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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...  Read more

View all comments by Alexander Sartorius
View all comments by Andreas Meyer-Lindenberg
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