Abstract
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.
Highlights
The habenula is a component of the diencephalon and, together with the pineal gland, makes up the epithalamus [1]
Given its unique capability to relay information from limbic forebrain to midbrain monoamine nuclei via high-density afferents to monoaminergic centers, the lateral habenula could potentially induce the down-regulation of the serotonergic, noradrenergic, and dopaminergic systems
corticotropin-releasing hormone (CRH) activates the lateral habenula [23]. This stress-mediated activation of habenula CRH receptors is likely to participate in the stress response, this premise remains to be validated
Summary
University of North Carolina at Chapel Hill, United States. 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, depressive symptomatology. 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 precipitates lateral habenula firing, while outcomes that meet or exceed expectations decrease lateral habenula firing and, in turn, increase midbrain dopaminergic and serotonergic neurotransmission. If the lateral habenula fires more frequently, it may lead to a state of continuous disappointment and hopelessness, akin to depression. 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
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