Emerging preclinical and clinical evidence indicate that the lateral habenula plays a major role in the pathophysiology of depressive illness. Aberrant increases in neuronal activity in the lateral habenula, an anti-reward center, signals down-regulation of brainstem dopaminergic and serotonergic firing, leading to anhedonia, helplessness, excessive focus on negative experiences, and, hence, depressive symptomatology. The lateral habenula has distinctive regulatory adaptive role to stress regulation in part due to its bidirectional connectivity with the hypothalamic-pituitary-adrenal (HPA) axis. In addition, studies show that increased lateral habenula activity affects components of sleep regulation including slow wave activity and rapid eye movement (REM), both disrupted in depressive illness. Lack of perceived reward experienced during the adverse outcomes also precipitates lateral habenula firing, while outcomes that meet or exceed expectations decrease lateral habenula firing and, in turn, increase midbrain dopaminergic and serotonergic neurotransmission. The ability to update expectations of the environment based on rewards and aversive stimuli reflects a potentially important survival mechanism relevant to the capacity to adapt to changing circumstances. What if one lives in a continuously aversive and invalidating environment or under the conditions of chronic stress? If there is a propensity of the habenula to release many burst discharges over time, an individual could habitually come to perceive the world as perpetually disappointing. Conceivably, the lateral habenula could learn to expect an adverse outcome systematically and communicate it more easily. Thus, if the lateral habenula fires more frequently, it may lead to a state of continuous disappointment and hopelessness, akin to depression. Furthermore, postmortem studies reveal that the size of the lateral habenula and total number of neurons are decreased in patients who had depressive illness. Novel research in the field shows that ketamine induces rapid and sustained antidepressant effect. Intriguingly, recent preclinical animal models show that ketamine abolishes N-methyl-D-aspartate receptor (NMDAR)-dependent lateral habenula bursting activity, leading to rapid resolution of depressive symptoms.
Keywords: HPA axis; NMDA-type receptors; ketamine; lateral habenula; major depressive disorder; sleep.
Ketamine Blocks Bursting in the Lateral Habenula to Rapidly Relieve DepressionY Yang et al. Nature 554 (7692), 317-322. PMID 29446381.The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its …
Lateral Habenular Burst Firing as a Target of the Rapid Antidepressant Effects of KetamineY Cui et al. Trends Neurosci 42 (3), 179-191. PMID 30823984. - ReviewThe revolutionary discovery of the rapid antidepressant ketamine has been a milestone in psychiatry field in the last half century. Unlike conventional antidepressants th …
Glial Dysfunction in the Mouse Habenula Causes Depressive-Like Behaviors and Sleep DisturbanceW Cui et al. J Neurosci 34 (49), 16273-85. PMID 25471567.The lateral habenula (LHb) regulates the activity of monoaminergic neurons in the brainstem. This area has recently attracted a surge of interest in psychiatry because st …
Decoding Depression: Insights From Glial and Ketamine Regulation of Neuronal Burst Firing in Lateral HabenulaY Cui et al. Cold Spring Harb Symp Quant Biol 83, 141-150. PMID 30718267.The rapid antidepressant effect of ketamine is arguably one of the most significant advances in the mental health field in the last half century. However, its mechanism o …
Overcoming Depression by Inhibition of Neural Burst FiringD Kim et al. Neuron 98 (5), 878-879. PMID 29879390. - ReviewThe N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine has been found to have rapid and long-lasting antidepressive effects. Two elegant studies from Hailan Hu's l …