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Synaptic Hyperactivity in the Lateral Habenula Linked to Depression

8 March 2011. A study in Nature published February 24 links a circuit in the lateral habenula (LHb) to learned helplessness in rats—a model for human depression. Specifically, LHb neurons that project to the dopamine neurons in the ventral tegmental area (VTA) receive hyperactive synaptic input that correlates with learned helplessness. Applying deep brain stimulation, a protocol used to alleviate depression in humans, to the LHb reduced learned helplessness in the rats.

Recent studies in monkeys find that LHb neurons are activated by unpleasant stimuli, including failure to receive an expected reward or anticipation of a negative stimulus (Matsumoto et al., 2007 and Matsumoto et al., 2009). This suggests that an overactive LHb underlies aspects of depression. Consistent with this, inactivating LHb in rats exhibiting learned helplessness has an antidepressant-like effect (Winter et al., 2011).

Anatomically, the LHb is in a good position to mediate depression-related behaviors (Hikosaka et al., 2008): tucked underneath the cortex, the LHb receives signals from multiple regions involved in stress responses and sends output to midbrain regions containing neuromodulators, such as dopamine and serotonin, which are involved in reward and motivation. Subsets of cells may form distinct circuits through the LHb, and slight alterations may route information differently to affect decision-making and motivational states. A recent postmortem study found abnormalities in LHb volume and cell density in depression, though not in schizophrenia (Ranft et al., 2010). Though abnormal habenula signals have been proposed to be related to the difficulties people with schizophrenia have in feedback-guided learning (Shepard et al., 2006), the bulk of research is focused on how LHb signaling relates to depression.

The new study from Roberto Malinow of the University of California in San Diego and colleagues focused on a subset of LHb neurons that communicates with dopamine-containing neurons of the VTA, because of the link between dopamine and depressive disorders. The researchers find overactive synaptic input to these LHb neurons in brain slices made from rats exhibiting learned helplessness, a paradigm used to model the lack of motivation to control the outcome of a situation that is thought to contribute to clinical depression in humans.

A synaptic view of learned helplessness
Rats that show learned helplessness fail to escape from a foot shock that they have the power to evade. For example, when placed into a chamber associated with foot shock, the rat will not consistently press a lever that can terminate the shock. Similarly, in a forced swim test they will also spend more time immobile in a pool of water, rather than paddling about. Learned helplessness can be induced in a rat by a stressful session of repeated, unpredictable, and inescapable foot shocks, and by selective breeding of rats prone to developing learned helplessness.

Making brain slices from rats that had acquired learned helplessness either acutely or congenitally, co-first authors Bo Li, now at Cold Spring Harbor Laboratory, and Joaquin Piriz recorded from VTA-projecting LHb neurons. They found that these LHb neurons received more synaptic input than controls did, as judged by the frequency of spontaneously occurring miniature excitatory post-synaptic currents (mEPSCs). Though these events occurred almost twice as frequently in learned helplessness as in controls, the actual mEPSC sizes did not differ from controls. In some neurons, mEPSCs occurred very frequently—eight times a second or more—and the proportion of neurons with such a high frequency ranged between 14-20 percent in rats with learned helplessness, but amounted to only 2 percent in control rats. Notably, mEPSC frequency correlated with how often the rat failed to escape foot shock (r2 = 0.69, p <0.001), suggesting that excitatory synaptic input onto LHb neurons relates to a particular animal's helpless behavior.

Further experiments indicated that this increase in mEPSC frequency stemmed from inputs that were more likely to release neurotransmitter. The output of these LHb neurons was increased, too, with spontaneous action potentials occurring three times more often in rats with learned helplessness than in controls. These results suggest that finding ways to turn down the hyperactive inputs onto VTA-projecting LHb neurons, or the overactive LHb neurons themselves, could rectify learned helplessness.

DBS: a human treatment for a rat
With this in mind, the researchers then tested the effects of a deep-brain stimulation (DBS) protocol used to treat human depression in rat LHb brain slices. Delivering the same pattern of high-frequency electrical stimulation to the LHb that had successfully reduced depression in one patient, the researchers found this diminished the size of evoked excitatory synaptic potentials, effectively reducing synaptic drive onto LHb neurons. When the researchers applied this DBS protocol in vivo in rats with learned helplessness, the rats attempted to escape more, making more lever presses in a shock chamber and spending less time immobile in a forced swim test than rats receiving the DBS protocol to a nearby part of the brain.

