Introduction

Lateral habenula (LHb) research has increased during the last decades as technological advancements and new discoveries were made regarding the role of the LHb in regulating negative reward through serotonin and dopamine nuclei.¹ As such, research has also examined the contribution of LHb dysfunction to major depressive disorder (MDD).³ Many pharmaceuticals were discovered to alleviate MDD symptoms including ketamine.^2,5 However, the mechanisms of action were not well understood. In the present study published in the journal Nature, Yang et al. investigated how ketamine acts within the lateral habenula to block bursting type neuronal firing to relieve depressive symptoms. It was found that ketamine blocks N-methyl-D-aspartate receptors (NMDAR) located in the lateral habenula.⁴ Normally, NMDARs are activated to generate burst firing which inhibits serotonin and dopamine nuclei activity. Because ketamine blocks NMDARs, serotonin and dopamine release were elevated, and depressive symptoms were alleviated. By understanding the mechanism of action of ketamine, finding other pharmaceuticals that block NMDARs would provide more treatment options for MDD. 

Background

The LHb suppresses motor behavior after failure to obtain a reward or in anticipation of aversive outcome. By connecting forebrain structures to midbrain and hindbrain structures which control serotonin and dopamine, the LHb prevents release of reward neurotransmitters to prevent strengthening of unfavorable motor pathways.⁶ The LHb comprises mainly glutamatergic neurons. However, it inhibits downstream reward centers suggesting the possibility of GABAergic interneurons or a missing structure in the antireward pathway.^8,9 

Ketamine is often associated with veterinary use as an animal anesthetic, particularly with large animals such as horses.⁷ Recently, however, it has been used as a pharmaceutical treatment for depressive symptoms. In the early 2000s, ketamine was discovered to be an effective antidepressant and work through antagonism of NMDA receptors.² It is known that LHb dysfunction causes depressive symptoms, and that ketamine rapidly relieves these symptoms.^2,3 However, the mechanism of ketamine was not known but was hypothesized to occur in the LHb as the LHb mediates reward centers important to MDD. The present study aims to examine this relationship and the role of the LHb in MDD. 

Methods

The study used electrophysiology and optogenetics in animal models of depression to understand the receptors within the lateral habenula and the effect of direct ketamine injections to this area.⁴ The study contained several parts to generate multiple lines of evidence in support of their hypothesis. In the first part, congenitally learned helpless (cLH) rats, a model of depression, were given injections of ketamine directly into both lateral habenulas and placed in the forced swim test (FST) to measure depressive symptoms. In the second part, an electrophysiology technique, the whole-cell patch-clamp, was used to measure current through whole neurons to understand the activity pattern of LHb neurons in control and chronic restraint stressed (CRS) mice, another model of depression. The third part was performed after observing the findings in part one. The third part examined whether NMDARs were required for LHb bursting activity by bathing slices of LHb tissue in ketamine and measuring the subsequent level of bursting type activity as compared to control NMDAR currents. In the fourth part, resting membrane potentials (RMP) of LHb neurons were altered to the RMP of bursting neurons to examine any changes to the pattern of activity in the LHb. Lastly, the effect of burst activity upon depressive symptoms was examined through optogenetics. The LHb neurons were inhibited and only excited when yellow light was shone on the tissue. Then freely behaving mice were tested in a real-time place aversion assay. The yellow light was activated in only one part of the chamber and the aversion of that area was measured.⁴ 

Results

The findings from the study reveal that ketamine binds to NMDARs which alleviates depressive symptoms in animal models of depression through the action of an inhibitory neuron.⁴ The LHb is intrinsically activated and comprises three types of neurons: silent, tonic-firing, and burst-firing neurons, and an electrically induced increase in activity of burst-firing neurons leads to depressive symptoms.^4,10 The RMP of the burst-firing neurons is hyperpolarized compared to the other two neuronal types and altering their RMPs can generate burst-firing neurons.⁴ Furthermore, it was determined that NMDARs are directly required for generating burst-firing activity.⁴

Significance

The study’s findings are important as they reveal depressive symptoms have a direct link to the activity of the LHb, and ketamine is an effective antidepressant because it acts upon this region of the brain.⁴ MDD is a common disorder affecting more than 250 million people worldwide.¹¹ Thus, it is important to understand the mechanism of depressive symptoms and the maladaptive molecular changes to the circuits within the brain.¹² The findings can aid with discovering new drugs that mediate LHb activity or new techniques of electrical stimulation to change RMP of the neurons to treat depressive symptoms thereby providing a higher quality of life to millions worldwide.

[+] References

[+] Other Work By Keziah Nguyen