Habenula

Subregions: Lateral and Medial Habenula Lateral habenula recieves inputs from forebrain limbic regions and submits outputs to dopaminergic and serotonergic midbrains structures. Numerous studies have shown excitation of habenula to punishments and predictions of punishments, as well as omissions of predicted rewards and predictions of reward omission. The habenula is also implicated in other functions including stress, anxiety, pain, learning and attention (Hikosaka 2009)

http://www.scholarpedia.org/article/Epithalamus

Neurosynth structure image: n/a

Neurosynth connectivity image:

Image from Ide Li 2011:
(Habenula in blue)

Images from Savitz 2011:

Image from Lawson 2013:

Image of connectivity (Hong, Jhou, Smith 2011)

• Matsumoto, M., & Hikosaka, O. (2009). Representation of negative motivational value in the primate lateral habenula. Nature neuroscience, 12(1), 77-84. doi:10.1038/nn.2233 Matsumoto Hikosaka 2009
• Hong, S., Jhou, T. C., Smith, M., Saleem, K. S., & Hikosaka, O. (2011). Negative Reward Signals from the Lateral Habenula to Dopamine Neurons Are Mediated by Rostromedial Tegmental Nucleus in Primates. Journal of Neuroscience, 31(32), 11457-11471. doi:10.1523/JNEUROSCI.1384-11.2011 hongjhousmithetal11.pdf
• Ide, J. S., & Li, C.-S. R. (2011). Error-related functional connectivity of the habenula in humans. Frontiers in human neuroscience, 5(March), 25. doi:10.3389/fnhum.2011.00025 ideli11.pdf
• Bromberg-Martin, E. S., Matsumoto, M., Hong, S., & Hikosaka, O. (2010). A pallidus-habenula-dopamine pathway signals inferred stimulus values. Journal of neurophysiology, 104(2), 1068-76. doi:10.1152/jn.00158.2010 brombergmartinmatsumotohongetal10.pdf
• Lawson, R. P., Seymour, B., Loh, E., Lutti, a., Dolan, R. J., Dayan, P., … Roiser, J. P. (2014). The habenula encodes negative motivational value associated with primary punishment in humans. Proceedings of the National Academy of Sciences, 1–6. doi:10.1073/pnas.1323586111 LawsonetAl14
• Lawson, R. P., Drevets, W. C., & Roiser, J. P. (2013). Defining the habenula in human neuroimaging studies. NeuroImage, 64, 722–7. doi:10.1016/j.neuroimage.2012.08.076 LawsonetAl13
• Shelton, L., Becerra, L., & Borsook, D. (2012). Unmasking the mysteries of the habenula in pain and analgesia. Progress in neurobiology, 96(2), 208-19. Elsevier Ltd. doi:10.1016/j.pneurobio.2012.01.004 SheltonetAl12
• Stamatakis, A. M., & Stuber, G. D. (2012). Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance. Nature neuroscience, 15(8), 1105–1107. doi:10.1038/nn.3145 :Stamatakis&Stuber12
• Shabel, S. J., Proulx, C. D., Trias, A., Murphy, R. T., & Malinow, R. (2012). Input to the Lateral Habenula from the Basal Ganglia Is Excitatory, Aversive, and Suppressed by Serotonin. Neuron, 74(3), 475–481. doi:10.1016/j.neuron.2012.02.037Shabel12
• Amat, J., Sparks, P. D., Matus-Amat, P., Griggs, J., Watkins, L. R., & Maier, S. F. (2001). The role of the habenular complex in the elevation of dorsal raphe nucleus serotonin and the changes in the behavioral responses produced by uncontrollable stress. Brain Research, 917(1), 118–126. doi:10.1016/S0006-8993(01)02934-1Amat01
• Li, B., Piriz, J., Mirrione, M., Chung, C., Proulx, C. D., Schulz, D., Henn, F., et al. (2011). Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature, 470(7335), 535–9. doi:10.1038/nature09742 LiPirizetAl11
• Friedman, A., Lax, E., Dikshtein, Y., Abraham, L., Flaumenhaft, Y., Sudai, E., Ben-Tzion, M., et al. (2011). Electrical stimulation of the lateral habenula produces an inhibitory effect on sucrose self-administration. Neuropharmacology, 60(2-3), 381–7. doi:10.1016/j.neuropharm.2010.10.006 FriedmanLaxEtAl11
• Pobbe, R. L. H., & Zangrossi, H. (2008). Involvement of the lateral habenula in the regulation of generalized anxiety- and panic-related defensive responses in rats. Life sciences, 82(25-26), 1256–61. doi:10.1016/j.lfs.2008.04.012 PobbeZangrossi08
• Parent, a, Gravel, S., & Boucher, R. (1981). The origin of forebrain afferents to the habenula in rat, cat and monkey. Brain research bulletin, 6(1), 23–38. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/7470948
• Parent, a. (1979). Identification of the pallidal and peripallidal cells projecting to the habenula in monkey. Neuroscience letters, 15(2-3), 159–64. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/119192
• Araki, M., McGeer, P. L., & Kimura, H. (1988). The efferent projections of the rat lateral habenular nucleus revealed by the PHA-L anterograde tracing method. Brain research, 441(1-2), 319–30. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2451982
• Strotmann B, Heidemann RM, Anwander A, Weiss M, Trampel R, Villringer A, Turner R (2014) High-resolution MRI and diffusion-weighted imaging of the human habenula at 7 tesla. J Magn Reson Imaging 39:1018–1026. https://www.ncbi.nlm.nih.gov/pubmed/24259421

