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

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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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Ketamine blocks bursting in the lateral habenula to rapidly relieve depression

Yan Yang, Yihui Cui, Kangning Sang … (2018)

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 mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the 'anti-reward center', the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.

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Drug-evoked synaptic plasticity in addiction: from molecular changes to circuit remodeling.

Christian Lüscher, Robert Malenka (2011)

Addictive drugs have in common that they target the mesocorticolimbic dopamine (DA) system. This system originates in the ventral tegmental area (VTA) and projects mainly to the nucleus accumbens (NAc) and prefrontal cortex (PFC). Here, we review the effects that such drugs leave on glutamatergic and GABAergic synaptic transmission in these three brain areas. We refer to these changes as drug-evoked synaptic plasticity, which outlasts the presence of the drug in the brain and contributes to the reorganization of neural circuits. While in most cases these early changes are not sufficient to induce the disease, with repetitive drug exposure, they may add up and contribute to addictive behavior. Copyright © 2011 Elsevier Inc. All rights reserved.

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Addiction and the brain antireward system.

George F Koob, Michel Le Moal (2008)

A neurobiological model of the brain emotional systems has been proposed to explain the persistent changes in motivation that are associated with vulnerability to relapse in addiction, and this model may generalize to other psychopathology associated with dysregulated motivational systems. In this framework, addiction is conceptualized as a cycle of decreased function of brain reward systems and recruitment of antireward systems that progressively worsen, resulting in the compulsive use of drugs. Counteradaptive processes, such as opponent process, that are part of the normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to repeatedly drive the allostatic state. Excessive drug taking thus results in not only the short-term amelioration of the reward deficit but also suppression of the antireward system. However, in the long term, there is worsening of the underlying neurochemical dysregulations that ultimately form an allostatic state (decreased dopamine and opioid peptide function, increased corticotropin-releasing factor activity). This allostatic state is hypothesized to be reflected in a chronic deviation of reward set point that is fueled not only by dysregulation of reward circuits per se but also by recruitment of brain and hormonal stress responses. Vulnerability to addiction may involve genetic comorbidity and developmental factors at the molecular, cellular, or neurocircuitry levels that sensitize the brain antireward systems.