covariation of activity in habenula and dorsal raphé nuclei following tryptophan depletion. Neuroimage 10, 163–172 (1999)

Shumake, J., Edwards, E. & Gonzalez-Lima, F. Opposite metabolic changes in the habenula and ventral tegmental area of a genetic model of helpless behavior. Brain Res. 963, 274–281 (2003)

Li, B. et al. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature 470, 535–539 (2011)

Li, K. et al. βCaMKII in lateral habenula mediates core symptoms of depression. Science 341, 1016–1020 (2013)

Lecca, S. et al. Rescue of GABAB and GIRK function in the lateral habenula by protein phosphatase 2A inhibition ameliorates depression-like phenotypes in mice. Nat. Med. 22, 254–261 (2016)

Aizawa, H., Kobayashi, M., Tanaka, S., Fukai, T. & Okamoto, H. Molecular characterization of the subnuclei in rat habenula. J. Comp. Neurol. 520, 4051–4066 (2012)

Tye, K. M. et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493, 537–541 (2013)

Hu, H. Reward and aversion. Annu. Rev. Neurosci. 39, 297–324 (2016)

Jhou, T. C., Fields, H. L., Baxter, M. G., Saper, C. B. & Holland, P. C. The rostromedial tegmental nucleus (RMTg), a GABAergic afferent to midbrain dopamine neurons, encodes aversive stimuli and inhibits motor responses. Neuron 61, 786–800 (2009)

Tian, J. & Uchida, N. Habenula lesions reveal that multiple mechanisms underlie dopamine prediction errors. Neuron 87, 1304–1316 (2015)

Zhou, L. et al. Organization of functional long-range circuits controlling the activity of serotonergic neurons in the dorsal raphe nucleus. Cell Reports 18, 3018–3032 (2017)

Chang, S. Y. & Kim, U. Ionic mechanism of long-lasting discharges of action potentials triggered by membrane hyperpolarization in the medial lateral habenula. J. Neurosci. 24, 2172–2181 (2004)

Weiss, T. & Veh, R. W. Morphological and electrophysiological characteristics of neurons within identified subnuclei of the lateral habenula in rat brain slices. Neuroscience 172, 74–93 (2011)

McCormick, D. A. & Bal, T. Sleep and arousal: thalamocortical mechanisms. Annu. Rev. Neurosci. 20, 185–215 (1997)

Grillner, S., McClellan, A., Sigvardt, K., Wallén, P. & Wilén, M. Activation of NMDA-receptors elicits “fictive locomotion” in lamprey spinal cord in vitro. Acta Physiol. Scand. 113, 549–551 (1981)

Schiller, J., Major, G., Koester, H. J. & Schiller, Y. NMDA spikes in basal dendrites of cortical pyramidal neurons. Nature 404, 285–289 (2000)

Zhu, Z. T., Munhall, A., Shen, K. Z. & Johnson, S. W. NMDA enhances a depolarization-activated inward current in subthalamic neurons. Neuropharmacology 49, 317–327 (2005)

Cheong, E. & Shin, H. S. T-type Ca2+ channels in normal and abnormal brain functions. Physiol. Rev. 93, 961–992 (2013)

Huguenard, J. R., Gutnick, M. J. & Prince, D. A. Transient Ca2+ currents in neurons isolated from rat lateral habenula. J. Neurophysiol. 70, 158–166 (1993)

Lisman, J. E. Bursts as a unit of neural information: making unreliable synapses reliable. Trends Neurosci. 20, 38–43 (1997)

Cui, Y. et al. Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature https://doi.org/10.1038/nature25752 (2018)

Henn, F. A. & Vollmayr, B. Stress models of depression: forming genetically vulnerable strains. Neurosci. Biobehav. Rev. 29, 799–804 (2005)

Gigliucci, V. et al. Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism. Psychopharmacology (Berl.) 228, 157–166 (2013)

Gören, M. Z. & Onat, F. Ethosuximide: from bench to bedside. CNS Drug Rev. 13, 224–239 (2007)

Gideons, E. S., Kavalali, E. T. & Monteggia, L. M. Mechanisms underlying differential effectiveness of memantine and ketamine in rapid antidepressant responses. Proc. Natl Acad. Sci. USA 111, 8649–8654 (2014)