Endnote Package Library (with PDFs)

Connectivity:

Lateral hypothalamus GPb (Globus pallidus border); other cells in pallidal region Entopeduncular nucleus (excitatory projection) (Main pathway in rats; in monkeys peri-pallidal cells and lateral hypothalamus appear to be the main inputs) Olfactory tubercule Vertical limb of diagonal band nucleus Lateral preoptic area SN pars reticulata

LHb: Primarily outputs through RMTg, which projects to SNc VTA DRN

Habenula has reciprocal connections with: -Lateral hypothalamic area -Thalamic nuclei -Dorsal and median raphe nuclei

Nucleus of diagonal band Ventral pallidum Substantia innominata

MHb: Interpenduncular nucleus

-Reward -Stress -Fear/Anxiety -Pain -Addiction -Sleep -Higher level cognitive functions: feedback and prediction errors

Habenular neurons show excitation to a target predicting an aversive stimulus or a stimulus predicting no reward, which precedes inhibition in dopamine neurons for reward omission (Matsumoto Hikosaka 2007). This habenula-VTA pathway is now thought to go through the RMTg. Habenula neurons also show excitation to conditioned stimuli predicting negative valence rewards or reward omissions (Matsumoto Hikosaka 2009)

* Deep brain stimulation of habenula neurons decreased sucrose self-administration levels (Friedman, Lax et al 2011) * DBS of habenula also led to aversion of a context associated with stimulation of that region

*Lesions of habenula increased sucrose seeking behavior, resulting in delayed extinction for substitution of sucrose with water (Friedman, Lax et al 2011)

(Shabel, Proulx, Trias et al 2012)

• Stimulation of the excitatory EP-LHb pathway produced avoidance behavior
• Serotonin injections caused inhibition of LHb neurons receiving input from EP neurons

• Reduced synaptic potentiation of habenula neurons caused by deep brain stimulation decreased helpless behavior in rats
• Increased synaptic potentiation of habenula neurons projecting to VTA in learned helplessness (Li, Piriz, Mirrone et al 2011)

• Habenular lesions eliminated the differential rise in DRN serotonin for rats exposed to inescapable/escapable shock (Amat, Sparks et al 2001)
• Habenula lesions impaired acquisition of inhibitory avoidance while facilitating escape in a T-Maze (Pobbe Zangrossi 08)

(Stamatakis, Stuber, 2012)

• Exposure to aversive stimuli increased LHb synaptic drive onto RMTg neurons
• Optogenetic stimulation of LHb to RMTg pathway increased passive avoidance behavior and conditioned avoidance
• LHb-RMTg pathway also serves as a punishment; mice given optogenetic stimulation of that pathway while consuming sucrose made significantly fewer nose pokes to get sucrose

*Injection of kainic acid (an excitatory amino acid) into habenula facilitated acquisition of inhibitory avoidance while impairing escape behaviors. Inhibitory avoidance is thought to be related to anxiety behaviors, while one-way escape is more related to fear. (Pobbe Zangrossi 08)

Coordinates (x, y, z): [4, -22, 4] , [-4, -22, 4] Say how overall coordinates were derived here: hand-drawn ROI on MNI 152 (close to average of studies below)

Specific study coordinates (if not too many)

(Ullsberger activations reported in Talairach coordinates -5,-25,8, converted to MNI for table)
(Hennigan activations reported in Talairach coordinates -2,-29,0, converted to MNI for table)
Ide Li activations include thalamus

ROI: habenula_roi.zip

Neurosynth results for coordinate(s)

<list studies here from Neurosynth database>