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Circuits and functions of the lateral habenula in health and in disease

Abstract

The past decade has witnessed exponentially growing interest in the lateral habenula (LHb) owing to new discoveries relating to its critical role in regulating negatively motivated behaviour and its implication in major depression. The LHb, sometimes referred to as the brain’s ‘antireward centre’, receives inputs from diverse limbic forebrain and basal ganglia structures, and targets essentially all midbrain neuromodulatory systems, including the noradrenergic, serotonergic and dopaminergic systems. Its unique anatomical position enables the LHb to act as a hub that integrates value-based, sensory and experience-dependent information to regulate various motivational, cognitive and motor processes. Dysfunction of the LHb may contribute to the pathophysiology of several psychiatric disorders, especially major depression. Recently, exciting progress has been made in identifying the molecular and cellular mechanisms in the LHb that underlie negative emotional state in animal models of drug withdrawal and major depression. A future challenge is to translate these advances into effective clinical treatments.

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Fig. 1: Evolutionary conservation of lateral habenular pathways and anatomical organization of the habenula in vertebrates.
Fig. 2: Anatomical divisions and cellular and electrophysiological properties of the LHb.
Fig. 3: Summary of the afferent and efferent circuitry of the LHb.
Fig. 4: The LHb is the only brain region showing consistent hyperactivity in multiple animal models of depression.
Fig. 5: Mechanisms of hyperactivity in the LHb in models of depression.

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Acknowledgements

The authors’ research work is supported by grants from the National Natural Science Foundation of China to H.H. (31830032, 81527901), to Y.C. (31922031) and to Y.Y. (81600954), the non-profit Central Research Institute Fund of the Chinese Academy of Medical Sciences (2017PT31038, 2018PT31041), the National Key R&D Program of China (2016YFA0501000), the Science and Technology Program of Guangdong Province (2018B030334001, 2018B030331001), the 111 Project (B13026) and the Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foundation to H.H. The authors thank the reviewers, whose comments greatly improved this Review.

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Correspondence to Hailan Hu.

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Supplementary information

Glossary

Reward

Psychologically, ‘reward’ refers to a positive emotional stimulus, which is reinforcing and promotes repeated responding to obtain the same stimulus.

Reward prediction error

(RPE). The difference between the actual outcome of a situation or action and the expected outcome. A positive RPE indicates the outcome was better than expected, whereas a negative RPE indicates it was worse than expected.

Optogenetic

Optogentics involves the use of genetically encoded light-activated proteins (for example, light-sensitive ion channels and pumps) to control the functional parameters (for example, membrane potential and firing rate) of targeted neuronal populations.

Deep brain stimulation

A method that involves chronically implanted electrodes for stimulation of specific subcortical brain areas to treat symptoms of neurological and psychiatric diseases.

Ketamine

An inhibitor of NMDA-type glutamate receptors; it was initially discovered as an anaesthetic drug and was later found to be a rapid-acting antidepressant treatment.

NMDA-type glutamate receptors

(NMDARs). NMDARs are one of the three types of ionotropic glutamate receptors. Calcium flux through the NMDAR is critical in synaptic plasticity, as well as burst firing in several brain regions.

Real-time place aversion

Behavioural tests in which an animal avoids a compartment that was paired with an aversive stimulus (is often mimicked by optogenetic stimulation) in a real-time manner.

Real-time place preference

Behavioural tests in which an animal approaches a compartment that was paired with a rewarding stimulus (is often mimicked by optogenetic stimulation) in a real-time manner.

Resilience

Psychologically, ‘resilience’ refers to the ability to maintain the original normal physiological and behavioural function in the face of severe stress.

Valences

Psychologically, ‘valence’ refers to the emotional value associated with a stimulus.

Anhedonia

A depression-like phenotype that refers to loss of the ability to experience pleasure from normally rewarding stimuli. In mice and rats, the anhedonia aspect of depression is classically modelled by the sucrose preference test.

Burst firing

Burst firing, or bursting, is an activity pattern of neurons involving clusters of rapid action potential spiking.

Despair

A depression-like phenotype that reflects the feeling that nothing will improve. In mice and rats, the despair aspect of depression is classically modelled by several behavioural paradigms, including the forced-swim test, the tail suspension test and the learned helplessness test.

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Hu, H., Cui, Y. & Yang, Y. Circuits and functions of the lateral habenula in health and in disease. Nat Rev Neurosci 21, 277–295 (2020). https://doi.org/10.1038/s41583-020-0292-4

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