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Li B, Piriz J, Mirrione M, Chung C, Proulx CD, Schulz D, Henn F, Malinow R. Synaptic potentiation onto habenula neurons in the learned helplessness model of depression. Nature. 2011 Feb 24 ; 470(7335):535-9. Pubmed Abstract

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Comment by:  Alexander SartoriusAndreas Meyer-Lindenberg
Submitted 16 March 2011
Posted 16 March 2011

Deep midline structures of our brain seem to contribute considerably to risk for psychiatric illnesses (Northoff et al., 2010). The lateral habenula could be a bottleneck of information flow between midline and cortical structures. Since efferents of the lateral habenula influence all three monoaminergic systems, a contribution to depression risk has been hypothesized (Sartorius and Henn, 2007). One efferent pathway projects via the rostromedial tegmental nucleus to the ventral tegmental area (VTA). Dopaminergic neurons then project to the ventral striatum, reflecting a major part of the brain’s reward system.

The paper by Li et al. further characterizes this pathway by means of electrophysiology and narrows the gap to human depression. It is the first time that not only overactivation of the whole structure but excessive firing rates of specific neurons within the structure were observed in an animal model of depression. Furthermore, dendritic spine density of VTA-projecting neurons was elevated in congenitally helpless animals—an alteration that could reflect neuroplastic adaptations to a trait related to depression. In a final step of their work, Li et al. demonstrate that functional inhibition of the lateral habenula (by deep-brain stimulation—DBS) alleviates depressive-like behavior. This translational aspect may specify one mechanism that has contributed to full remission in our first severely depressed patient after DBS of the lateral habenula (Sartorius et al., 2010). That DBS of other structures within the reward system can efficiently treat depressive symptoms has been already demonstrated in a study by Bewernick et al., where especially aspects of anhedonia improved significantly (Bewernick et al., 2010). Consequently, these findings argue that anhedonia (Sanchis-Segura et al., 2005) should be quantified in further animal experiments exploring the DBS effects onto the reward pathway.

Other monoaminergic systems relevant for depression, such as the serotonergic and noradrenergic ones, should be explored next to fully understand the role of the habenula in orchestrating these fundamental neuromodulator circuits. The Network of European Funding for Neuroscience Research (NEURON) has recently funded a multinational project to further elaborate on the role of the habenula in risk for depression and the monoaminergic systems by means of functional human and animal imaging.


Northoff G, Wiebking C, Feinberg T, Panksepp J. The “resting-state hypothesis” of major depressive disorder-A translational subcortical-cortical framework for a system disorder. Neurosci Biobehav Rev. 2010 Dec 28. Abstract

Bewernick BH, Hurlemann R, Matusch A, Kayser S, Grubert C, Hadrysiewicz B, Axmacher N, Lemke M, Cooper-Mahkorn D, Cohen MX, Brockmann H, Lenartz D, Sturm V, Schlaepfer TE. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry. 2010 Jan 15;67(2):110-6. Abstract

Sanchis-Segura C, Spanagel R, Henn FA, Vollmayr B. Reduced sensitivity to sucrose in rats bred for helplessness: a study using the matching law. Behav Pharmacol. 2005 Jul;16(4):267-70. Abstract

Sartorius A, Kiening KL, Kirsch P, von Gall CC, Haberkorn U, Unterberg AW, Henn FA, Meyer-Lindenberg A. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol Psychiatry. 2010 Jan 15;67(2):e9-e11. Abstract

Sartorius A, Henn FA. Deep brain stimulation of the lateral habenula in treatment resistant major depression. Med Hypotheses. 2007;69(6):1305-8. Abstract

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