Synaptic inhibition in the lateral habenula shapes reward anticipation.

The lateral habenula (LHb) supports learning processes enabling the prediction of upcoming rewards. While reward-related stimuli decrease the activity of LHb neurons, whether this anchors on synaptic inhibition to guide reward-driven behaviors remains poorly understood. Here, we combine in vivo two-photon calcium imaging with Pavlovian conditioning in mice and report that anticipatory licking emerges along with decreases in cue-evoked calcium signals in individual LHb neurons. In vivo multiunit recordings and pharmacology reveal that the cue-evoked reduction in LHb neuronal firing relies on GABAA-receptor activation. In parallel, we observe a postsynaptic potentiation of GABAA-receptor-mediated inhibition, but not excitation, onto LHb neurons together with the establishment of anticipatory licking. Finally, strengthening or weakening postsynaptic inhibition with optogenetics and GABAA-receptor manipulations enhances or reduces anticipatory licking, respectively. Hence, synaptic inhibition in the LHb shapes reward anticipation.

Neuronal adaptations in the lateral habenula during drug withdrawal: Preclinical evidence for addiction therapy.

The epithalamic lateral habenula (LHb) regulates monoaminergic systems and contributes to the expression of both appetitive and aversive behaviours. Over the past years, the LHb has emerged as a vulnerable brain structure in mental illnesses including addiction. Behavioural and functional evidence in humans and rodents provide substantial support for a role of LHb in the negative affective symptoms emerging during withdrawal from addictive substances. Multiple forms of cellular and synaptic adaptations that take hold during drug withdrawal within the LHb are causally linked with the emergence of negative affective symptoms. These results indicate that targeting drug withdrawal-driven adaptations in the LHb may represent a potential strategy to normalize drug-related behavioural adaptations. In the current review we describe the mechanisms leading to functional alterations in the LHb, as well as the existing interventions used to counteract addictive behaviours. Finally, closing this loop we discuss and propose new avenues to potentially target the LHb in humans in light of the mechanistic understanding stemming from pre-clinical studies. Altogether, we provide an overview on how to leverage cellular-level understanding to envision clinically-relevant approaches for the treatment of specific aspects in drug addiction.

Output-Specific Adaptation of Habenula-Midbrain Excitatory Synapses During Cocaine Withdrawal.

Projections from the lateral habenula (LHb) control ventral tegmental area (VTA) neuronal populations' activity and both nuclei shape the pathological behaviors emerging during cocaine withdrawal. However, it is unknown whether cocaine withdrawal modulates LHb neurotransmission onto subsets of VTA neurons that are part of distinct neuronal circuits. Here we show that, in mice, cocaine withdrawal, drives discrete and opposing synaptic adaptations at LHb inputs onto VTA neurons defined by their output synaptic connectivity. LHb axons innervate the medial aspect of VTA, release glutamate and synapse on to dopamine and non-dopamine neuronal populations. VTA neurons receiving LHb inputs project their axons to medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and lateral hypothalamus (LH). While cocaine withdrawal increases glutamate release from LHb onto VTA-mPFC projectors, it reduces presynaptic release onto VTA-NAc projectors, leaving LHb synapses onto VTA-to-LH unaffected. Altogether, cocaine withdrawal promotes distinct adaptations at identified LHb-to-VTA circuits, which provide a framework for understanding the circuit basis of the negative states emerging during abstinence of drug intake.

Morphine withdrawal recruits lateral habenula cytokine signaling to reduce synaptic excitation and sociability.

The lateral habenula encodes aversive stimuli contributing to negative emotional states during drug withdrawal. Here we report that morphine withdrawal in mice leads to microglia adaptations and diminishes glutamatergic transmission onto raphe-projecting lateral habenula neurons. Chemogenetic inhibition of this circuit promotes morphine withdrawal-like social deficits. Morphine withdrawal-driven synaptic plasticity and reduced sociability require tumor necrosis factor-α (TNF-α) release and neuronal TNF receptor 1 activation. Hence, habenular cytokines control synaptic and behavioral adaptations during drug withdrawal.