Lateral Habenula Beyond Avoidance: Roles in Stress, Memory, and Decision-Making With Implications for Psychiatric Disorders

Abstract

In this Perspective review, we highlight some of the less explored aspects of lateral habenula (LHb) function in contextual memory, sleep, and behavioral flexibility. We provide evidence that LHb is well-situated to integrate different internal state and multimodal sensory information from memory-, stress-, motivational-, and reward-related circuits essential for both survival and decision making. We further discuss the impact of early life stress (ELS) on LHb function as an example of stress-induced hyperactivity and dysregulation of neuromodulatory systems within the LHb that promote anhedonia and motivational deficits following ELS. We acknowledge that recent technological advancements in manipulation and recording of neural circuits in simplified and well-controlled behavioral paradigms have been invaluable in our understanding of the critical role of LHb in motivation and emotional regulation as well as the involvement of LHb dysfunction in stress-induced psychopathology. However, we also argue that the use of ethologically-relevant behaviors with consideration of complex aspects of decision-making is warranted for future studies of LHb contributions in a wide range of psychiatric illnesses. We conclude this Perspective with some of the outstanding issues for the field to consider where a multi-systems approach is needed to investigate the complex nature of LHb circuitry interactions with environmental stimuli that predisposes psychiatric disorders.

Involvement of Lateral Habenula Dysfunction in Repetitive Mild Traumatic Brain Injury-Induced Motivational Deficits

“…Therefore, it was likely that mTBI alters the function of subcortical regions which receive direct 40-45 and indirect 39, 46-50 projections from mPFC and ACC, such as the LHb, a critical stress- and reward-related brain region that promotes anhedonia and motivational deficits. We observed that tonic firing LHb neurons were more prevalent following mTBI which is consistent with the literature that LHb hyperactivity in general contributes to the development of depression-like motivational and social deficits, and anhedonic phenotypes 2, 20, 24, 29, 51-53 . Intriguingly, mTBI was associated with fewer LHb bursting neurons.…”

“…Chronic mood-related psychiatric morbidity following mTBI often presents as affective deficits (e.g., major depressive disorder, apathy) and associated dysregulation of emotional and social behaviors (irritability, aggression, suicidality, social withdrawal, anxiety) 1 . Compelling evidence from animal and human studies suggest that long-term negative effects on social functioning and mood states are related to dysfunction of brain reward and motivational circuits including the lateral habenula (LHb) 2,8,9 . The LHb is a diencephalic structure that has emerged as an anti-reward hub for motivation and decision-making which links forebrain limbic structures with midbrain monoaminergic centers [10][11][12][13] .…”

“… Abstract Affective disorders including depression (characterized by reduced motivation, social withdrawal and anhedonia), anxiety and irritability are frequently reported as long-term consequences of mild traumatic brain injury (mTBI) 1 in addition to cognitive deficits, suggesting a possible dysregulation within mood/motivational neural circuits. One of the important brain regions that control motivation and mood is the lateral habenula (LHb) whose hyperactivity is associated with depression 2 . Here we used a repetitive closed head injury mTBI model that is associated with social deficits in adult male mice 3 and explored the possible long-term alterations in LHb activity and motivated behavior 10-14 days post-injury.…”

Involvement of Lateral Habenula Dysfunction in Repetitive Mild Traumatic Brain Injury–Induced Motivational Deficits

“…We observed that tonic firing LHb neurons were more prevalent following mTBI, which is consistent with the literature that LHb hyperactivity in general contributes to the development of depression-like motivational and social deficits, and anhedonic phenotypes. 6 , 19 , 23 , 29 , 51-53 Intriguingly, mTBI was associated with fewer LHb bursting neurons. This is in contrast with the most common finding of pre-clinical models of depression, where NMDA receptor–dependent LHb bursting are also elevated 18 , 23 , 29 , 30 and is shown to be the critical target for anti-depressant effects of ketamine.…”

“… 3 Compelling evidence from animal and human studies suggest that long-term negative effects on social functioning and mood states are related to dysfunction of brain reward and motivational circuits including the lateral habenula (LHb). 6-8 …”