Though more research will have to identify the exact effects the DBS protocol had on the VTA-projecting neurons of the LHb, these findings bolster the use of the learned helplessness paradigm in rats to study human depression, and highlight a role for the LHb. From the network of connections in which the LHb participates, the study offers up one part of the circuitry—the excitatory inputs onto VTA-projecting neurons—as a specific location where things go wrong in learned helplessness, and which may spur aberrant patterns of dopamine release. It's interesting that the hyperactive synaptic input found in a smallish proportion of neurons may tilt the circuit toward learned helplessness—therapeutically, this may mean that only a small population of neurons needs to be retuned to reduce depression. These details may also help researchers understand abnormal habenula signaling that has been found in people with schizophrenia in the context of learning from errors, and perhaps also contribute to understanding anhedonia or other negative symptoms of schizophrenia.—Michele Solis.

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; 470:535-539. Abstract

Comments on News and Primary Papers
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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Related News: Studies Dissect Depression’s Circuitry

Comment by:  Anthony Grace, SRF Advisor (Disclosure)
Submitted 16 January 2013
Posted 17 January 2013
  I recommend the Primary Papers

The Nature articles on the role of dopamine and depression add greatly to our understanding of this transmitter system in affective disorders. While on the surface such studies may be viewed as being opposite in nature, both are highly consistent with results from our lab and others. We (Valenti et al., 2011) and others have shown that strong, acute stressors can activate dopamine neuron activity; however, when measured after long bouts of inescapable stress or following an incubation period, the activity of these neurons is markedly depressed (Moore et al., 2001; Valenti et al., 2012; Chang and Grace, 2013). These studies suggest that dopamine system activation during the stressor may be a precedent for dopamine system downregulation following termination of the stressor. Indeed, in the uncontrollable chronic stress model and in the learned helplessness model of depression (Chang and Grace, 2012; Belujon et al., 2012), we have found that dopamine neuron population activity depression correlates with behavioral indices of depressive-like behavior in rats.

The data from the Han and Deisseroth laboratories are actually highly consistent with these data. Thus, Han showed that phasic activation of dopamine neurons potentiates the effects of stress on subsequent depression (consistent with our studies showing dopamine activation during the initial stress events), whereas restoring dopamine activity during the depressed condition in Deisseroth's paper relieves the symptoms due to dopamine system downregulation.

Therefore, in our opinion, each phase of the depression process may have a dopamine component: an activation during the induction phase and an attenuation during symptom expression. Taken together, these findings provide unique insights into the process and expression of depression.


Belujon, P., Dollish, H.D. and Grace, A.A. (2012) Ketamine restores activity of the dopamine system selectively in rats exhibiting learned helplessness in an animal model of depression. Program No. 774.02.2012. Neuroscience Meeting Planner, New Orleans, LA. Society for Neuroscience, 2012. Online.

Chang, C.H. and Grace, A.A. (2012) Chronic mild stress induces anxiety-like behavior and down-regulation of dopamine system activity in rats. Program No. 774.13.2012. Neuroscience Meeting Planner, New Orleans, LA. Society for Neuroscience, 2012. Online.

Chang, C.-H. and Grace, A.A. (2013) Amygdala beta noradrenergic receptors modulate delayed down-regulation of dopamine activity following restraint. Journal of Neuroscience (in press).

Moore, H., Rose, H.J.. and Grace, A.A. (2001) Chronic cold stress reduces the spontaneous activity of ventral tegmental dopamine neurons. Neuropsychopharmacology 24: 410-419. Abstract

Valenti, O., Lodge, D.J. and Grace, A.A. (2011) Aversive stimuli alter ventral tegmental area dopamine neuron activity via a common action in the ventral hippocampus. Journal of Neuroscience 31: 4280-4289. Abstract

Valenti, O., Gill, K.M. and Grace, A.A. (2012) Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: Response alteration by stress pre-exposure. European Journal of Neuroscience 35: 1312-1321. Abstract

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