Ambert, N. et al. Computational studies of NMDA receptors: differential effects of neuronal activity on efficacy of competitive and non-competitive antagonists. Open Access Bioinformatics 2, 113–125 (2010)

Endo, M ., Kurachi, Y . & Mishina, M. Pharmacology of Ionic Channel Function: Activators and Inhibitors Vol. 147 (Springer Science & Business Media, 2012)

Mehrke, G., Zong, X. G., Flockerzi, V. & Hofmann, F. The Ca++-channel blocker Ro 40-5967 blocks differently T-type and L-type Ca++ channels. J. Pharmacol. Exp. Ther. 271, 1483–1488 (1994)

Hasan, M. et al. Quantitative chiral and achiral determination of ketamine and its metabolites by LC-MS/MS in human serum, urine and fecal samples. J. Pharm. Biomed. Anal. 139, 87–97 (2017)

Kim, K. S. & Han, P. L. Optimization of chronic stress paradigms using anxiety- and depression-like behavioral parameters. J. Neurosci. Res. 83, 497–507 (2006)

Powell, T. R., Fernandes, C. & Schalkwyk, L. C. Depression-related behavioral tests. Curr. Protoc. Mouse Biol. 2, 119–127 (2012)

Zhu, Y., Wienecke, C. F., Nachtrab, G. & Chen, X. A thalamic input to the nucleus accumbens mediates opiate dependence. Nature 530, 219–222 (2016)

Gradinaru, V. et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154–165 (2010)

Lin, J. Y., Lin, M. Z., Steinbach, P. & Tsien, R. Y. Characterization of engineered channelrhodopsin variants with improved properties and kinetics. Biophys. J. 96, 1803–1814 (2009)

Ren, M., Cao, V., Ye, Y., Manji, H. K. & Wang, K. H. Arc regulates experience-dependent persistent firing patterns in frontal cortex. J. Neurosci. 34, 6583–6595 (2014)

Coulter, D. A., Huguenard, J. R. & Prince, D. A. Calcium currents in rat thalamocortical relay neurones: kinetic properties of the transient, low-threshold current. J. Physiol. (Lond.) 414, 587–604 (1989)

Shabel, S. J., Proulx, C. D., Piriz, J. & Malinow, R. Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment. Science 345, 1494–1498 (2014)

Valentinova, K. & Mameli, M. mGluR-LTD at excitatory and inhibitory synapses in the lateral habenula tunes neuronal output. Cell Reports 16, 2298–2307 (2016)

Zhu, Z. T., Munhall, A., Shen, K. Z. & Johnson, S. W. Calcium-dependent subthreshold oscillations determine bursting activity induced by N-methyl-d-aspartate in rat subthalamic neurons in vitro. Eur. J. Neurosci. 19, 1296–1304 (2004)

Rateau, Y. & Ropert, N. Expression of a functional hyperpolarization-activated current (Ih) in the mouse nucleus reticularis thalami. J. Neurophysiol. 95, 3073–3085 (2006)

Bon, C. L., Paulsen, O. & Greenfield, S. A. Association between the low threshold calcium spike and activation of NMDA receptors in guinea-pig substantia nigra pars compacta neurons. Eur. J. Neurosci. 10, 2009–2015 (1998)

Zhong, P. & Yan, Z. Differential regulation of the excitability of prefrontal cortical fast-spiking interneurons and pyramidal neurons by serotonin and fluoxetine. PLoS One 6, e16970 (2011)

Caiati, M. D. & Cherubini, E. Fluoxetine impairs GABAergic signaling in hippocampal slices from neonatal rats. Front. Cell. Neurosci. 7, 63 (2013)

Lin, L. et al. Large-scale neural ensemble recording in the brains of freely behaving mice. J. Neurosci. Methods 155, 28–38 (2006)

Fries, P., Roelfsema, P. R., Engel, A. K., König, P. & Singer, W. Synchronization of oscillatory responses in visual cortex correlates with perception in interocular rivalry. Proc. Natl Acad. Sci. USA 94, 12699–12704 (1997)

Rutishauser, U., Ross, I. B., Mamelak, A. N. & Schuman, E. M. Human memory strength is predicted by theta-frequency phase-locking of single neurons. Nature 464, 903–907 (2010)